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Ageing Neur Dis 2022;2:17. 10.20517/and.2022.19 © The Author(s) 2022.

Rat models of major neurodegenerative disorders

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Department of Human Genetics, Ruhr University Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.

#These authors have contributed equally.

Correspondence to: Prof. Huu Phuc Nguyen, Department of Human Genetics, Ruhr University Bochum, Universitaetsstrasse 150, Bochum 44801, Germany. E-mail:

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.


No single animal model can recapitulate all the features of a particular human disease on its own. Historically, rats have been used to study neurobiology and underlying functional networks. Likewise, rat models have been created to study neurodegenerative mechanisms and therapeutic interventions. In the last decades, a shift towards the use of mice has been observed in many research fields, not least because of the comparatively easier genetic manipulation of mice. However, with the full sequence of the rat genome being available, advances in genetic manipulation of the rat, and advanced test regimens and biomarkers at hand, the rat presents itself once more as a valuable model organism for studying neurodegenerative disorders. This review provides an overview of currently available, well-characterized rat models of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, as well as their advantages for studying neurodegenerative disorders and evaluating therapeutic interventions.


Genetic rat models, phenotypic rat models, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease


Rattus norvegicus, the laboratory rat, was the first mammal to be domesticated and kept in captivity for research purposes[1,2]. Over time many inbred rat strains have been obtained to study various physiological aspects, disease mechanisms, and pharmacological questions. Both mice and rat models have been relied on in basic and preclinical research. Their short generation times, relatively easy to establish housing conditions, and genetic similarities to humans have made them the largest group amongst animal models in research (EU commission, 2019 report). In general, rats are considered an ideal species for behavioral studies, and have been used far more than mice in behavioral research in the past, although the increasing use of transgenic mice in behavioral testing in recent years has inverted this trend[3]. Rats are easy to handle by experimenters and less aggressive towards conspecifics (i.e., members of the same species) than mice[4]. Rat behavior has been well characterized, and several behavioral tasks currently used in rodents may better fit the rat[5,6], as they were originally developed in rats[7,8]. In cognitive tests which are used to model cognitive deficits of human disorders, especially for tasks requiring swimming, such as the Morris water maze, rats display less floating and thigmotaxis[9] and perform better than mice[10,11], probably because they are adapted to the water environment and are natural swimmers. In a decision-making task, rats were shown to learn the task faster than mice[12]. Furthermore, compared to mice, rats display a more complex behavioral repertoire which is likely to result from the species’ evolutionary history[13]. Increasing evidence in the last 15 years suggests that, similar to primates, rats present metacognition, that is, the awareness of one’s own cognitive processes[14-16]. In the context of neurodegenerative disorders (NDs), this is relevant given that metacognitive impairment is a feature of Alzheimer’s disease (AD) and other dementias[17].

Consequently, using rats to model cognitive symptoms could increase the robustness of cognitive assessments and enhance the accuracy of phenotypes. However, it is important to bear in mind that different rodent species differ in their behavioral traits[18,19] that could best mimic specific aspects of a human disorder, emphasizing the importance of using multiple model species, especially given the heterogeneity of deficits in several neurodegenerative disorders.

The rat’s body size further offers advantages over mice and other small animal models, as surgical procedures can be performed more reliably and consistently. Repeated blood and cerebrospinal fluid (CSF) sampling of larger volumes is possible in rats, and neuroimaging and electrophysiological measurements are preferentially performed in rats. The rat remains the classical animal model in toxicological studies, as the eradication of toxins is more closely related between human and rat, than between human and mouse[20]. However, a close examination of the individual biological processes affected is necessary, as many differences exist between species[21]. Both mouse and rat genomes were published in the early 2000s[22,23] opening the way for genetic studies investigating rat genes that share similar traits in rats and humans[20]. With the advancement of genetic tools, mice have been favored over rats due to technical challenges in creating rat models carrying genetic mutations. By improving methods for harnessing rat embryonic stem cells and advances in genetic tools, like zinc finger nuclease and CRISPR/Cas systems, rat models have been created more successfully in the last two decades. However, with a certain time delay in comparison to respective mouse models[24].

For NDs, like AD, Parkinson’s disease (PD), and Huntington’s disease (HD), no natural mutation in the rat exists that would provide a rat strain to model the human disease. Therefore, rat lines have been created that mostly carry and overexpress the human disease gene, in order to elicit phenotypes that resemble pathology and behavioral alterations, reminiscent of what is observed in patients. However, the most prevalent NDs, AD and PD, are not monogenetic disorders, with a low proportion of familial cases and, therefore, inherently difficult to model.

AD is the most common neurodegenerative disorder. Patients suffer from progressive cognitive decline, affecting, for example, memory and orientation and with disease progression limiting activities of daily life. The decline in cognitive abilities and behavioral alterations are caused by preceding, exaggerated amyloid beta (Aβ) peptide plaque formation and tau tangles. Progressive neuronal loss in the hippocampus and other brain regions further leads to reduced levels of neurotransmitters[25].

PD, like AD, is a highly prevalent neurodegenerative disorder that has a multifactorial etiology and is most often of idiopathic origin. Genetic and environmental factors contribute to the disorder that is primarily characterized by the lack of the neurotransmitter dopamine, leading to bradykinesia and other motor deficits in patients. Several PD-causing and PD-risk genes have been identified. Mutations in α-Synuclein (SNCA), Parkin (PARK2), PTEN-induced kinase 1 (PINK1), Protein deglycase DJ-1 (DJ-1), and Leucine-rich repeat kinase 2 (LRRK2) amongst others can cause the familial form of the disorder. On the cellular level, PD is characterized by mitochondrial dysfunction, altered protein degradation pathways, and increased neuroinflammation leading to synaptic dysfunction and neuronal loss in the substantia nigra pars compacta[26].

HD is a monogenetic ND caused by a CAG repeat expansion in exon 1 of the huntingtin gene (HTT), which translates to a poly-glutamine tract in the huntingtin protein (HTT)[27,28]. HD commonly manifests in adulthood, with CAG expansions in a range of 36 to 60 CAG repeats[29]. More than 60 CAG repeats are associated with juvenile HD, leading to symptom onset before the age of 20 years[30]. The neuropathological hallmarks of HD are extensive cell loss in the striatum and HTT aggregates localized in the neuropil, perikarya, and nucleus[31-33]. The clinical manifestations include motor deficits, cognitive impairment, and psychiatric disturbances[34].

This review provides an overview of rat models that have been generated to study the above-mentioned NDs, AD, PD, and HD. Neuropathological characteristics and behavioral phenotypes of well-characterized genetic models are summarized and stand in contrast to phenotypic/aspect-replicating rat models that are historically and currently more commonly used in biomedical research. We aim to highlight the advantages both types of rat models offer in terms of readouts and study design opportunities to improve translatability to human treatment.


Neuropathological phenotypes

Neurodegenerative diseases represent a large group of neurological disorders with progressive loss of particular subsets of neurons. The most common NDs are Alzheimer’s disease (AD) and Parkinson’s disease (PD); and as a monogenic disease, Huntington’s disease (HD), is well-studied. In addition to the progressive and selective neuronal cell loss, the second central characteristic of NDs is the presence of protein aggregates composed of misfolded proteins, specifically, the N-terminal fragment of mutant huntingtin in HD, Aβ peptide and hyperphosphorylated tau in AD, and α-synuclein (α-syn) in PD. The role of protein aggregates in NDs, whether neurotoxic or neuroprotective, is still a matter of debate since the distribution of protein aggregates does not reliably match the patterns of neuronal loss in different diseases[35]. Nevertheless, due to its commonality among NDs and its dependency on a specific molecular cascade (i.e., misfolding, oligomerization, and fibrillization), protein aggregate formation remains an important aspect of ND research. Thus, animal models that recapitulate the disease’s characteristic protein aggregation pathologies can make great contributions to understanding the disease mechanisms and aid in the development of therapeutic strategies. For genetically modified animal models of NDs, the presence, as well as the regional and subcellular location of protein aggregates, depends on the genetic construct’s promoter, protein expression levels, and genetic background of the animal. Mouse models have closely recapitulated the features of human NDs and provided essential insight into neuropathology. However, no single animal model can mimic all aspects of human diseases, not even all mouse models, collectively. Rats and mice are closely related species, but still have genetic and physiological differences, such as the distinct expression pattern and localization of certain protein isoforms. These diversities lead to some variance between both species in resembling human pathological processes, making rat models a meaningful complement to mouse models. This section discusses the commonly used genetic rat models for AD, PD, and HD [Table 1], and describes to what extent they recapitulate the characteristic protein aggregate pathology.

Table 1

Genetic rat models of Alzheimer’s, Parkinson’s, and Huntington’s disease

Early onset AD
(McGill-R-Thy1-APP rats, TgF344-AD)
Later onset AD
(APOE epsilon 4 knock-in)
Autosomal recessive
Autosomal dominant
(α-synuclein BAC, LRRK2 KO)
Juvenile-onset HD
Adult-onset HD
Molecular and biological basis Mutation in APP, PSEN1, hyperphosphorylation of tau rRsk factors, e.g., APOE variants Mainly loss-of-function, e.g., PARKIN, PINK1 and DJ-1 Mainly gain-of function, e.g., SNCA, LRRK2 CAG expansion > 60 CAG expansion < 60
Strategy ● Expression/knock-in of a combination of multiple mutations in APP
● Expression of mutations in APP + PSEN
● Expression of mutations in MAPT
● Humanization of loci of AD relevant mutations ● Knock out of PARKIN, PINK1 or DJ-1 ● Overexpression of wild-type or mutant SNCA ● Overexpression of wild-type or mutant LRRK2
● KO
● Overexpression of full-length mutant HTT ● Overexpression of the N-terminal fragment of mutant HTT
Pros ● Early and progressive recapitulation of neuropathological features
● Tangle-like pathology
● Spatial cognition deficits
● Physiological levels of protein expression ● Mitochondrial pathology can be studied
● Cranial sensorimotor deficits can be studied (DJ-1 KO and PINK1 KO)
● LB pathology can be studied ● Effect of impaired dopamine homeostasis can be studied ● Early and progressive recapitulation of the HTT aggregation phenotype
● Displays HD-like behavioral phenotypes
● Represents the major form of HD
● Displays HD-like behavioral phenotypes
Cons ● Non-physiological condition
● Represents a small portion of disease form (early onset AD accounts for < 5% of AD cases)
● Need to verify and characterize identified novel risk factors ● Most of them do not mimic the LB pathology of PD patients?
● No motor behavior impairment in PARKIN KO
● No dopaminergic neurodegeneration ● Represent only juvenile HD
● Long CAG repeats may change the HTT protein properties
● Mild and slow recapitulation of disease pathology
Literature Reviewed in[36-39] Reviewed in[40-42] Reviewed in[43-47] Reviewed in[48]

Neuropathological phenotypes in genetic rat models of Alzheimer’s disease: APPNL-G-F knock-in, TgF344-AD and McGill-R-Thy1-APP transgenic rats

Amyloid plaques containing Aβ peptide and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated microtubule-associated protein (tau) make up the typical protein aggregate forms in AD. While some studies suggested that tangles may precede plaques, it is commonly accepted that the amyloid plaques are formed first and trigger tau agglomeration (see review[49]). Nevertheless, both amyloid plaque and tau tangles are characteristic features of AD. The development of amyloid plaques appears to be dependent on the initial accumulation of Aβ, which is derived from amyloid beta precursor protein (APP) through sequential proteolytic cleavage by β and γ-secretase. Mutations in APP close to the main APP cleavage site and in the catalytic subunit of γ-secretase presenilin (PSEN) are major genetic causes of familial AD[50,51]. Ultimately, overexpression of APP with a combination of multiple mutations has been used to generate APP transgenic models[52-54], while double transgenic models expressing mutant APP and mutant PSEN represent APP/PSEN models (see review[36]).

Many transgenic APP mouse models recapitulate amyloid plaque formation and disease manifestation of AD and have thereby made essential contributions to understanding Aβ pathology in familial AD. In comparison, APP rat models often develop less accumulation of Aβ peptide and amyloid plaques. This cannot be simply explained by lower expression levels of transgenes in rats, or different transgene protein isoforms, or the applied promoters. One rat model, however, displays full amyloid pathology. Leon et al. developed an APP transgenic rat model expressing hAPP751 under the control of the murine Thy1.2 promoter and containing the Swedish and Indiana mutations of APP (McGill-R-Thy1-APP rats)[55]. This rat model carries one copy of the transgene hemizygously and accordingly presents approximately double the amount of APP protein (i.e., both endogenous and transgenic) as wild-type rats. Homozygous rats show an early-onset and progressive accumulation of Aβ peptide starting at 1 week of age and develop extracellular Aβ deposition at 6 months of age. Particularly, at 20 months of age, McGill-R-Thy1-APP transgenic rats display dense-core plaques in most brain areas with predominant presence in the entorhinal and parietal cortices, and hippocampus, the typical brain structures that are vulnerable to AD[56-58]. In summary, despite the lower expression level of the transgene, McGill-R-Thy1-APP transgenic rats develop early-onset, progressive, characteristic amyloid plaque pathology making this model valuable for studying Aβ pathogenesis in a close to physiological condition.

In fact, the distribution and burden of amyloid plaques in AD patients do not correlate with neuronal loss, disease severity, or disease duration. In contrast, NFT formation strongly correlates with neuronal death and follows a typical progression from the frontal cortex and the CA1 area of hippocampus to the anterodorsal thalamus, and in later stages (IV), the CA4 region of hippocampus[59,60]. Instead, NFTs have only been found in AD mouse models carrying human mutant tau, mostly with P301L mutation[36]. P301L missense mutation in tau is the genetic cause of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17); this mutation causes tau hyperphosphorylation and its subsequent aggregation into NFTs[61,62]. Different from FTDP-17, tau is not the only hyperphosphorylated neuronal protein in AD, and hyperphosphorylated tau is the result of a protein phosphorylation/dephosphorylation unbalance (see review[63]). This raises the debate of whether the P301L resulting tau aggregation can represent tau pathology in AD. Tau is a microtubule-associated protein stabilizing microtubules in the polymerized state[64,65]. Alternative splicing of tau in humans generates six isoforms containing microtubule-binding domain, including three (3R) or four (4R) microtubule-binding repeats[66]. It has been shown that rats express all six tau isoforms as humans, while mice only possess 3R tau isoforms[67].

The TgF344-AD rat is an AD transgenic model that carries transgenic constructs, expressing both the Swedish human mutant APP and the PSEN1(PS1ΔE9). These rats exhibit 2.6-fold human APP and 6.2-fold human presenilin-1 expression, respectively, compared to the endogenous rat homologs. Around 16 months of age, TgF344-AD rats develop amyloid plaques, some of which are thioflavin S-positive dense-core plaques. Strikingly, abundant insoluble tau structures have also been demonstrated in the cortex and hippocampus of aged transgenic animals, whose morphology recapitulates human NFTs. Frank and progressive neurodegeneration combined with neuroinflammation and cell apoptosis have been found in the same brain areas[68]. Similarly, tangle-like tau aggregates were also observed in a wild-type rat injection model expressing mutant APP and PSIN1(PS1M146L) mediated by adeno-associated viruses[69].

Very recently, Pang and colleagues generated an APP KI rat model, AppNL-G-F rats, which carry three family App mutations G676R, F681Y, and R684H[70]. Both homo- and heterozygous rats manifested amyloid plaques rapidly at 1 and 4 months of age, respectively. Notably, the amyloid plaque manifestation in AppNL-G-F rats preceded faster in females compared to males[71]. Whether this sex difference in Aβ aggregation can be linked to the higher incidence rates of AD in women than in men requires further investigation. Interestingly, aggregated tau was found in 12-month-old homozygous AppNL-G-F rats and further manifested into NFTs at 22 months of age. Increased gliosis, apoptotic cell death and brain atrophy have been observed in AppNL-G-F rats at 12 months of age and older.

Taken together, several APP rat models have shown common AD neuropathological features in AD-affected brain areas, in particular NFT formation, a key pathogenic event in the disease process, which have not been recapitulated in APP mouse models. The lack of the 4R isoforms in mice may be the cause for the two rodents’ differing abilities to model human tau pathology.

Neuropathological phenotypes in genetic rat models of Parkinson’s disease: PINK1 KO, DJ-1 KO, and a-synuclein BAC rats

The characteristic neuropathological features of PD are intracellular α-synuclein positive inclusions known as Lewy bodies (LBs), and selective neuronal loss in the substantia nigra, which is strongly related to mitochondrial dysfunction (see review[72]). About 20 genes have been identified to cause familial PD, inherited in an autosomal dominant or recessive mode. In the following, we will focus on three PD genetic rat models, which made significant contributions to the PD field as compensations for mouse models: the α-synuclein transgenic rats, PINK1 KO rats, and DJ-1-KO rats.

α-synuclein BAC transgenic rat model
The major component of LBs is α-synuclein, which is encoded by the SNCA gene. This was the first gene revealed to have a causal link to PD development. To this date, six autosomal dominant SNCA point mutations (A53T, A30P, E46K, G51D, H50Q, and A53E) have been identified[73]. Moreover, duplication, triplication and quadruplication of the SNCA locus have been reported to be causal in genetically unrelated PD families[74-77]. A number of transgenic mice models bearing human mutant or wild-type SNCA have been generated. Many of these models exhibit proteinase K resistant, detergent-insoluble, and thioflavin S positive α-synuclein aggregates (see review[78]). Mouse models also show a neuronal loss in PD-relevant brain areas, that is, substantia nigra, neocortex, and hippocampus[79-83]. An α-synuclein BAC transgenic rat model using a bacterial artificial chromosome (BAC) construct consisting of full-length human wild-type SNCA locus with the upstream regulatory promoter sequences has been generated by the Riess lab[84]. These BAC transgenic rats showed key pathological features of PD, including progressive misfolding and accumulation of α-synuclein aggregates, striatal dopamine depletion, decreased TH-positive cell numbers, and characteristic dark dopamine neurons in the substantia nigra. These pathological features have been modeled comparably in α-synuclein transgenic mice. However, with larger body sizes, rats offer unique possibilities for surgical manipulations of the brain, serial sampling of cerebrospinal fluid and blood, and brain imaging.

Rat models for autosomal recessive mutations
Autosomal recessive forms of PD commonly present an early onset phenotype[85,86]. All three known autosomal recessive PD genes, PARKIN, PINK1, and DJ-1, are closely associated with mitochondrial dysfunction[87-89]. The PTEN-induced kinase 1 (PINK1) and Parkin are involved in the same pathway leading to the degradation of damaged mitochondria. PINK1 acts as a sensor for depolarization of mitochondrial membrane potential[85,90-93], recruiting the E3 ubiquitin ligase Parkin which ubiquitinates substrates on the outer mitochondrial membrane, thus eliciting a vicious cycle resulting in mitophagy[94]. Protein deglycase DJ-1 is a stress-dependent chaperone localized in mitochondria, which plays an essential role in ATP production and complex I activity[95,96]. Interestingly, it has been observed that Lewy bodies can be absent in PD patients with either PARKIN, PINK1, or DJ-1 mutation (see review[97]). In comparison, mitochondrial pathology and neuronal loss in animal models of autosomal recessive PD are expected as important pathological phenotypes. PINK1 knockout (KO) rats show decreased complex I level and increased proton leak in the electron transport chain, indicating a mitochondrial respiration defect, as well as a reduced number of TH-positive neurons and proteinase K resistant α-synuclein aggregates[47,98]. By contrast, no evidence reflecting neurodegeneration was found in PINK1 KO mice[99], not even in the triple knockout mice with deficiency of Parkin/PINK1/DJ-1, all known gene deficiencies related to autosomal recessive PD forms[100]. Similarly, DJ-1 KO rats show significantly progressive neuronal loss with approximately 50% dopaminergic cell loss at 8 months of age in the substantia nigra, combined with altered mitochondrial respiration[101,102]. In contrast to rat models, no dopaminergic neuron loss-related event or mitochondrial dysfunction has been observed in all existing DJ-1 KO mouse models, while one DJ-1 KO mouse model only shows increased sensitivity to the neurotoxin MPTP[103-105]. Notably, PARKIN KO mice and rats also have been generated, while PARKIN KO mice exhibited increased striatal extracellular DA concentration, which is opposite as expected[106], PARKIN KO rats did not show any neuropathological differences compared to wild-type controls[101]. Whether these results can be explained by the genetic and biological differences between human and rodent remains unaddressed. Nevertheless, both PINK1 and DJ-1 monogenic KO rat models are valuable for investigating mitochondrial pathology in autosomal recessive PD, whereas the comparable mouse models lack disease-related neuropathological phenotypes.

Neuropathological phenotypes in genetic rat models of Huntington’s disease: tgHD and BACHD rats

To date, two genetic rat models have been generated and well characterized for HD research. One carries the whole genomic sequence and regulatory elements of human HTT with 97 mixed CAG-CAA repeats in a bacterial artificial chromosome construct (BACHD rats), thereby bearing the mutation in its appropriate genomic context as in HD patients[107]. The interruption in CAG repeats avoids somatic instability of polyQ size and variation in repeat length within the animal colony. The other rat model carries N-terminal rat Htt cDNA fragments under the rat Htt promoter, with 51 CAG repeats (tgHD rats)[108]. In humans, the CAG length present in the tgHD construct would lead to an adult-onset of disease, whereas 97 CAGs, as in the BACHD rats, would result in the juvenile form of the disorder. Both BACHD and tgHD rat models have a wide expression pattern of transgene HTT/Htt throughout the brain that, to some extent, resembles the human condition. BACHD rats have a 4.5-fold higher expression level of transgenic HTT as the endogenous Htt, while tgHD rats show a strongly reduced transgene expression level compared to the endogene[107,108]. Both rat models show subtle evidence for neurodegeneration, including structural changes in white matter[109,110], reduced brain volume in BACHD rats[111], and age-dependent enlarged ventricles in tgHD rats.

Although neuronal loss in HD patients is most prominent in the striatum, mHTT aggregates have been more frequently detected in the cerebral cortex. Subcellular localization studies revealed a prevalent neuropil localization of mHTT aggregates, while smaller amounts of mHTT inclusion bodies were found in the nucleus[31-33]. One of these studies reported that in all 12 investigated HD brains, only 1%-4 % of striatal neurons had nuclear inclusion bodies, while a large number of mHTT aggregates were detected in the cortex with prominent subcellular localization in neuropil and perikarya. Although juvenile HD patients show an increased number of nuclear inclusion bodies compared to patients with adult-onset, neuropil aggregates were still predominantly distributed in the striatum and cortex[32]. Consistent with these observations, BACHD rats exhibit more prominent mHTT aggregates in the cerebral cortex compared to subcortical areas, with aggregates distributed through all cortical layers, primarily in neurites. tgHD rats display a similar aggregate distribution pattern. Notably, tgHD rats display abundant mHTT aggregates in the dorsomedial part of the striatum and BACHD rats have been found to show a similar aggregate load in the lateral striatum. Interestingly, both HD rat models show a prevalent distribution of HTT aggregates in the limbic structures, with notable aggregate loads in the ventral striatum (nucleus accumbens), striatal terminal bed nucleus, and central nucleus amygdala[107,112,113]. In the BACHD rats, aggregates were also found in the hippocampus and hypothalamus. It is difficult to judge to what extent this relates to human disease, as the distribution of aggregates outside the striatum and cortex has barely been studied in HD patients.

In contrast to the aggregate pathology seen in patients and rat models, most mouse models display nuclear inclusion bodies rather than neuropil aggregates. Moreover, they display more abundant aggregates in the striatum compared to the cerebral cortex, regardless of the genetic construct or modification they are based on[114]. It is therefore clear that BACHD and tgHD rats provide a meaningful complement to HD mouse models for modeling and understanding the mHTT neuropathogenic mechanisms. mHTT aggregation is affected by several intrinsic factors, including polyQ-flanking sequences of mHTT, mHTT interaction partners, protein fragmentation, and post-translational modifications (see review[115]). Different subcellular localization of aggregates may initiate different cellular quality-control processes, resulting in different pathogenic processes. Working with a combination of mouse and rat models of HD, could therefore help tease apart what exactly causes one type of pathology over the other.

Behavioral phenotypes

Behavioral phenotypes in genetic rat models of Alzheimer’s disease: APPNL-G-F knock-in, TgF344-AD, and McGill-R-Thy1-APP transgenic rats

Memory impairment is an early symptom in AD patients, followed by language and mathematical deficits, decreased visuospatial orientation, and attention deficits[116,117]. One of the most common symptoms in subjects affected by AD is an impairment of spatial navigation which is the ability to define and retain trajectories between places[118]. Although attributing cognitive functions to specific brain areas does not embrace the complexity of brain networks regulating cognition, hippocampus and medial entorhinal cortex represent essential areas for spatial navigation[119] and are already affected in the early phases of AD[120]. Similar brain areas in humans and rodents appear to be involved in the regulation of specific types of memory, for example, spatial memory[9,121,122], which is important for modeling cognitive deficits in animal models.

Most of the behavioral results in AD genetic models come from the characterization of mouse models. On the other hand, the use of genetic rat models is increasing, and these models may be advantageous from a behavioral perspective, given that cognitive testing is central to AD research. In McGill-R-Thy1-APP transgenic rats, spatial learning and memory deficits already manifest by 3 months of age, prior to amyloid plaque deposition and are present in both homozygous and hemizygous rats which can sometimes differ in the degree of impairment. Spatial cognition deficits include reference and working memory impairment as detected in maze tasks for spatial learning, and problems with object location memory[55,123-125]. TgF344-AD transgenic rats show spatial cognition deficits as early as 4 months of age[126,127]. Similar to the McGill-R-Thy1-APP rats, they were shown to have a deficient performance in several paradigms for spatial cognition including tasks for reference and working memory[68,126,128,129] as well as reversal learning[68,130,131]. Moreover, TgF344-AD rats display a decreased accuracy in spatial trajectories[132]. In line with the results in the transgenic models of AD, five months old APPNL-G-F knock-in rats were reported to display impaired spatial learning abilities[70]. Hence, defective spatial cognition is reproduced among different categories of AD genetic rat models.

A crucial factor in the process of translating behavioral readouts from animal models to humans is the similarity of the deficits measured in each species. Using similar assessments in animal models and patients is of great advantage, as this could ultimately increase the predictability of therapy effects. Accordingly, hippocampus-dependent navigation tasks, commonly used in rats, for example, the Morris water maze, were adapted for humans in the form of real and virtual versions, and revealed impairments in spatial memory and navigation abilities in AD subjects[133,134], consistent with results in transgenic rat models assessed in mazes for spatial learning[55,123,125,132]. Comparative water maze testing in healthy humans and wild-type rats showed a similar effect of scopolamine and donepezil normally used to model cognitive dysfunction and to treat cognitive deficits, respectively[135], indicating similar behavioral responses to pharmacological cholinergic modulation across species. The direct comparison of AD patients and genetic AD rat models would be more informative regarding the analogy between human and rat results in the context of AD.

Episodic memory, which allows to store and retrieve information about personal experiences along with the related spatial and temporal contexts, is dysfunctional in AD[136]. Recognition memory and associative learning, linked to episodic memory, are impaired as well[137-139]. McGill-R-Thy1-APP and TgF344-AD rats display deficits in some aspects of recognition memory and associative learning. In both rat models, deficits in novel object recognition have been reported, although results are overall mixed[123,124,140-143]. There are also signs of associative learning impairment in passive avoidance setups[142,144,145]. Additionally, fear conditioning analyses revealed that multiple memory recall components are impaired in homozygous and hemizygous McGill-R-Thy1-APP rats[124]. Moreover, testing on automated touch screen setups showed impaired associative learning in the McGill-R-Thy1-APP rat model and deficits in episodic-like memory in APPNL-G-F knock-in rats[70,146]. Touchscreen methods like those applied in McGill-R-Thy1-APP rats are meaningful as analogous to platforms applied to assess cognition in AD patients[147].

A large portion of AD patients suffers from subtle neuropsychiatric symptoms, and the most common are apathy, depression, anxiety, and sleep disturbances[148]. Neuropsychiatric disorders, especially depression, have been associated with phenomena such as decreased hippocampal volume, inflammation, and alterations of the monoaminergic systems[149-152]. Mood alterations in rodent models of AD and other neurodegenerative disorders are most commonly assessed in terms of anxiety and depression-like behavior. Both phenotypes have been more extensively characterized in the TgF344-AD rat model relative to the McGill-R-Thy1-APP model. In TgF344-AD transgenic rats, anxiety-like behavior was detected at different ages in the elevated plus maze[128,145,153,154]. In McGill-R-Thy1-APP rats by the age of 5 months, there is evidence for anxiety-like behavior in the light-dark box[125]. Results obtained in the open field in both rat models are contradictory[123,125,143-145,154]. Regarding depression-related parameters, anhedonia-like behavior as well as behavioral despair were shown in TgF344-AD rats aged 10 months or older[131,145,154]. One of these studies assessed both males and females but did not report sex differences[131]. Nevertheless, given the evidence for sex differences in the prevalence of depression and apathy in AD[155], it would be worth examining sex differences more thoroughly in transgenic rat models. Also, the time course of depression-like phenotypes and cognitive impairment in TgF344-AD rats cannot be easily defined from the behavioral analyses in the model. Moreover, given that in AD, depression can predate cognitive symptoms[156], the assessment of depression-like behaviors in animal models from very early ages would be advisable. Apathy, the most frequent behavioral disturbance in AD[149], has not been assessed in detail in the genetic rat models reviewed here. Signs of apathy-related behavior could be inferred from the presence of anhedonia-like behavior and the reduced motivation to engage in goal-directed behaviors in some experiments in TgF344-AD; for example, rats display a decreased number of attempts in a maze test[128]. Similarly, in mouse models of AD, parameters of object and social exploration, as well as locomotor activity, have been used as measures of apathy[157,158]. Alternative approaches, e.g., progressive ratio tasks[159], used in AD mice[160], may provide more compelling information on apathy-related motivational aspects.

Sleep disturbances are tightly linked to mood and behavioral disturbances. Sleep behavior characterization in 17-month-old TgF344-AD rats showed changes in sleep architecture, such as increased sleep fragmentation and alterations in sleep microstructure, consistent with the sleep alterations observed in the prodromal phase of AD[161]. Sleep analyses in McGill-R-Thy1-APP rats are lacking, although changes in circadian activity have been reported in this rat model by the age of 8-10 months[125]. In conclusion, both the McGill-R-Thy1-APP and TgF344-AD rat models reproduce the dysfunction in key memory aspects, typical of AD patients. Similar deficits are found in APPNL-G-F knock-in rats, although only limited information is available on their phenotype so far, as this is a recent model. Neuropsychiatric changes have been examined in more detail in the TgF344-AD rats which manifest anxiety- and depression-like behaviors as well as sleep disruption. Apathy, a key symptom of AD, remains instead largely unexplored in these models.

Behavioral phenotypes in genetic rat models of Parkinson’s disease: PINK1 KO, DJ-1 KO, and a-synuclein BAC rats

Typical motor symptoms in PD patients are bradykinesia, impaired fine motor skills, tremor, muscle rigidity, and deficits in gait, posture, and balance[162-164]. Homozygous PINK1 KO and DJ-1 KO rats display numerous abnormalities reminiscent of the human PD symptomatology. They have deficits in limb motor coordination and balance as well as rearing, gait and grip strength[46,101,165-168]. DJ-1 KO rats additionally show postural instability[167], whereas PINK1 KO rats display decreased locomotor activity[101,165]. Interestingly, female PINK1 KO rats do not exhibit limb motor deficits like the ones observed in males of comparable age[169], indicating possible sex differences in the sensorimotor phenotype or in the age when the phenotype becomes manifest. Similar to the other models, the main features of motor impairments in α-synuclein BAC rats are decreased activity and rearing, impaired balance, and gait deficits, although most motor abnormalities in these rats start later compared to PINK1 KO and DJ-1 KO rats[84,170,171]. Tremor, present in PD patients, was, to the best of our knowledge, not reported in the literature for any of these models. Fine paw skills for which specific assays are established in rodents[172,173] have been scarcely assessed, despite the impairments of fine motor skills and hand grasping in PD patients[162,164].

Olfactory dysfunction, dysphagia (i.e., difficulty swallowing), as well as hypokinetic dysarthria, a speech motor control disorder involving reduced voice loudness and altered articulation, are important components of PD symptomatology in a high percentage of patients[174,175]. These changes are not responsive to standard dopaminergic treatments[176], and knowledge of the underlying brain changes is rather limited.

Altered phonation in PD patients has been related to the rigidity of the phonatory posture of the larynx, and laryngeal muscle impairment has been associated with deficient motor control by the basal ganglia[174]. Moreover, an altered perception of speech volume in PD patients[177] has been suggested to result in poor control of speech production[174]. Studies in PD patients also showed deficits in the production and perception of speech-related emotions. The latter seems to be connected with cognitive impairment in the disease[177].

Vocalization in humans and ultrasonic vocalizations in rats share similar anatomical structures and neural pathways[178-182]. The periaqueductal gray, especially, plays an important role in the control of vocalization in mammals[183]. It receives motor and sensory inputs[183] as well as input from multiple limbic areas including cortex, amygdala, and hypothalamus[184-186] that could regulate social and motivational aspects of vocalization. The periaqueductal gray has also been linked to vocalization deficits in PD. This is consistent with several results in animal models: (i) in mice overexpressing α-synuclein, vocalization deficits are paralleled by α-synuclein aggregates in the periaqueductal gray[187]; and (ii) in PINK1 KO rats, gene expression analyses identified associations between the expression of specific gene modules in this brain region and female vocal behavior[188].

Both the PINK1 KO and DJ-1 KO rat models exhibit ultrasonic vocalization deficits[46,47]. DJ-1 KO rats display an altered call profile and produce ultrasonic vocalization with decreased intensity, as reported between 2 and 8 months of age[46]. Similarly, male and female PINK1 KO rats have a decreased ultrasonic vocalization average intensity at the same age[47,169], although opposite observations have been reported regarding ultrasonic vocalization intensity in male PINK1 KO rats at a later age[189]. The vocalization intensity deficits in PINK1 KO rats are stronger compared to PINK1 KO mice[190]. The decreased ultrasonic vocalization intensity in genetic rat models resembles the decreased vocal intensity or loudness in PD subjects, which occurs in the early disease stages. Given that the vocalizations recorded in male and female rats are experimentally induced by exposure to a female and male, respectively, it remains unclear whether a possibly altered interest in the conspecific of different sex may have contributed to this phenotype in PINK1 KO rats. This is important for two reasons: (i) decreased sexual interest and sexual dysfunction are reported in PD patients[191], and (ii) brain areas controlling vocalization in rats are also involved in sexual behavior[192,193]. Moreover, the connection of the periaqueductal gray, controlling rat vocalization, with limbic areas may involve emotional and cognitive aspects in control and in the impairment of vocalization, which would be interesting to assess in rat models of PD.

Characterization of vocalizations in PINK1 KO male rats indicated progressively decreased peak frequency[189] and altered bandwidth[47] of frequency-modulated calls, in addition to deficits in call intensity. Although translating these changes from rats to patients seems not as straightforward as the vocalization intensity, the examined variables may be relevant indicators of vocalization dysfunction in rat models. Besides altered vocalization, similar to PD patients, both PINK1 KO and DJ-1 KO rats present early oromotor abnormalities[46,47,194]. Already at early ages, DJ-1 KO rats have a decreased ability to regulate tongue force[46] and PINK1 KO rats display an altered tongue function and biting deficits[47]. Videofluoroscopy, normally used to detect swallowing deficits in PD patients[195], showed that PINK1 KO rats are dysphagic as assessed at the age of 4 months[194]. Hence, PINK1 KO and DJ-1 KO rats seem promising models regarding phenotypes of cranial sensorimotor dysfunction. However, the information on olfactory abilities in these rat models remains scarce. Sixteen-month-old DJ-1 rats were shown to have increased olfactory abilities, which is opposite to observations in patients[167]. On the contrary, analyses in the BAC α-synuclein rats detected smell discrimination impairment at 3 months, before the appearance of motor deficits[84], which would temporally mimic the manifestation of symptoms in human PD.

PD patients show non-motor symptoms, including psychiatric and cognitive symptoms, sleep disorders, and autonomic dysfunction[196-199]. Most PD patients experience disturbances such as apathy, anxiety, depression, and psychosis and several studies on PD have also reported disorders of impulsive control[197]. Even though some disturbances, for example, psychosis and impulsive control, may in part arise from or be enhanced by treatments, neuropsychiatric symptoms are already observed in the early phases of the disease[197,198,200]. Despite the obvious limitations in translating neuropsychiatric assessments between animal models and humans, genetic rodent models still offer the possibility to relate neuropsychiatric-like behaviors to relevant brain changes on multiple levels in treatment-free conditions, and to dissect their temporal dynamics. To date, neuropsychiatric-like phenotypes have not been characterized in depth in the genetic rat models described here, and the results obtained so far require further corroboration. Research on these PD genetic rat models hardly focused on apathy and impulsivity-related behaviors, although altered motivation has been indirectly suggested in α-synuclein BAC rats, based on a faster decline in activity and a decreased exploration of the central zone of an automated cage apparatus over time, along with suppressed feeding[170]. Regarding depression, DJ-1 KO rats show signs of behavioral despair by 6 months[167], and in PINK1 KO female rats, there is evidence for anhedonia by the age of 8 months, whilst PINK1 KO males were not assessed simultaneously[169]. In the α-synuclein BAC rats, both increased and decreased anxiety-like behaviors have been reported[84,201]. In the same rats, locomotor activity is enhanced in a novel environment by 3 months of age, and deficits in prepulse inhibition emerge as well at a more advanced age[201]. Both behavioral features have been associated with psychosis-like behavior in rodent models[202]. It is worth noting that the psychosis-like phenotype is stronger in α-synuclein BAC male rats relative to females, in agreement with evidence for sex differences in the PD symptomatology in patients[203]. This supports the assessment of sex differences in psychosis in the human population.

A significant percentage of PD patients suffer from a mild cognitive impairment which can convert into dementia with disease progression[196,199]. Cognitive deficits in early PD stages commonly impact several facets of executive functioning, visuospatial skills and memory and have been related to dysfunction in multiple neurotransmitter systems as well as common PD neuropathological alterations[199]. Analyses of some cognitive components have been performed in lesion rat models of PD, which present though some limitations in terms of cognitive phenotypes that can be reproduced[204,205]. On the contrary, cognition has rarely been investigated in PD genetic rat models. PINK1 KO rats display normal recognition and spatial memory when tested at 3 months[206]. DJ-1 KO rats were found to have altered short-term memory by 4.5 months, but unchanged goal-directed behavior[166,167]. Changes in short-term memory were also observed in DJ-1 KO mice, but at a later age compared to PINK1 KO rats[207]. Although it may not reflect the deficits in patients, the early rat phenotype is more consistent with the early appearance of cognitive deficits in human symptomatology, if the same temporal dynamics also apply to the familiar PD forms. In the α-synuclein BAC rats, knowledge of cognitive aspects is very limited.

In summary, all three PD rat models reflect, to a certain extent, the motor impairment in the disease. DJ-1 KO and PINK1 KO rats are ideal for reproducing cranial sensorimotor deficits and studying the underlying mechanisms. The α-synuclein BAC rats mimic the olfactory dysfunction and specific psychiatric features of the disease, but cognition remains scarcely examined in any of these models. Apathy, a frequent symptom in PD patients, has not been sufficiently investigated in genetic rat models of PD. Moreover, tremor, a main motor feature in the disease, does not appear to be reproduced in genetic rat models.

Behavioral phenotypes in genetic rat models of Huntington’s disease: tgHD and BACHD rats

HD patients present motor impairment, cognitive deficits and psychiatric manifestations[208]. The tgHD and BACHD genetic rat models mimic many of these HD behavioral features. Compared to mouse fragment models, especially R6/2 mice, the phenotype in tgHD rats develops later and progresses at a slower pace[108,209]. Motor impairment starts earlier and has faster progression in BACHD rats compared to tgHD rats, with the first BACHD rat motor abnormalities starting at the age of 1 month[107] and the motor deficits in tgHD rats beginning at about 6 months[210]. In the tgHD rat model, phenotypes appear stronger in homozygous compared to hemizygous animals[210] and male rats were reported to be more sensitive to motor coordination impairment relative to females[211], while in the BACHD rat model, homozygous females seem to develop a stronger motor, emotional, and cognitive phenotype than males[212], although information on sex differences and homozygous animals in this model is still limited.

In general, the tgHD and BACHD rat models exhibit reduced motor coordination and balance[107,108,210,211,213,214], altered locomotor activity and rearing[107,211,213,215,216], decreased muscle endurance[215,217] and gait abnormalities[107,213,218]. At late time points, tgHD rats are also affected by choreiform neck movements which are more frequent in homozygous individuals[219]. Prepulse inhibition of the startle response, a measure of sensorimotor gating, is decreased in HD patients[220]. In BACHD rats, there are mild sensorimotor gating deficits at the age of 9 months[213], whereas in tgHD rats, no sensorimotor deficits have been detected[216,221].

Emotional and behavioral symptoms in HD patients can precede motor symptoms by decades. A variety of psychiatric symptoms characterize the disease where apathy, depression, irritability, aggression, and anxiety are frequently reported[222]. Likewise, cognitive deficits in HD patients can be found several years before motor diagnosis[223] and are heterogeneous, embracing problems with executive function, visuomotor integration, psychomotor speed, and social cognition[224-227]. While the available tests in rodents can only partially assess the multidimensional nature of the neuropsychiatric disturbances in HD patients, emotional changes have been shown with different behavioral paradigms in HD rat genetic models. Both tgHD and BACHD rats show a low anxiety phenotype in different behavioral setups[107,108,210,211,214,228]. In tgHD rats, the emotional phenotype is already detectable at the age of 1 month, before motor deficits[210], whilst motor and emotional alterations in BACHD rats follow the opposite temporal pattern[107]. In BACHD rats, evidence for increased anxiety-like behavior was also found in specific paradigms[229], in line with human data. The contradictory anxiety phenotype remains mostly unexplained, although it could in part be dependent on age and on the different components of anxiety targeted by different typologies of behavioral tests which could in turn rely on distinct brain mechanisms. One study demonstrated that the disinhibition of the central nucleus of amygdala via GABAA receptor antagonist in BACHD rats increased avoidance and escape responses in an avoidance task as well as the social exploration in a social test[230], implicating an altered activity in the central nucleus of the amygdala as one of the mechanisms at the base of anxiety-related behavioral alterations. Further investigations of emotional phenotypes in tgHD rats revealed enhanced emotional learning in discriminative Pavlovian fear conditioning and hyperreactivity to aversive emotional events which were paralleled but not explained by shrinkage of the central nucleus of the amygdala[217].

Depression-like behavior reported in multiple studies in HD fragment and full-length mouse models[231-234] has not been studied in much detail in HD rat genetic models. An impaired hedonic reaction in response to sucrose in tgHD rats has been associated with anhedonia-like behavior[217] which was though not confirmed by later analyses[228]. BACHD rats show decreased sucrose preference at 3 months and this effect is maintained at later time points[235]. Along with hedonic deficits, BACHD rats present impaired reward-directed behavior by the age of 3 months[235], indicating a lack of motivation which could be representative of apathy, a core symptom of HD[223]. However, the BACHD rat shows notable obesity, and it is currently uncertain how that might interact with behavioral tests that are based on food rewards. Still, there do seem to be some indicators of the animals putting a lower hedonic value on small reward pellets[236,237].

A key cognitive impairment in HD is executive dysfunction. One of the main executive function deficits is impaired inhibitory control, which can be detected in specific behavioral tests in HD patients[238,239]. It was also shown in HD fragment and knock-in mouse models[240,241] and in transgenic rats[242-245]. Rat models, in general, may be advantageous over mouse models in the applied paradigms and have been largely used in preclinical research on impulsive control[246]. Impulsive-like behavior in tgHD rats was detected in both sexes at 15 months and with different strain backgrounds[243,245]. Deficits consistent with the inability to withhold inappropriate lever responses have been shown in BACHD rats already by the age of 3-4 months[242,244]. tgHD and BACHD rats further mimic several other facets of cognitive dysfunction in HD patients[223,247,248]. Deficits in both animal models were reported at different ages depending on the cognitive aspect considered. In both BACHD and tgHD rats, the first cognitive deficits were found early, at 3 and 4 months, respectively. In tgHD rats, cognitive deficits concern, among others, cognitive flexibility, attention, working memory, visuospatial and visual object memory, temporal perception and psychomotor performance[210,219,221,249-251]. BACHD rats show impaired reversal learning[111,214,252], deficits consistent with fronto-striatal dysfunction in different short-term memory tests[253], decreased performance in a decision-making task[254] and impaired associative memory[252].

Several aspects of social behavior and social cognition are abnormal in HD patients who face problems with emotion recognition and awareness as well as theory of mind and, to a certain extent, empathy, which have been associated with altered social skills and self-reported social distress[224,255-257]. Transgenic fragment and full-length HD mouse models display changes in various social behavior parameters[258-262]. Compared to mice, rats show lower group aggression[4] and are more interested in the interaction with male conspecifics[18]. Therefore, free social interaction experiments in males can be better performed in rats. Both male and female tgHD rats tend to interact more than wild-type rats with the same sex conspecific starting from 1 or 2 months of age, which was interpreted as a low anxiety-like phenotype[210,211]. An automated analysis of the BACHD rat behavior in a social interaction test between 2 and 8 months of age demonstrated alterations in multiple social interaction parameters[263]. Other analyses in the model further revealed changes in other areas of social cognition[229,263]. It is difficult to draw direct parallels between social behavior parameters measured in humans and rats as social behavior is highly species-specific. Nevertheless, given that brain correlates of social behavior are under several aspects comparable in humans and rodents[264], it is still reasonable to model main social behavior related functions in rats. Depending on age, in the BACHD rats, we find a more aggressive play behavior, decreased tendency to search for or interact with a conspecific and a decreased social preference[229,263], which in part indicates higher anxiety and may altogether be representative of a disrupted socio-cognitive function. It would then be important to relate social behavior alterations to changes in brain areas relevant to social behavior. In the BACHD rat model, in addition to the evidence for an involvement of the amygdala in the modulation of anxiety in a social context[230], a decreased BDNF gene expression was also reported in the ventral striatum[263]. While the striatum does not have a primary social function, it has been suggested to integrate social information into main striatal functions, like reward[265]. Future analyses could consider assessing the expression of markers relevant to social behavior, such as oxytocin and vasopressin[265,266], and focus on other brain areas affected in HD, like the hypothalamus, which shows changes in neuronal populations expressing these markers[267]. In HD patients, cerebrospinal fluid oxytocin levels were also found to be decreased and to correlate with social cognitive scores[268]. As part of social behavior, aggression is often reported in HD patients[255], but has not been assessed in transgenic rat models. While analyses of aggression could take advantage of well-established tests in rats, they may be sensitive to the model strain, which adds to the complexity of a phenotypic profile.

Altogether the BACHD and tgHD rat models reproduce many features of the HD triad of symptoms. Both models present motor and cognitive deficits, and some have been reproduced across studies. These rat models also display emotional alterations. The bidirectional anxiety phenotype in the BACHD rat model supports further assessments, especially in terms of underlying mechanisms. Furthermore, several phenotypes in the HD rat models and in the models of other neurodegenerative disorders have been assessed only once. Thus, their repeatability must still be determined. In addition, it remains largely unclear to what extent specific phenotypes in animal models and similar symptoms in humans share the same biological mechanisms, thereby representing the same kind of impairment.


There is still a vast gap between preclinical studies to effective treatments for patients[269-271]. To date, translatability from animal models to humans in terms of treatment efficacy, adverse effects, and tolerability has been found to often not correlate[272-274]. And likewise, a proportion of unknown size of therapeutics fails to enter the clinic, being not beneficial in animal models, though they might be effective in humans.

Despite the discouraging success rates in finding new therapies for NDs, rats have been essential for discerning many aspects of neurological functions. However, with the more readily genetic manipulation of mice and the discovery of many disease-causing genes for NDs, mice have outnumbered rats in studies evaluating behavioral aspects of neuroscientific questions in the last two decades[275]. Also, in studies describing therapeutic approaches in AD, PD, and HD, this trend towards using mice is reflected by the number of publications listed in PubMed [Figure 1].

Rat models of major neurodegenerative disorders

Figure 1. Studies referencing mice or rats in therapy approaches for Alzheimer’s, Parkinson’s and Huntington’s disease. Results of PubMed search with terms “mice”/“mouse” and “rat”/“rats” in combination with above mentioned neurodegenerative disorders and “therapy”. Review articles have been removed from the year in which they were published.

Preclinical studies require a model to present a phenotype that is robust, fast developing, replicating key aspects of the human disease, and compatible with the form of treatment investigated. Some aspects of human disease are, however, only ever hardly modeled in animals. As one important example, cell loss is often not found in genetic models of neurodegeneration or only towards the end of the lifespan. Additionally, genetic rat models often display milder phenotypes than mouse models when based on the same construct, and these phenotypes often take relatively long to develop[276]. Therefore, we briefly describe in this section models with induced cell loss - though fairly artificial - which have helped to model neuronal demise and to evaluate therapies that can halt or even reverse this process. Commonly used models, with such induced neurodegenerative phenotypes, are summarized in Table 2. Their fast-appearing nature and cost-effectiveness, in comparison to generating new genetic rat lines, make them a resource to be relied upon frequently.

Table 2

Commonly used phenotypic models of NDs

Physical/chemical lesion of cholinergic centers Aβ injection LPS 6-OHDA QA 3-NP
Aspect of disease reproduced Degeneration of cholinergic neurons Memory deficits behavioral alteration
Aβ accumulation
Local cell loss
Neuroinflammation cognitive deficits
Aβ and tau accumulation
Sickness behavior
Dopaminergic cell loss, lesions
Sensitivity to apomorphine
Striatal lesions
Behavioral alterations
Excitotoxicity-induced cell loss
Striatal neurodegeneration of MSN
Motor deterioration and behavior alterations
impairs mitochondrial energy production
Acute or progressive? Acute Single injection (acute)
Osmotic pump (progressive)
Acute, severity can be modulated by the amount of LPS challenges Acute, compensatory mechanisms possible Acute, chronic Progressive over multiple injections
Pros ● Different protocols available
● Easy to implement
● Systemic injections are possible with some chemicals
● Rapid appearance of Aβ accumulation ● Aspects of neuroinflammation can be studied
● Systemic injections
● Lesion intensity can be modulated
● Dopaminergic neurons are targeted
● Similar to the pattern of cell loss in HD patients ● Systemic injections
● Histological similarities to HD
Cons ● Many variables (age at lesioning, size/type of lesion, strain, etc.)
● Limited to the lesioned brain area
● No Aβ or tau pathology
● High concentration needed
● Aging as a pathological factor neglected
● Brain injury
● No AD/ PD-specific pathology
● Variability within animals
● Compensatory effects in unilateral lesions
● Many variables (age at lesioning, size/type of lesion, strain, etc.) ● High inter-animal variability in lesioning
● Many variables (age at lesioning, size/type of lesion, strain, etc.)
Literature Reviewed in[277] Reviewed in[277,278] Reviewed in[279] Reviewed in[280] Reviewed in[281-283] Reviewed in[284]

Phenotypic rat models of Alzheimer’s disease

AD poses a challenge for finding appropriate models, because sporadic cases caused by mutations in AD-risk genes outnumber familial cases[285]. While rats are genetically closer to humans in terms of tau isoforms, rats seem to be more resistant to developing characteristic neuropathological features of AD when expressing human genes. They present fewer plaques and tau tangles are not present[67,276]. Injection of neurotoxins or overexpressing constructs of Aβ into the brain are commonly used to induce local cell death and to model the AD typical neuropathology. For this, the larger brain size of the rat offers advantages over mice, as stereotactic injections can be performed more consistently and with larger volumes. Additionally, these models have been mostly used in preclinical studies.

Rats with diminished cholinergic neuron populations or severed neuronal circuits show memory deficits and impaired learning[278], thereby resembling the cognitive symptoms observed in patients, but not the pathobiological origin of the disorder. Ibotenic and okadaic acid, amongst other cholinergic neuron harming compounds, or surgically lesioned rats, have been used to study neuroprotective or even regenerating therapies. Exemplary, with these phenotypic models, it was possible to demonstrate that neuronal stem cells or mesenchymal stem cells can replace or protect cholinergic neurons and improve spatial learning and memory[286-288]. Recapitulating early pathobiological events, Aβ-injected models have also been used to investigate the beneficial effects of stem cell transplantation[289-291]. It should be noted in this regard that the concentrations needed to induce the pathological phenotype by Aβ-injections exceed any physiological concentrations, and the stereotactic injections always produce unwanted tissue damage at the injection site. Genetic mouse models of AD have been used to elucidate the mechanisms underlying the observed amelioration in the genetic context of AD[292,293]. A meta-analysis of preclinical studies on stem cell therapy for AD found a large variation in the models used and origin of cells but concluded overall beneficial effects on memory and learning. Approximately 60% of the analyzed studies were performed on non-genetic rat models[294].

Aside from lesion models, what needs to be noted in AD and PD are lipopolysaccharide (LPS)-induced models, as chronic inflammation is associated with cognitive impairment in AD patients and the exacerbation of AD and PD pathology in models of the disease (reviewed in[295,296]). These models recapitulate the involvement of the immune system in the pathogenesis and show an increase in Aβ and phosphorylated tau and cognitive impairment[279,297,298].

Over the past decade, improvements in biomarker identification and quantification and improved preclinical study design have been implemented to increase translatability to human studies. Incorporating such study design, a genetic rat model has been used in a preclinical study with improved longitudinal assessment of biomarkers to improve translatability. Continuous CSF and plasma collection for measurement of Aβ and neurofilament light chain in combination with PET and MRI imaging have been used to evaluate an anti-amyloid therapy in McGill-R-Thy1-APP transgenic rats[299].

Phenotypic rat models of Parkinson’s disease

Due to the multifactorial etiology of PD and most cases being of idiopathic origin, neurotoxin and lesion models are mostly relied on for preclinical Parkinson’s research. The main neuropathological feature of the disease, the loss of dopaminergic neurons in the substantia nigra can be modeled through the injection of hydroxydopamine (6-OHDA) in most studies into the substantia nigra pars compacta or in the medial forebrain bundle[300]. Next to cell loss, lesioned rats show motoric deficits that are correlated to the degree of dopaminergic neuron loss, oxidative stress, and neuroinflammation[280,301]. Test paradigms have been developed to assess motor deficits, resembling akinesia, fine motor impairment, and showing rotational response to dopaminomimetic agents when extensive unilateral lesioning is produced[301]. While the lesions produced resemble cell loss in humans, unilateral lesions are mostly used in experimental settings, inducing cell loss in one hemisphere only. These lesions are mostly produced in rats, as mice are more prone to weight loss and post-lesion mortality which can be circumvented by modification of the injection sites and improved post-surgical surveillance[302-304].

Another neurotoxin model is the MPTP mouse model. In contrast to 6-OHDA, which does not cross the blood-brain barrier, MPTP can be administered systemically, but shows larger variation in neuronal loss in the substantia nigra and the motor phenotype is not fully equivalent to PD patients[305]. MPTP has been mainly used to mimic PD in mice in many different treatment studies, as rats are highly resistant to MPTP. One rat model of unilateral brain infusion with MPP+ has been developed, which shows progressive loss of dopaminergic neurons[306].

Phenotypic rat models of Huntington’s disease

Only few preclinical studies have been performed in transgenic rat models of HD despite the monogenetic etiology of HD[111,307]. To a greater extent, neurotoxin models are used to model histopathological characteristics of the disease or mechanism of neuronal demise to test preventive therapies or therapies aiming at restoring functionality. The two most commonly used substances are quinolinic acid (QA) and 3-nitropropionic acid (3-NP). QA is an excitotoxin, binding to the N-methyl-d-aspartate (NMDA) receptor and more strongly affecting neurons within the hippocampus, striatum, and neocortex. It can induce different neuron and glia-damaging effects, also dependent on the dosage[308]. The lesions produced are structurally similar to HD characteristic lesions within the striatum and limited to the area around the injection site[283,309]. Impairment of paw use can be assessed in cylinder test, altered grooming behavior has been described, and learning and motoric abilities are altered in this model[310-312].

Systemic injection with 3-NP, an irreversible inhibitor of succinate dehydrogenase in the mitochondria, leads to striatal neuronal degeneration, as well. Rats are more sensitive to 3-NP than mice and develop lesions and behavioral alterations[284,313]. The lesions produced by 3-NP are more severe and cause a phenotype that includes learning impairment, reduced grip strength, and balance deficits that are more severe than in the QA model[310].

In current treatment approaches and clinical trials, HTT is lowered independently of the mutation or in an allele-selective manner[314]. Preclinical studies lowering HTT by micro-RNA (miRNA) have been performed in genetic mouse models of HD, an acute rat model of HD, a large animal model, and non-human primates[315-317]. Acute and local expression of HTT by lentiviral- or adenoviral vectors produces models that replicate typical neuropathological features HD, like aggregation and neuronal dysfunction[315,318,319]. This rat model can be used to evaluate the HTT lowering effects before a long preclinical trial is initiated, for example, by investigating behavioral readouts. Most allele selective therapies utilize heterozygous single nucleotide polymorphisms (SNPs) that are associated with the mutation-carrying allele. These therapeutic targets are only found in fractions of a population, and accordingly, they are also not necessarily present in the constructs that have been used to generate genetic models. Therefore, acute rat models can be used to test combinations and variations of SNP targeting molecules to advance personalized therapies.


Huge strides have been made towards generating genetic rat models in the past 20 years. These genetic models are an important asset for research on NDs to study physiological and pathophysiological mechanisms. Rats add to the functional understanding of disease by allowing electrophysiological measurements, harvesting of primary cell cultures and a wider range of surgical procedures. They offer the possibility to evaluate therapeutic effects more precisely due to their genetic similarities to humans, larger body size compared to mice, and the associated possibility of multiple sampling of biofluids over time. Many behavioral tests have been developed in rats, enabling a more robust assessment of behavioral phenotypes in rat models. Moreover, rats display a more complex behavioral repertoire than mice, allowing more sophisticated extrapolation to the human condition. Often efforts are being made to provide a complete characterization of the models, offering a good starting point to find an adequate fit for the biological question to be answered. Despite the long list of advantages rats offer, they are less represented in biomedical studies than mice. One reason for this is that genetic models have been generated with a delay due to the technically challenging manipulation of the rat genome. This, economic reasons, and the multifactorial etiology of many NDs have made phenotypic rat models commonly used models in preclinical research. Still today, they fill a gap when genetic models cannot reproduce certain aspects of disease, highlighting that in most cases only a combination of readouts, models, and model species can answer biomedical questions adequately. New rat models have been developed and characterized recently and can offer additional insight into disease mechanisms. Whether rats as models, combined with improved study design, can increase the translational value of biomedical research remains to be seen.


Authors’ contributions

Drafting, writing, revision of manuscript: Novati A, Singer-Mikosch E, Yu-Taeger L, Clemensson E, Nguyen HP

Availability of data and materials

Not applicable.

Financial support and sponsorship

Not applicable.

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

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Consent for publication

Not applicable.


© The Author(s) 2022.


1. Modlinska K, Pisula W. The Norway rat, from an obnoxious pest to a laboratory pet. Elife 2020;9:e50651.

2. Jacob HJ. The rat: a model used in biomedical research. Methods Mol Biol 2010;597:1-11.

3. Hånell A, Marklund N. Structured evaluation of rodent behavioral tests used in drug discovery research. Front Behav Neurosci 2014;8:252.

4. Kondrakiewicz K, Kostecki M, Szadzińska W, Knapska E. Ecological validity of social interaction tests in rats and mice. Genes Brain Behav 2019;18:e12525.

5. Frick KM, Stillner ET, Berger-Sweeney J. Mice are not little rats: species differences in a one-day water maze task. Neuroreport 2000;11:3461-5.

6. Whishaw I. A comparison of rats and mice in a swimming pool place task and matching to place task: Some surprising differences. Physiology & Behavior 1995;58:687-93.

7. Ellenbroek B, Youn J. Rodent models in neuroscience research: is it a rat race? Dis Model Mech 2016;9:1079-87.

8. Hok V, Poucet B, Duvelle É, Save É, Sargolini F. Spatial cognition in mice and rats: similarities and differences in brain and behavior. Wiley Interdiscip Rev Cogn Sci 2016;7:406-21.

9. D’hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Research Reviews 2001;36:60-90.

10. Stranahan AM. Similarities and differences in spatial learning and object recognition between young male C57Bl/6J mice and Sprague-Dawley rats. Behav Neurosci 2011;125:791-5.

11. Whishaw IQ, Tomie J. Of mice and mazes: similarities between mice and rats on dry land but not water mazes. Physiology & Behavior 1996;60:1191-7.

12. Jaramillo S, Zador AM. Mice and rats achieve similar levels of performance in an adaptive decision-making task. Front Syst Neurosci 2014;8:173.

13. Whishaw IQ, Metz GA, Kolb B, Pellis SM. Accelerated nervous system development contributes to behavioral efficiency in the laboratory mouse: a behavioral review and theoretical proposal. Dev Psychobiol 2001;39:151-70.

14. Foote AL, Crystal JD. Metacognition in the rat. Curr Biol 2007;17:551-5.

15. Templer VL, Lee KA, Preston AJ. Rats know when they remember: transfer of metacognitive responding across odor-based delayed match-to-sample tests. Anim Cogn 2017;20:891-906.

16. Templer VL. Slow progress with the most widely used animal model: ten years of metacognition research in rats, 2009-2019. Anim Behav Cogn 2019;6:273-7.

17. Bertrand E, Landeira-Fernandez J, Mograbi DC. Metacognition and perspective-taking in Alzheimer’s disease: a mini-review. Front Psychol 2016;7:1812.

18. Netser S, Meyer A, Magalnik H, et al. Distinct dynamics of social motivation drive differential social behavior in laboratory rat and mouse strains. Nat Commun 2020;11:5908.

19. Young JW, Jentsch JD, Bussey TJ, Wallace TL, Hutcheson DM. Consideration of species differences in developing novel molecules as cognition enhancers. Neurosci Biobehav Rev 2013;37:2181-93.

20. Szpirer C. Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes. J Biomed Sci 2020;27:84.

21. Cunningham ML. A mouse is not a rat is not a human: species differences exist. Toxicol Sci 2002;70:157-8.

22. Waterston RH, Lindblad-Toh K, Birney E, et al. Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 2002;420:520-62.

23. Gibbs RA, Weinstock GM, Metzker ML, et al. Rat Genome Sequencing Project Consortium. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 2004;428:493-521.

24. Chenouard V, Remy S, Tesson L, et al. Advances in genome editing and application to the generation of genetically modified rat models. Front Genet 2021;12:615491.

25. Cummings JL, Cole G. Alzheimer disease. JAMA 2002;287:2335-8.

26. Antony PM, Diederich NJ, Krüger R, Balling R. The hallmarks of Parkinson’s disease. FEBS J 2013;280:5981-93.

27. Macdonald M. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971-83.

28. Walker FO. Huntington’s disease. Lancet 2007;369:218-28.

29. Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med 1994;330:1401-6.

30. Hansotia P, Cleeland CS, Chun RW. Juvenile Huntington’s chorea. Neurology 1968;18:217-24.

31. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;277:1990-3.

32. Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, et al. Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 1999;19:2522-34.

33. Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, et al. Huntington aggregates may not predict neuronal death in Huntington’s disease. Ann Neurol 1999;46:842-9.

34. Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol 1998;57:369-84.

35. Hodgson J, Agopyan N, Gutekunst C, et al. A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 1999;23:181-92.

36. Poon CH, Wang Y, Fung ML, Zhang C, Lim LW. Rodent models of amyloid-beta feature of Alzheimer’s disease: development and potential treatment implications. Aging Dis 2020;11:1235-59.

37. Mckean NE, Handley RR, Snell RG. A review of the current mammalian models of Alzheimer’s disease and challenges that need to be overcome. International Journal of Molecular Sciences 2021;22:13168.

38. Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol 2017;133:155-75.

39. Do Carmo S, Cuello AC. Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 2013;8:37.

40. Baglietto-Vargas D, Forner S, Cai L, et al. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology. Nat Commun 2021;12:2421.

41. Jankowsky JL, Zheng H. Practical considerations for choosing a mouse model of Alzheimer’s disease. Mol Neurodegener 2017;12:89.

42. Kulkarni P, Grant S, Morrison TR, et al. Characterizing the human APOE epsilon 4 knock-in transgene in female and male rats with multimodal magnetic resonance imaging. Brain Res 2020;1747:147030.

43. Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson’s disease. Neuron 2010;66:646-61.

44. Creed RB, Goldberg MS. New developments in genetic rat models of Parkinson’s disease. Mov Disord 2018;33:717-29.

45. Seegobin SP, Heaton GR, Liang D, et al. Progress in LRRK2-associated Parkinson’s disease animal models. Front Neurosci 2020;14:674.

46. Yang KM, Blue KV, Mulholland HM, Kurup MP, Kelm-Nelson CA, Ciucci MR. Characterization of oromotor and limb motor dysfunction in the DJ1-/- model of Parkinson disease. Behav Brain Res 2018;339:47-56.

47. Grant LM, Kelm-Nelson CA, Hilby BL, et al. Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson’s disease. J Neurosci Res 2015;93:1713-27.

48. Stricker-shaver J, Novati A, Yu-taeger L, Nguyen HP. Genetic rodent models of Huntington disease. In: Nóbrega C, Pereira de Almeida L, editors. Polyglutamine disorders. Cham: Springer International Publishing; 2018. p. 29-57.

49. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014;71:505-8.

50. De Strooper B, Annaert W. Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol 2010;26:235-60.

51. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741-66.

52. Mucke L, Masliah E, Yu G, et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000;20:4050-8.

53. Sturchler-Pierrat C, Abramowski D, Duke M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 1997;94:13287-92.

54. Kitazawa M, Medeiros R, Laferla FM. Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr Pharm Des 2012;18:1131-47.

55. Leon WC, Canneva F, Partridge V, et al. A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis 2010;20:113-26.

56. Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain 2015;138:2814-33.

57. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59.

58. Gómez-Isla T, Hollister R, West H, et al. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 1997;41:17-24.

59. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 1992;42:631-9.

60. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 2019;14:32.

61. Spillantini MG, Bird TD, Ghetti B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 1998;8:387-402.

62. Mirra SS, Murrell JR, Gearing M, et al. Tau pathology in a family with dementia and a P301L mutation in tau. J Neuropathol Exp Neurol 1999;58:335-45.

63. Perluigi M, Barone E, Di Domenico F, Butterfield DA. Aberrant protein phosphorylation in Alzheimer disease brain disturbs pro-survival and cell death pathways. Biochim Biophys Acta 2016;1862:1871-82.

64. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 1975;72:1858-62.

65. Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 1992;3:1141-54.

66. Goedert M, Spillantini M, Jakes R, Rutherford D, Crowther R. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989;3:519-26.

67. Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M. Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J Neurochem 2009;108:1167-76.

68. Cohen RM, Rezai-Zadeh K, Weitz TM, et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci 2013;33:6245-56.

69. Audrain M, Souchet B, Alves S, et al. βAPP processing drives gradual tau pathology in an age-dependent amyloid rat model of Alzheimer’s disease. Cereb Cortex 2018;28:3976-93.

70. Pang K, Jiang R, Zhang W, et al. An App knock-in rat model for Alzheimer’s disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments. Cell Res 2022;32:157-75.

71. Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 2014;6:37-48.

72. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers 2017;3:17013.

73. Dorszewska J, Kowalska M, Prendecki M, Piekut T, Kozłowska J, Kozubski W. Oxidative stress factors in Parkinson’s disease. Neural Regen Res 2021;16:1383-91.

74. Singleton AB, Farrer M, Johnson J, et al. Alpha-synuclein locus triplication causes Parkinson’s disease. Science 2003;302:841.

75. Olgiati S, Thomas A, Quadri M, et al. Early-onset parkinsonism caused by α-synuclein gene triplication: clinical and genetic findings in a novel family. Parkinsonism Relat Disord 2015;21:981-6.

76. Chartier-harlin M, Kachergus J, Roumier C, et al. α-synuclein locus duplication as a cause of familial Parkinson’s disease. The Lancet 2004;364:1167-9.

77. Ferese R, Modugno N, Campopiano R, et al. Four copies of SNCA responsible for autosomal dominant Parkinson’s disease in two Italian siblings. Parkinsons Dis 2015;2015:546462.

78. Koprich JB, Kalia LV, Brotchie JM. Animal models of α-synucleinopathy for Parkinson disease drug development. Nat Rev Neurosci 2017;18:515-29.

79. Lin X, Parisiadou L, Sgobio C, et al. Conditional expression of Parkinson’s disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J Neurosci 2012;32:9248-64.

80. Janezic S, Threlfell S, Dodson PD, et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc Natl Acad Sci U S A 2013;110:E4016-25.

81. Lin X, Parisiadou L, Gu XL, et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant α-synuclein. Neuron 2009;64:807-27.

82. Hodge D. Endotracheal suctioning and the infant: a nursing care protocol to decrease complications. Neonatal Netw 1991;9:7-15.

83. Price DL, Rockenstein E, Ubhi K, et al. Alterations in mGluR5 expression and signaling in Lewy body disease and in transgenic models of α-synucleinopathy - implications for excitotoxicity. PLoS One 2010;5:e14020.

84. Nuber S, Harmuth F, Kohl Z, et al. A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats. Brain 2013;136:412-32.

85. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004;304:1158-60.

86. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256-9.

87. Lücking CB, Dürr A, Bonifati V, et al. French Parkinson’s Disease Genetics Study Group. , European Consortium on Genetic Susceptibility in Parkinson’s Disease. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000;342:1560-7.

88. Valente EM, Salvi S, Ialongo T, et al. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol 2004;56:336-41.

89. Rohé CF, Montagna P, Breedveld G, Cortelli P, Oostra BA, Bonifati V. Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism. Ann Neurol 2004;56:427-31.

90. Kondapalli C, Kazlauskaite A, Zhang N, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol 2012;2:120080.

91. Gautier CA, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A 2008;105:11364-9.

92. Amo T, Sato S, Saiki S, et al. Mitochondrial membrane potential decrease caused by loss of PINK1 is not due to proton leak, but to respiratory chain defects. Neurobiol Dis 2011;41:111-8.

93. Kane LA, Lazarou M, Fogel AI, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol 2014;205:143-53.

94. Wang XL, Feng ST, Wang ZZ, Yuan YH, Chen NH, Zhang Y. Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control in Parkinson’s disease. Cell Mol Neurobiol 2021;41:1395-411.

95. Heo JY, Park JH, Kim SJ, et al. DJ-1 null dopaminergic neuronal cells exhibit defects in mitochondrial function and structure: involvement of mitochondrial complex I assembly. PLoS One 2012;7:e32629.

96. Hayashi T, Ishimori C, Takahashi-Niki K, et al. DJ-1 binds to mitochondrial complex I and maintains its activity. Biochem Biophys Res Commun 2009;390:667-72.

97. Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson’s disease. Mov Disord 2012;27:831-42.

98. Villeneuve LM, Purnell PR, Boska MD, Fox HS. Early expression of Parkinson’s disease-related mitochondrial abnormalities in PINK1 knockout rats. Mol Neurobiol 2016;53:171-86.

99. Gispert S, Ricciardi F, Kurz A, et al. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS One 2009;4:e5777.

100. Kitada T, Tong Y, Gautier CA, Shen J. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J Neurochem 2009;111:696-702.

101. Dave KD, De Silva S, Sheth NP, et al. Phenotypic characterization of recessive gene knockout rat models of Parkinson’s disease. Neurobiol Dis 2014;70:190-203.

102. Almikhlafi MA, Stauch KL, Villeneuve LM, Purnell PR, Lamberty BG, Fox HS. Deletion of DJ-1 in rats affects protein abundance and mitochondrial function at the synapse. Sci Rep 2020;10:13719.

103. Chandran JS, Lin X, Zapata A, et al. Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function. Neurobiol Dis 2008;29:505-14.

104. Kim RH, Smith PD, Aleyasin H, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A 2005;102:5215-20.

105. Chen L, Cagniard B, Mathews T, et al. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 2005;280:21418-26.

106. Goldberg MS, Fleming SM, Palacino JJ, et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 2003;278:43628-35.

107. Yu-Taeger L, Petrasch-Parwez E, Osmand AP, et al. A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease. J Neurosci 2012;32:15426-38.

108. von Horsten S, Schmitt I, Nguyen HP, Holzmann C, Schmidt T, et al. Transgenic rat model of Huntington’s disease. Hum Mol Genet 2003;12:617-24.

109. Teo RT, Hong X, Yu-Taeger L, et al. Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease. Hum Mol Genet 2016;25:2621-32.

110. Blockx I, Van Camp N, Verhoye M, et al. Genotype specific age related changes in a transgenic rat model of Huntington’s disease. Neuroimage 2011;58:1006-16.

111. Clemens LE, Weber JJ, Wlodkowski TT, et al. Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat. Brain 2015;138:3632-53.

112. Petrasch-Parwez E, Nguyen HP, Löbbecke-Schumacher M, et al. Cellular and subcellular localization of Huntingtin [corrected] aggregates in the brain of a rat transgenic for Huntington disease. J Comp Neurol 2007;501:716-30.

113. Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL. Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 2004;10:36-44.

114. Wang CE, Tydlacka S, Orr AL, et al. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington’s disease. Hum Mol Genet 2008;17:2738-51.

115. Kuiper EF, de Mattos EP, Jardim LB, Kampinga HH, Bergink S. Chaperones in polyglutamine aggregation: beyond the Q-stretch. Front Neurosci 2017;11:145.

116. Bondi MW, Jak AJ, Delano-Wood L, Jacobson MW, Delis DC, Salmon DP. Neuropsychological contributions to the early identification of Alzheimer’s disease. Neuropsychol Rev 2008;18:73-90.

117. Skelton WP 3rd, Skelton NK. Alzheimer’s disease. Recognizing and treating a frustrating condition. Postgrad Med 1991;90:33-4, 37.

118. Lithfous S, Dufour A, Després O. Spatial navigation in normal aging and the prodromal stage of Alzheimer’s disease: insights from imaging and behavioral studies. Ageing Res Rev 2013;12:201-13.

119. Vorhees CV, Williams MT. Assessing spatial learning and memory in rodents. ILAR J 2014;55:310-32.

120. Coughlan G, Laczó J, Hort J, Minihane AM, Hornberger M. Spatial navigation deficits - overlooked cognitive marker for preclinical Alzheimer disease? Nat Rev Neurol 2018;14:496-506.

121. Burgess N, Maguire EA, O’keefe J. The Human hippocampus and spatial and episodic memory. Neuron 2002;35:625-41.

122. Morellini F. Spatial memory tasks in rodents: what do they model? Cell Tissue Res 2013;354:273-86.

123. Galeano P, Martino Adami PV, Do Carmo S, et al. Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer’s disease. Front Behav Neurosci 2014;8:321.

124. Iulita MF, Allard S, Richter L, et al. Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathol Commun 2014;2:61.

125. Petrasek T, Vojtechova I, Lobellova V, et al. The McGill transgenic rat model of Alzheimer’s disease displays cognitive and motor impairments, changes in anxiety and social behavior, and altered circadian activity. Front Aging Neurosci 2018;10:250.

126. Fowler CF, Goerzen D, Devenyi GA, Madularu D, Chakravarty MM, Near J. Neurochemical and cognitive changes precede structural abnormalities in the TgF344-AD rat model. Brain Commun 2022;4:fcac072.

127. Proskauer Pena SL, Mallouppas K, Oliveira AMG, Zitricky F, Nataraj A, Jezek K. Early spatial memory impairment in a double transgenic model of Alzheimer’s disease TgF-344 AD. Brain Sci 2021;11:1300.

128. Tournier BB, Barca C, Fall AB, et al. Spatial reference learning deficits in absence of dysfunctional working memory in the TgF344-AD rat model of Alzheimer’s disease. Genes Brain Behav 2021;20:e12712.

129. Saré RM, Cooke SK, Krych L, Zerfas PM, Cohen RM, Smith CB. Behavioral phenotype in the TgF344-AD rat model of Alzheimer’s disease. Front Neurosci 2020;14:601.

130. Rorabaugh JM, Chalermpalanupap T, Botz-Zapp CA, et al. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease. Brain 2017;140:3023-38.

131. Voorhees JR, Remy MT, Cintrón-Pérez CJ, et al. (-)-P7C3-S243 protects a rat model of Alzheimer’s disease from neuropsychiatric deficits and neurodegeneration without altering amyloid deposition or reactive glia. Biol Psychiatry 2018;84:488-98.

132. Berkowitz LE, Harvey RE, Drake E, Thompson SM, Clark BJ. Progressive impairment of directional and spatially precise trajectories by TgF344-Alzheimer’s disease rats in the Morris Water Task. Sci Rep 2018;8:16153.

133. Laczó J, Andel R, Vyhnalek M, et al. Human analogue of the morris water maze for testing subjects at risk of Alzheimer’s disease. Neurodegener Dis 2010;7:148-52.

134. Possin KL, Sanchez PE, Anderson-Bergman C, et al. Cross-species translation of the Morris maze for Alzheimer’s disease. J Clin Invest 2016;126:779-83.

135. Laczó J, Markova H, Lobellova V, et al. Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans. Psychopharmacology (Berl) 2017;234:535-47.

136. Tromp D, Dufour A, Lithfous S, Pebayle T, Després O. Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studies. Ageing Res Rev 2015;24:232-62.

137. Goldstein FC, Loring DW, Thomas T, Saleh S, Hajjar I. Recognition memory performance as a cognitive marker of prodromal Alzheimer’s disease. J Alzheimers Dis 2019;72:507-14.

138. Quenon L, de Xivry JJ, Hanseeuw B, Ivanoiu A. Investigating associative learning effects in patients with prodromal Alzheimer’s disease using the temporal context model. J Int Neuropsychol Soc 2015;21:699-708.

139. Hampstead BM, Stringer AY, Stilla RF, Amaraneni A, Sathian K. Where did I put that? Neuropsychologia 2011;49:2349-61.

140. Chaney AM, Lopez-Picon FR, Serrière S, et al. Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study. Theranostics 2021;11:6644-67.

141. Goodman AM, Langner BM, Jackson N, Alex C, McMahon LL. Heightened hippocampal β-adrenergic receptor function drives synaptic potentiation and supports learning and memory in the TgF344-AD rat model during prodromal Alzheimer’s disease. J Neurosci 2021;41:5747-61.

142. Habif M, Do Carmo S, Báez MV, et al. Early long-term memory impairment and changes in the expression of synaptic plasticity-associated genes, in the McGill-R-Thy1-APP rat model of Alzheimer’s-like brain amyloidosis. Front Aging Neurosci 2020;12:585873.

143. Morrone CD, Bazzigaluppi P, Beckett TL, et al. Regional differences in Alzheimer’s disease pathology confound behavioural rescue after amyloid-β attenuation. Brain 2020;143:359-73.

144. Wu C, Yang L, Li Y, et al. Effects of exercise training on anxious-depressive-like behavior in Alzheimer rat. Med Sci Sports Exerc 2020;52:1456-69.

145. Yang L, Wu C, Li Y, et al. Long-term exercise pre-training attenuates Alzheimer’s disease-related pathology in a transgenic rat model of Alzheimer’s disease. Geroscience 2022;44:1457-77.

146. Wilson EN, Abela AR, Do Carmo S, et al. Intraneuronal amyloid beta accumulation disrupts hippocampal CRTC1-dependent gene expression and cognitive function in a rat model of Alzheimer disease. Cereb Cortex 2017;27:1501-11.

147. Blackwell AD, Sahakian BJ, Vesey R, Semple JM, Robbins TW, Hodges JR. Detecting dementia: novel neuropsychological markers of preclinical Alzheimer’s disease. Dement Geriatr Cogn Disord 2004;17:42-8.

148. Wolinsky D, Drake K, Bostwick J. Diagnosis and management of neuropsychiatric symptoms in Alzheimer’s disease. Curr Psychiatry Rep 2018;20:117.

149. Cortés N, Andrade V, Maccioni RB. Behavioral and neuropsychiatric disorders in Alzheimer’s disease. J Alzheimers Dis 2018;63:899-910.

150. Morgese MG, Trabace L. Monoaminergic system modulation in depression and Alzheimer’s disease: A New Standpoint? Front Pharmacol 2019;10:483.

151. Sawyer K, Corsentino E, Sachs-Ericsson N, Steffens DC. Depression, hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls. Aging Ment Health 2012;16:753-62.

152. Selles MC, Oliveira MM, Ferreira ST. Brain inflammation connects cognitive and non-cognitive symptoms in Alzheimer’s disease. J Alzheimers Dis 2018;64:S313-27.

153. Pentkowski NS, Berkowitz LE, Thompson SM, Drake EN, Olguin CR, Clark BJ. Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer’s disease. Neurobiol Aging 2018;61:169-76.

154. Yang L, Wu C, Tucker L, et al. Photobiomodulation therapy attenuates anxious-depressive-like behavior in the TgF344 rat model. J Alzheimers Dis 2021;83:1415-29.

155. Eikelboom WS, Pan M, Ossenkoppele R, et al. Sex differences in neuropsychiatric symptoms in Alzheimer’s disease dementia: a meta-analysis. Alzheimers Res Ther 2022;14:48.

156. Chi S, Yu JT, Tan MS, Tan L. Depression in Alzheimer’s disease: epidemiology, mechanisms, and management. J Alzheimers Dis 2014;42:739-55.

157. Kosel F, Pelley JMS, Franklin TB. Behavioural and psychological symptoms of dementia in mouse models of Alzheimer’s disease-related pathology. Neurosci Biobehav Rev 2020;112:634-47.

158. Pardossi-Piquard R, Lauritzen I, Bauer C, Sacco G, Robert P, Checler F. Influence of genetic background on apathy-like behavior in triple transgenic AD mice. Curr Alzheimer Res 2016;13:942-9.

159. Hailwood JM, Heath CJ, Robbins TW, Saksida LM, Bussey TJ. Validation and optimisation of a touchscreen progressive ratio test of motivation in male rats. Psychopharmacology (Berl) 2018;235:2739-53.

160. Järvenpää JP, Kopanitsa MV, Miszczuk D, Oksman J, Puoliväli J. P3-082: faster responding of Tg2576 mice in the touch screen version of the progressive ratio task. Alzheimers Dement 2019;15:957.

161. Kreuzer M, Keating GL, Fenzl T, et al. Sleep/wake behavior and EEG signatures of the TgF344-AD rat model at the prodromal stage. Int J Mol Sci 2020;21:9290.

162. Iakovakis D, Chaudhuri KR, Klingelhoefer L, et al. Screening of Parkinsonian subtle fine-motor impairment from touchscreen typing via deep learning. Sci Rep 2020;10:12623.

163. Park JH, Kang YJ, Horak FB. What is wrong with balance in Parkinson’s disease? J Mov Disord 2015;8:109-14.

164. Fasano A, Mazzoni A, Falotico E. Reaching and grasping movements in Parkinson’s disease: a review. J Parkinsons Dis 2022;12:1083-113.

165. de Haas R, Heltzel LCMW, Tax D, et al. To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease. Brain Commun 2019;1:fcz016.

166. Giangrasso DM, Furlong TM, Keefe KA. Characterization of striatum-mediated behavior and neurochemistry in the DJ-1 knock-out rat model of Parkinson’s disease. Neurobiol Dis 2020;134:104673.

167. Kyser TL, Dourson AJ, McGuire JL, Hemmerle AM, Williams MT, Seroogy KB. Characterization of motor and non-motor behavioral alterations in the Dj-1 (PARK7) knockout rat. J Mol Neurosci 2019;69:298-311.

168. Vazquez-Mayorga E, Grigoruta M, Dagda R, Martinez B, Dagda RK. Intraperitoneal administration of forskolin reverses motor symptoms and loss of midbrain dopamine neurons in PINK1 knockout rats. J Parkinsons Dis 2022;12:831-50.

169. Marquis JM, Lettenberger SE, Kelm-Nelson CA. Early-onset Parkinsonian behaviors in female Pink1-/- rats. Behav Brain Res 2020;377:112175.

170. Kohl Z, Ben Abdallah N, Vogelgsang J, et al. Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC α-synuclein transgenic rat model of Parkinson’s disease. Neurobiol Dis 2016;85:206-17.

171. Timotius IK, Moceri S, Plank AC, et al. Silhouette-length-scaled gait parameters for motor functional analysis in mice and rats. eNeuro 2019;6:ENEURO.

172. Bova A, Kernodle K, Mulligan K, Leventhal D. Automated rat single-pellet reaching with 3-dimensional reconstruction of paw and digit trajectories. J Vis Exp 2019; doi: 10.3791/59979.

173. Klein A, Dunnett SB. Analysis of skilled forelimb movement in rats: the single pellet reaching test and staircase test. Curr Protoc Neurosci 2012;Chapter 8:Unit8.28.

174. Dashtipour K, Tafreshi A, Lee J, Crawley B. Speech disorders in Parkinson’s disease: pathophysiology, medical management and surgical approaches. Neurodegener Dis Manag 2018;8:337-48.

175. Simons JA. Swallowing dysfunctions in Parkinson’s disease. Nonmotor Parkinson’s: the hidden face - management and the hidden face of related disorders. Elsevier; 2017. p. 1207-38.

176. Schulz GM, Grant MK. Effects of speech therapy and pharmacologic and surgical treatments on voice and speech in Parkinson’s disease. J Commun Disord 2000;33:59-88.

177. Kwan LC, Whitehill TL. Perception of speech by individuals with Parkinson’s disease: a review. Parkinsons Dis 2011;2011:389767.

178. Smotherman MS. Sensory feedback control of mammalian vocalizations. Behav Brain Res 2007;182:315-26.

179. Depaulis A, Keay KA, Bandler R. Longitudinal neuronal organization of defensive reactions in the midbrain periaqueductal gray region of the rat. Exp Brain Res 1992;90:307-18.

180. Fardin V, Oliveras J, Besson J. A reinvestigation of the analgesic effects induced by stimulation of the periaqueductal gray matter in the rat. I. The production of behavioral side effects together with analgesia. Brain Research 1984;306:105-23.

181. Schulz GM, Varga M, Jeffires K, Ludlow CL, Braun AR. Functional neuroanatomy of human vocalization: an H215O PET study. Cereb Cortex 2005;15:1835-47.

182. Van Daele DJ, Cassell MD. Multiple forebrain systems converge on motor neurons innervating the thyroarytenoid muscle. Neuroscience 2009;162:501-24.

183. Jürgens U. The role of the periaqueductal grey in vocal behaviour. Behavioural Brain Research 1994;62:107-17.

184. Beart P, Summers R, Stephenson J, Christie M. Excitatory amino acid projections to the nucleus of the solitary tract in the rat: a retrograde transport study utilizing d-[3H]aspartate and [3H]GABA. J Auton Nerv Syst 1994;50:109-22.

185. Bennett PJG, Maier E, Brecht M. Involvement of rat posterior prelimbic and cingulate area 2 in vocalization control. Eur J Neurosci 2019;50:3164-80.

186. Oka T, Tsumori T, Yokota S, Yasui Y. Neuroanatomical and neurochemical organization of projections from the central amygdaloid nucleus to the nucleus retroambiguus via the periaqueductal gray in the rat. Neurosci Res 2008;62:286-98.

187. Grant LM, Richter F, Miller JE, et al. Vocalization deficits in mice over-expressing α-synuclein, a model of pre-manifest Parkinson’s disease. Behav Neurosci 2014;128:110-21.

188. Kelm-Nelson CA, Gammie S. Gene expression within the periaqueductal gray is linked to vocal behavior and early-onset parkinsonism in Pink1 knockout rats. BMC Genomics 2020;21:625.

189. Johnson RA, Kelm-Nelson CA, Ciucci MR. Changes to ventilation, vocalization, and thermal nociception in the Pink1-/- rat model of Parkinson’s disease. J Parkinsons Dis 2020;10:489-504.

190. Kelm-Nelson CA, Brauer AFL, Barth KJ, et al. Characterization of early-onset motor deficits in the Pink1-/- mouse model of Parkinson disease. Brain Res 2018;1680:1-12.

191. Kummer A, Cardoso F, Teixeira AL. Loss of libido in Parkinson’s disease. J Sex Med 2009;6:1024-31.

192. Murphy AZ, Hoffman GE. Distribution of gonadal steroid receptor-containing neurons in the preoptic-periaqueductal gray-brainstem pathway: a potential circuit for the initiation of male sexual behavior. J Comp Neurol 2001;438:191-212.

193. Normandin JJ, Murphy AZ. Nucleus paragigantocellularis afferents in male and female rats: organization, gonadal steroid receptor expression, and activation during sexual behavior. J Comp Neurol 2008;508:771-94.

194. Cullen KP, Grant LM, Kelm-Nelson CA, et al. Pink1-/- rats show early-onset swallowing deficits and correlative brainstem pathology. Dysphagia 2018;33:749-58.

195. van Hooren MRA, Vos R, Florie MGMH, Pilz W, Kremer B, Baijens LWJ. Swallowing assessment in Parkinson’s disease: patient and investigator reported outcome measures are not aligned. Dysphagia 2021;36:864-74.

196. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers 2021;7:47.

197. Aarsland D, Kramberger MG. Neuropsychiatric symptoms in Parkinson’s disease. J Parkinsons Dis 2015;5:659-67.

198. Chen JJ, Marsh L. Anxiety in Parkinson’s disease: identification and management. Ther Adv Neurol Disord 2014;7:52-9.

199. Fang C, Lv L, Mao S, Dong H, Liu B. Cognition deficits in Parkinson’s disease: mechanisms and treatment. Parkinsons Dis 2020;2020:2076942.

200. Weintraub D, Simuni T, Caspell-Garcia C, et al. Parkinson’s Progression Markers Initiative. Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson’s disease. Mov Disord 2015;30:919-27.

201. Polissidis A, Koronaiou M, Kollia V, et al. Psychosis-like behavior and hyperdopaminergic dysregulation in human α-synuclein BAC transgenic rats. Mov Disord 2021;36:716-28.

202. Forrest AD, Coto CA, Siegel SJ. Animal models of psychosis: current state and future directions. Curr Behav Neurosci Rep 2014;1:100-16.

203. Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Front Neuroendocrinol 2014;35:370-84.

204. Grospe GM, Baker PM, Ragozzino ME. Cognitive flexibility deficits following 6-OHDA lesions of the rat dorsomedial striatum. Neuroscience 2018;374:80-90.

205. Marshall CA, King KM, Kortagere S. Limitations of the rat medial forebrain lesion model to study prefrontal cortex mediated cognitive tasks in Parkinson’s disease. Brain Res 2019;1702:105-13.

206. Ferris CF, Morrison TR, Iriah S, et al. Evidence of neurobiological changes in the presymptomatic PINK1 knockout rat. J Parkinsons Dis 2018;8:281-301.

207. Pham TT, Giesert F, Röthig A, et al. DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments. Genes Brain Behav 2010;9:305-17.

208. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers 2015;1:15005.

209. Mangiarini L, Sathasivam K, Seller M, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996;87:493-506.

210. Nguyen HP, Kobbe P, Rahne H, et al. Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington’s disease. Hum Mol Genet 2006;15:3177-94.

211. Bode FJ, Stephan M, Suhling H, et al. Sex differences in a transgenic rat model of Huntington’s disease: decreased 17beta-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males. Hum Mol Genet 2008;17:2595-609.

212. Kurat S, Heinrich P, Molnar-Kasza A, Loeffler T, Flunkert S, Hutter-Paier B. Homozygosity of BACHD rats not only causes strong behavioral deficits in young female rats but also a reduced breeding success. Brain Res 2021;1761:147396.

213. Abada YS, Nguyen HP, Schreiber R, Ellenbroek B. Assessment of motor function, sensory motor gating and recognition memory in a novel BACHD transgenic rat model for Huntington disease. PLoS One 2013;8:e68584.

214. Novati A, Manfré G, Flunkert S, et al. Validation of behavioral phenotypes in the BACHD rat model. Behav Brain Res 2020;393:112783.

215. Manfré G, Clemensson EKH, Kyriakou EI, et al. The BACHD rat model of Huntington disease shows specific deficits in a test battery of motor function. Front Behav Neurosci 2017;11:218.

216. Urbach YK, Raber KA, Canneva F, et al. Automated phenotyping and advanced data mining exemplified in rats transgenic for Huntington’s disease. J Neurosci Methods 2014;234:38-53.

217. Faure A, Höhn S, Von Hörsten S, et al. Altered emotional and motivational processing in the transgenic rat model for Huntington’s disease. Neurobiol Learn Mem 2011;95:92-101.

218. Ortiz AN, Osterhaus GL, Lauderdale K, et al. Motor function and dopamine release measurements in transgenic Huntington’s disease model rats. Brain Res 2012;1450:148-56.

219. Cao C, Temel Y, Blokland A, et al. Progressive deterioration of reaction time performance and choreiform symptoms in a new Huntington’s disease transgenic ratmodel. Behav Brain Res 2006;170:257-61.

220. Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR. Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 1995;58:192-200.

221. Höhn S, Dallérac G, Faure A, et al. Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for Huntington disease. J Neurosci 2011;31:8986-97.

222. Goh AM, Wibawa P, Loi SM, Walterfang M, Velakoulis D, Looi JC. Huntington’s disease: neuropsychiatric manifestations of Huntington’s disease. Australas Psychiatry 2018;26:366-75.

223. Paulsen JS, Miller AC, Hayes T, Shaw E. Cognitive and behavioral changes in Huntington disease before diagnosis. Huntington disease. Elsevier; 2017. p. 69-91.

224. Bora E, Velakoulis D, Walterfang M. Social cognition in Huntington’s disease: a meta-analysis. Behav Brain Res 2016;297:131-40.

225. Herben-Dekker M, van Oostrom JC, Roos RA, et al. Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington’s disease. J Neurol 2014;261:1387-97.

226. Say MJ, Jones R, Scahill RI, et al. TRACK-HD Investigators. Visuomotor integration deficits precede clinical onset in Huntington’s disease. Neuropsychologia 2011;49:264-70.

227. You SC, Geschwind MD, Sha SJ, et al. Executive functions in premanifest Huntington’s disease. Mov Disord 2014;29:405-9.

228. Zeef DH, Vlamings R, Lim LW, et al. Motor and non-motor behaviour in experimental Huntington’s disease. Behav Brain Res 2012;226:435-9.

229. Lamirault C, Nguyen HP, Doyère V, El Massioui N. Age-related alteration of emotional regulation in the BACHD rat model of Huntington disease. Genes Brain Behav 2020;19:e12633.

230. Lamirault C, Yu-Taeger L, Doyère V, Riess O, Nguyen HP, El Massioui N. Altered reactivity of central amygdala to GABAAR antagonist in the BACHD rat model of Huntington disease. Neuropharmacology 2017;123:136-47.

231. Aharony I, Ehrnhoefer DE, Shruster A, et al. A Huntingtin-based peptide inhibitor of caspase-6 provides protection from mutant Huntingtin-induced motor and behavioral deficits. Hum Mol Genet 2015;24:2604-14.

232. Chiu CT, Liu G, Leeds P, Chuang DM. Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington’s disease. Neuropsychopharmacology 2011;36:2406-21.

233. Hult Lundh S, Nilsson N, Soylu R, Kirik D, Petersén Å. Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington’s disease. Hum Mol Genet 2013;22:3485-97.

234. Pouladi MA, Stanek LM, Xie Y, et al. Marked differences in neurochemistry and aggregates despite similar behavioural and neuropathological features of Huntington disease in the full-length BACHD and YAC128 mice. Hum Mol Genet 2012;21:2219-32.

235. Zlebnik NE, Gildish I, Sesia T, et al. Motivational impairment is accompanied by corticoaccumbal dysfunction in the BACHD-Tg5 rat model of Huntington’s disease. Cereb Cortex 2019;29:4763-74.

236. Clemensson EKH, Clemensson LE, Fabry B, Riess O, Nguyen HP, Fleming SM. Further investigation of phenotypes and confounding factors of progressive ratio performance and feeding behavior in the BACHD rat model of Huntington disease. PLoS ONE 2017;12:e0173232.

237. Jansson EK, Clemens LE, Riess O, Nguyen HP. Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy. PLoS One 2014;9:e105662.

238. Beste C, Saft C, Andrich J, Gold R, Falkenstein M. Response inhibition in Huntington’s disease-a study using ERPs and sLORETA. Neuropsychologia 2008;46:1290-7.

239. Rao JA, Harrington DL, Durgerian S, et al. Disruption of response inhibition circuits in prodromal Huntington disease. Cortex 2014;58:72-85.

240. Curtin PC, Farrar AM, Oakeshott S, et al. Cognitive training at a young age attenuates deficits in the zQ175 mouse model of HD. Front Behav Neurosci 2015;9:361.

241. Oakeshott S, Farrar A, Port R, et al. Deficits in a simple visual go/no-go discrimination task in two mouse models of Huntington’s disease. PLoS Curr 2013;5:ecurrents.

242. Clemensson EKH, Novati A, Clemensson LE, Riess O, Nguyen HP. The BACHD rat model of Huntington disease shows slowed learning in a Go/No-Go-like test of visual discrimination. Behav Brain Res 2019;359:116-26.

243. El Massioui N, Lamirault C, Yagüe S, et al. Impaired decision making and loss of inhibitory-control in a rat model of Huntington disease. Front Behav Neurosci 2016;10:204.

244. Manfré G, Doyère V, Bossi S, Riess O, Nguyen HP, El Massioui N. Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease. Behav Brain Res 2016;299:6-10.

245. Plank AC, Canneva F, Raber KA, et al. Early alterations in operant performance and prominent huntingtin aggregation in a congenic F344 rat line of the classical CAGn51trunc model of Huntington disease. Front Neurosci 2018;12:11.

246. Winstanley CA. The utility of rat models of impulsivity in developing pharmacotherapies for impulse control disorders. Br J Pharmacol 2011;164:1301-21.

247. Beste C, Saft C, Andrich J, Müller T, Gold R, Falkenstein M. Time processing in Huntington’s disease: a group-control study. PLoS One 2007;2:e1263.

248. Lawrence AD, Watkins LH, Sahakian BJ, Hodges JR, Robbins TW. Visual object and visuospatial cognition in Huntington’s disease: implications for information processing in corticostriatal circuits. Brain 2000;123 ( Pt 7):1349-64.

249. Brooks S, Fielding S, Döbrössy M, von Hörsten S, Dunnett S. Subtle but progressive cognitive deficits in the female tgHD hemizygote rat as demonstrated by operant SILT performance. Brain Res Bull 2009;79:310-5.

250. Fink KD, Rossignol J, Crane AT, et al. Early cognitive dysfunction in the HD 51 CAG transgenic rat model of Huntington’s disease. Behav Neurosci 2012;126:479-87.

251. Zeef DH, van Goethem NP, Vlamings R, et al. Memory deficits in the transgenic rat model of Huntington’s disease. Behav Brain Res 2012;227:194-8.

252. Abada YS, Nguyen HP, Ellenbroek B, Schreiber R. Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease. PLoS One 2013;8:e71633.

253. Clemensson EK, Clemensson LE, Riess O, Nguyen HP. The BACHD rat model of Huntington disease shows signs of fronto-striatal dysfunction in two operant conditioning tests of short-term memory. PLoS One 2017;12:e0169051.

254. Adjeroud N, Yagüe S, Yu-Taeger L, et al. Reduced impact of emotion on choice behavior in presymptomatic BACHD rats, a transgenic rodent model for Huntington Disease. Neurobiol Learn Mem 2015;125:249-57.

255. Brown A, Sewell K, Fisher CA. Characterisation of aggression in Huntington’s disease: rates, types and antecedents in an inpatient rehabilitation setting. J Clin Nurs 2017;26:2922-31.

256. Kempnich CL, Andrews SC, Fisher F, Wong D, Georgiou-Karistianis N, Stout JC. Emotion recognition correlates with social-neuropsychiatric dysfunction in Huntington’s disease. J Int Neuropsychol Soc 2018;24:417-23.

257. Mason SL, Schaepers M, Barker RA. Problems with social cognition and decision-making in Huntington’s disease: why is it important? Brain Sci 2021;11:838.

258. Cheong RY, Tonetto S, von Hörsten S, Petersén Å. Imbalance of the oxytocin-vasopressin system contributes to the neuropsychiatric phenotype in the BACHD mouse model of Huntington disease. Psychoneuroendocrinology 2020;119:104773.

259. Ciamei A, Morton AJ. Rigidity in social and emotional memory in the R6/2 mouse model of Huntington’s disease. Neurobiol Learn Mem 2008;89:533-44.

260. Pietropaolo S, Delage P, Cayzac S, Crusio WE, Cho YH. Sex-dependent changes in social behaviors in motor pre-symptomatic R6/1 mice. PLoS One 2011;6:e19965.

261. Rudenko O, Tkach V, Berezin V, Bock E. Effects of FGF receptor peptide agonists on animal behavior under normal and pathological conditions. Neurosci Res 2010;68:35-43.

262. Wood NI, Morton AJ. Social behaviour is impaired in the R6/2 mouse model of Huntington’s disease. J Huntingtons Dis 2015;4:61-73.

263. Manfré G, Novati A, Faccini I, et al. BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates. PLoS One 2018;13:e0192289.

264. Ko J. Neuroanatomical substrates of rodent social behavior: the medial prefrontal cortex and its projection patterns. Front Neural Circuits 2017;11:41.

265. Báez-Mendoza R, Schultz W. The role of the striatum in social behavior. Front Neurosci 2013;7:233.

266. Lukas M, Toth I, Reber SO, Slattery DA, Veenema AH, Neumann ID. The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology 2011;36:2159-68.

267. Cheong RY, Gabery S, Petersén Å. The role of hypothalamic pathology for non-motor features of Huntington’s disease. J Huntingtons Dis 2019;8:375-91.

268. Hellem MNN, Cheong RY, Tonetto S, et al. Decreased CSF oxytocin relates to measures of social cognitive impairment in Huntington’s disease patients. Parkinsonism Relat Disord 2022;99:23-9.

269. Hooijmans CR, Ritskes-Hoitinga M. Progress in using systematic reviews of animal studies to improve translational research. PLoS Med 2013;10:e1001482.

270. Perel P, Roberts I, Sena E, et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007;334:197.

271. Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I. Reviewing Animal Trials Systematically (RATS) Group. Where is the evidence that animal research benefits humans? BMJ 2004;328:514-7.

272. Bracken MB. Why animal studies are often poor predictors of human reactions to exposure. J R Soc Med 2009;102:120-2.

273. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother 2010;1:94-9.

274. McGonigle P, Ruggeri B. Animal models of human disease: challenges in enabling translation. Biochem Pharmacol 2014;87:162-71.

275. Moulin TC, Covill LE, Itskov PM, Williams MJ, Schiöth HB. Rodent and fly models in behavioral neuroscience: an evaluation of methodological advances, comparative research, and future perspectives. Neurosci Biobehav Rev 2021;120:1-12.

276. Smolek T, Jadhav S, Brezovakova V, et al. First-in-rat study of human Alzheimer’s disease tau propagation. Mol Neurobiol 2019;56:621-31.

277. Van Dam D, De Deyn PP. Animal models in the drug discovery pipeline for Alzheimer’s disease. Br J Pharmacol 2011;164:1285-300.

278. Lecanu L, Papadopoulos V. Modeling Alzheimer’s disease with non-transgenic rat models. Alzheimers Res Ther 2013;5:17.

279. Zakaria R, Wan Yaacob WM, Othman Z, Long I, Ahmad AH, Al-Rahbi B. Lipopolysaccharide-induced memory impairment in rats: a model of Alzheimer’s disease. Physiol Res 2017;66:553-65.

280. Deumens R, Blokland A, Prickaerts J. Modeling Parkinson’s disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol 2002;175:303-17.

281. Beal M, Ferrante R, Swartz K, Kowall N. Chronic quinolinic acid lesions in rats closely resemble Huntington’s disease. J Neurosci 1991;11:1649-59.

282. DiFiglia M. Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends in neurosciences 1990;13:286-9.

283. Schwarcz R, Guidetti P, Sathyasaikumar KV, Muchowski PJ. Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog Neurobiol 2010;90:230-45.

284. Borlongan CV, Koutouzis TK, Sanberg PR. 3-Nitropropionic acid animal model and Huntington’s disease. Neurosci Biobehav Rev 1997;21:289-93.

285. Bali J, Gheinani AH, Zurbriggen S, Rajendran L. Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides. Proc Natl Acad Sci U S A 2012;109:15307-11.

286. Xuan AG, Luo M, Ji WD, Long DH. Effects of engrafted neural stem cells in Alzheimer’s disease rats. Neurosci Lett 2009;450:167-71.

287. Moghadam FH, Alaie H, Karbalaie K, Tanhaei S, Nasr Esfahani MH, Baharvand H. Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats. Differentiation 2009;78:59-68.

288. Wu S, Sasaki A, Yoshimoto R, et al. Neural stem cells improve learning and memory in rats with Alzheimer’s disease. Pathobiology 2008;75:186-94.

289. Esmaeilzade B, Artimani T, Amiri I, et al. Dimethyloxalylglycine preconditioning enhances protective effects of bone marrow-derived mesenchymal stem cells in Aβ- induced Alzheimer disease. Physiol Behav 2019;199:265-72.

290. Gholamigeravand B, Shahidi S, Afshar S, et al. Synergistic effects of adipose-derived mesenchymal stem cells and selenium nanoparticles on streptozotocin-induced memory impairment in the rat. Life Sci 2021;272:119246.

291. Nasiri E, Alizadeh A, Roushandeh AM, Gazor R, Hashemi-Firouzi N, Golipoor Z. Melatonin-pretreated adipose-derived mesenchymal stem cells efficeintly improved learning, memory, and cognition in an animal model of Alzheimer’s disease. Metab Brain Dis 2019;34:1131-43.

292. Lu MH, Ji WL, Chen H, et al. Intranasal transplantation of human neural stem cells ameliorates Alzheimer’s disease-like pathology in a mouse model. Front Aging Neurosci 2021;13:650103.

293. Blurton-Jones M, Kitazawa M, Martinez-Coria H, et al. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A 2009;106:13594-9.

294. Wang Z, Peng W, Zhang C, et al. Effects of stem cell transplantation on cognitive decline in animal models of Alzheimer’s disease: A systematic review and meta-analysis. Sci Rep 2015;5:12134.

295. Xie J, Van Hoecke L, Vandenbroucke RE. The impact of systemic inflammation on Alzheimer’s disease pathology. Front Immunol 2021;12:796867.

296. Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener 2015;4:19.

297. Hauss-wegrzyniak B, Dobrzanski P, Stoehr JD, Wenk GL. Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease. Brain Research 1998;780:294-303.

298. Wang LM, Wu Q, Kirk RA, Horn KP, Ebada Salem AH, et al. Lipopolysaccharide endotoxemia induces amyloid-β and p-tau formation in the rat brain. Am J Nucl Med Mol Imaging 2018;8:86-99.

299. Kang MS, Shin M, Ottoy J, et al. Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic. J Cereb Blood Flow Metab 2022;42:788-801.

300. Blandini F, Armentero MT, Martignoni E. The 6-hydroxydopamine model: news from the past. Parkinsonism Relat Disord 2008;14 Suppl 2:S124-9.

301. Simola N, Morelli M, Carta AR. The 6-hydroxydopamine model of Parkinson’s disease. Neurotox Res 2007;11:151-67.

302. Mendes-Pinheiro B, Soares-Cunha C, Marote A, et al. Unilateral intrastriatal 6-hydroxydopamine lesion in mice: a closer look into non-motor phenotype and glial response. Int J Mol Sci 2021;22:11530.

303. Thiele SL, Warre R, Nash JE. Development of a unilaterally-lesioned 6-OHDA mouse model of Parkinson’s disease. J Vis Exp ;2012:3234.

304. Masini D, Plewnia C, Bertho M, Scalbert N, Caggiano V, Fisone G. A guide to the generation of a 6-hydroxydopamine mouse model of Parkinson’s disease for the study of non-motor symptoms. Biomedicines 2021;9:598.

305. Meredith GE, Rademacher DJ. MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis 2011;1:19-33.

306. Yazdani U, German DC, Liang CL, Manzino L, Sonsalla PK, Zeevalk GD. Rat model of Parkinson’s disease: chronic central delivery of 1-methyl-4-phenylpyridinium (MPP+). Exp Neurol 2006;200:172-83.

307. Rossignol J, Fink K, Davis K, et al. Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of Huntington’s disease. Stem Cells 2014;32:500-9.

308. Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J 2012;279:1356-65.

309. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB. Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 1986;321:168-71.

310. Shear DA, Dong J, Gundy CD, Haik-creguer KL, Dunbar GL. Comparison of intrastriatal injections of quinolinic acid and 3-nitropropionic acid for use in animal models of Huntington’s disease. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:1217-40.

311. McBride JL, Behrstock SP, Chen EY, et al. Human neural stem cell transplants improve motor function in a rat model of Huntington’s disease. J Comp Neurol 2004;475:211-9.

312. Tartaglione AM, Armida M, Potenza RL, Pezzola A, Popoli P, Calamandrei G. Aberrant self-grooming as early marker of motor dysfunction in a rat model of Huntington’s disease. Behav Brain Res 2016;313:53-7.

313. Túnez I, Tasset I, Pérez-De La Cruz V, Santamaría A. 3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington’s disease: past, present and future. Molecules 2010;15:878-916.

314. Marxreiter F, Stemick J, Kohl Z. Huntingtin lowering strategies. Int J Mol Sci 2020;21:2146.

315. Miniarikova J, Zimmer V, Martier R, et al. AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther 2017;24:630-9.

316. Spronck EA, Brouwers CC, Vallès A, et al. AAV5-miHTT gene therapy demonstrates sustained huntingtin lowering and functional improvement in Huntington disease mouse models. Mol Ther Methods Clin Dev 2019;13:334-43.

317. Vallès A, Evers MM, Stam A, et al. Widespread and sustained target engagement in Huntington’s disease minipigs upon intrastriatal microRNA-based gene therapy. Sci Transl Med 2021;13:eabb8920.

318. de Almeida LP, Ross CA, Zala D, Aebischer P, Déglon N. Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J Neurosci 2002;22:3473-83.

319. Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D. AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol Ther 2008;16:947-56.

Cite This Article

OAE Style

Novati A, Singer-Mikosch E, Yu-Taeger L, Clemensson E, Nguyen HP. Rat models of major neurodegenerative disorders. Ageing Neur Dis 2022;2:17.

AMA Style

Novati A, Singer-Mikosch E, Yu-Taeger L, Clemensson E, Nguyen HP. Rat models of major neurodegenerative disorders. Ageing and Neurodegenerative Diseases. 2022; 2(4): 17.

Chicago/Turabian Style

Novati, Arianna, Elisabeth Singer-Mikosch, Libo Yu-Taeger, Erik Clemensson, Huu Phuc Nguyen. 2022. "Rat models of major neurodegenerative disorders" Ageing and Neurodegenerative Diseases. 2, no.4: 17.

ACS Style

Novati, A.; Singer-Mikosch E.; Yu-Taeger L.; Clemensson E.; Nguyen HP. Rat models of major neurodegenerative disorders. Ageing. Neur. Dis. 2022, 2, 17.



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