Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

Progressive olfactory impairment is one of the earliest markers of neurodegeneration. However, the underlying mechanism for this dysfunction remains unclear. The present study investigated the possible role of microgliosis in olfactory deficits using a mouse model of Niemann–Pick disease type C1 (NPC1), which is an incurable neurodegenerative disorder with disrupted lipid trafficking. At 7 weeks of age, NPC1 mutants showed a distinct olfactory impairment in an olfactory test compared with age-matched wild-type controls (WT). The marked loss of olfactory sensory neurons within the NPC1 affected olfactory bulb (NPC1-OB) suggests that NPC1 dysfunction impairs olfactory structure. Furthermore, the pool of neuroblasts in the OB was diminished in NPC1 mice despite the intact proliferative capacity of neural stem/progenitor cells in the subventricular zone. Instead, pro-inflammatory proliferating microglia accumulated extensively in the NPC1-OB as the disease progressed. To evaluate the impact of abnormal microglial activation on olfaction in NPC1 mice, a microglial inhibition study was performed using the anti-inflammatory agent Cyclosporin A (CsA). Importantly, long-term CsA treatment in NPC1 mice reduced reactive microgliosis, restored the survival of newly generated neurons in the OB and improved overall performance on the olfactory test. Therefore, our study highlights the possible role of microglia in the regulation of neuronal turnover in the OB and provides insight into the possible therapeutic applications of microglial inhibition in the attenuation or reversal of olfactory impairment.     

DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase‐β (Polβ) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild‐type and 3xTgAD mice with normal or reduced Polβ levels. Compared to wild‐type control mice, Polβ heterozygous (Polβ^+/?), and 3xTgAD mice, 3xTgAD/Polβ^+/? mice exhibited impaired performance in a buried food test of olfaction. Polβ deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Polβ^+/? and 3xTgAD mice, and by over 60% in the 3xTgAD/Polβ^+/? mice compared to wild‐type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Polβ^+/? mice compared to 3xTgAD mice. Levels of amyloid β‐peptide (Aβ) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Polβ^+/? mice, and cultured Polβ‐deficient neurons exhibited increased vulnerability to Aβ‐induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD.     

Sex Differences in High‐fat Diet‐induced Obesity,Metabolic Alterations and Learning,and Synaptic Plasticity Deficits in Mice

Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high‐fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex‐specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step‐down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open‐field and hot‐plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired‐pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long‐term potentiation (LTP) and long‐term depression (LTD)) were lower at the Schaffer collateral‐CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex‐specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.     

Comparison between touchscreen operant chambers and water maze to detect early prefrontal dysfunction in mice

The relative lack of sensitive and clinically valid tests of rodent behavior might be one of the reasons for the limited success of the clinical translation of preclinical Alzheimer's disease (AD) research findings. There is a general interest in innovative behavioral methodology, and protocols have been proposed for touchscreen operant chambers that might be superior to existing cognitive assessment methods. We assessed and analyzed touchscreen performance in several novel ways to examine the possible occurrence of early signs of prefrontal (PFC) functional decline in the APP/PS1 mouse model of AD. Touchscreen learning performance was compared between APP/PS1-21 mice and wildtype littermates on a C57BL/6J background at 3, 6 and 12 months of age in parallel to the assessment of spatial learning, memory and cognitive flexibility in the Morris water maze (MWM). We found that older mice generally needed more training sessions to complete the touchscreen protocol than younger ones. Older mice also displayed defects in MWM working memory performance, but touchscreen protocols detected functional changes beginning at 3 months of age. Histological changes in PFC of APP/PS1 mice indeed occurred as early as 3 months. Our results suggest that touchscreen operant protocols are more sensitive to PFC dysfunction, which is of relevance to the use of these tasks and devices in preclinical AD research and experimental pharmacology.     

Motor-Coordination-Dependent Learning,More than Others,Is Impaired in Transgenic Mice Expressing Pseudorabies Virus Immediate-Early Protein IE180

The cerebellum in transgenic mice expressing pseudorabies virus immediate-early protein IE180 (TgIE96) was substantially diminished in size, and its histoarchitecture was severely disorganized, resulting in severe ataxia. TgIE96 mice can therefore be used as an experimental model to study the involvement of cerebellar circuits in different learning tasks. The performance of three-month-old TgIE96 mice was studied in various behavioral tests, including associative learning (classical eyeblink conditioning), object recognition, spatial orientation (water maze), startle response and prepulse inhibition, and passive avoidance, and compared with that of wild-type mice. Wild-type and TgIE96 mice presented similar reflexively evoked eyeblinks, and acquired classical conditioned eyelid responses with similar learning curves for both trace and delay conditioning paradigms. The two groups of mice also had similar performances during the object recognition test. However, they showed significant differences for the other three tests included in this study. Although both groups of animals were capable of swimming, TgIE96 mice failed to learn the water maze task during the allowed time. The startle response to a severe tone was similar in both control and TgIE96 mice, but the latter were unable to produce a significant prepulse inhibition. TgIE96 mice also presented evident deficits for the proper accomplishment of a passive avoidance test. These results suggest that the cerebellum is not indispensable for the performance of classical eyeblink conditioning and for object recognition tasks, but seems to be necessary for the proper performance of water maze, prepulse inhibition, and passive avoidance tests.     

A mini review: Tau transgenic mouse models and olfactory dysfunction in Alzheimer's Disease

Alzheimer's Disease(AD) is a chronic neurodegenerative disease that usually takes many years from preclinical phase to prodromal phase characterized by mild symptoms before the onset of dementia. Once diagnosed with AD, the brain is already severely damaged and the disease will process quickly to the most severe stages since there is no medications that reverse the neuronal injuries in the brain. Thus, simple, inexpensive, and widely available methods for detecting potential AD patients during their preclinical phases are urgently needed. In such case, olfactory testing may offer a chance for early diagnosis of AD. However, there are limitations in these olfactory tests due to the complexity of the brain areas it extends to and the frequently olfactory fatigue occurred in the behavioral olfactory tests. Great efforts have been done epidemiologically to investigate the correlation between olfactory functions and possibility of developing AD. Different patterns of olfactory dysfunction have been found in AD at early stages and even mild cognitive impairment(MIC), but the cause of the dysfunction remained unclear. Various kinds of AD animal models have been used in the field to clarify the existence of olfactory dysfunctions and thus study the underling mechanism of the dysfunction. In this review we discuss(1) the function of Tau physiologically and pathologically;(2) the genetic background and biological characteristics of the most commonly used Tau transgenic mice;(3) the structural and molecule basis of olfaction;(4) the possible relationship between Tau pathology and olfactory dysfunction. Finally, we suggest that the tau transgenic mouse models may be helpful in studying the possible mechanisms of the dysfunction.     

Testosterone levels and cognitive functioning in women with polycystic ovary syndrome and in healthy young women

We investigated the possible influence of testosterone (T) on cognitive functioning in women with polycystic ovary syndrome (PCOS), an endocrine disorder associated with elevated levels of free testosterone (free T). Performance on a battery of neuropsychological tests in 29 women with elevated free T levels due to PCOS was compared to the performance of 22 age- and education-matched, healthy control women with free T levels in the normal female range. Women with PCOS had significantly higher levels of free T (estimated by the free androgen index) and demonstrated significantly worse performance on tests of verbal fluency, verbal memory, manual dexterity, and visuospatial working memory than the healthy control women. No differences between the groups were found on tests of mental rotation, spatial visualization, spatial perception, or perceptual speed. These results suggest that, in women, elevations in free T may be associated with poorer performance on cognitive tasks that tend to show a female advantage.     

Long-term individual housing in C57BL/6J and DBA/2 mice: assessment of behavioral consequences

The aim of the present study was to investigate the effects of individual housing on mouse behavior. The male mice of the C57BL/6J and DBA/2 strains were separated at the age of 4 weeks and kept in individual housing for 7 weeks until behavioral testing began. Their behavior was compared to the group-housed mice in a battery of tests during the following 7 weeks. The single-housed mice were hyperactive and displayed reduced habituation in the tests assessing activity and exploration. Reduced anxiety was established in the elevated plus-maze, but an opposite effect was observed in the dark-light (DL) and hyponeophagia tests. Immobility in the forced swimming test was reduced by social isolation. The DBA mice displayed higher anxiety-like behavior than the B6 mice in the plus-maze and DL exploration test, but hyponeophagia was reduced in the DBA mice. Moreover, all effects of individual housing on the exploratory and emotional behavior were more evident in the DBA than in the B6 mice. Novel object recognition and fear conditioning (FC) were significantly impaired in the single-housed mice, whereas water-maze (WM) learning was not affected. Marked strain differences were established in all three learning tests. The B6 mice performed better in the object recognition and FC tasks. Initial spatial learning in the WM was faster and memory retention slightly enhanced in the B6 mice. The DBA mice displayed lower preference to the new and enhanced preference to the old platform location than the B6 mice after reversal learning in the WM. We conclude that individual housing has strong strain- and test-specific effects on emotional behavior and impairs memory in certain tasks.     

Visuospatial Function in Early Alzheimer’s Disease—The Use of the Visual Object and Space Perception (VOSP) Battery

Alzheimer’s disease (AD) is the most frequent cause of dementia. The clinical symptoms of AD begin with impairment of memory and executive function followed by the gradual involvement of other functions, such as language, semantic knowledge, abstract thinking, attention, and visuospatial abilities. Visuospatial function involves the identification of a stimulus and its location and can be impaired at the beginning of AD. The Visual Object and Space Perception (VOSP) battery evaluates visuospatial function, while minimizing the interference of other cognitive functions.

Objectives

To evaluate visuospatial function in early AD patients using the VOSP and determine cutoff scores to differentiate between cognitively healthy individuals and AD patients.

Methods

Thirty-one patients with mild AD and forty-four healthy elderly were evaluated using a neuropsychological battery and the VOSP.

Results

In the VOSP, the AD patients performed more poorly in all subtests examining object perception and in two subtests examining space perception (Number Location and Cube Analysis). The VOSP showed good accuracy and good correlation with tests measuring visuospatial function.

Conclusion

Visuospatial function is impaired in the early stages of AD. The VOSP battery is a sensitive battery test for visuospatial deficits with minimal interference by other cognitive functions.     

Olfactory Functions in Parkinson's Disease and Alzheimer's Disease

The aim of this investigation was to compare olfactory functionsof patients suffering from Parkinson's disease (PD) and Alzheimer'sdisease (AD). Olfactory threshold, odor identification abilityand odor memory performance were assessed in 21 non-dementedPD patients and in 22 AD patients. Both patient groups wereimpaired in relation to an age-matched control group for themeasure of odor identification. AD patients showed a higherolfactory threshold and poorer odor memory performance. ChemSenses 22: 105–110, 1997.     

ApoB100/LDLR-/- hypercholesterolaemic mice as a model for mild cognitive impairment and neuronal damage

Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD). Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions) concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing) and impairment of the episodic-like memory (determined by the integrated memory test). This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.     

Working memory impairment in a transgenic amyloid precursor protein TgCRND8 mouse model of Alzheimer's disease

The most profound deficits observed in Alzheimer's disease (AD) are in domains of episodic and working memory systems. Transgenic (Tg) mice expressing mutated human amyloid precursor protein (APP) genes offer a model to study the effect of AD pathology on cognition. We reported previously that APP TgCRND8 mice showed deficits in a reference and working memory evaluated in a Morris water-maze test. In this study, we evaluated the working memory of TgCRND8 mice comparing two training paradigms in a six-arm radial water maze. In the first paradigm, the exploration of the maze was constrained, forcing the mice to use a spatial mapping strategy. In the second paradigm, mice were unconstrained in their exploration of the maze. TgCRND8 mice proved to be significantly impaired in spatial working memory in both paradigms as compared with their non-transgenic littermates. The analysis of data revealed that forcing mice to use a spatial strategy during training caused only a moderate improvement in the performance of all mice. However, unconstrained exploration of the maze not only resulted in a fast learning in control mice, but also facilitated the development of a chaining strategy in spatially impaired TgCRND8 mice. In conclusion, TgCRND8 mice showed impairment in spatial working memory but retained a plasticity to choose alternative search strategies.     

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

Apolipoprotein E4 (apoE4) allele is the major genetic risk factor for sporadic Alzheimer disease (AD) due to the higher prevalence and earlier onset of AD in apoE4 carriers. Accumulating data suggest that the interaction between the N- and the C-terminal domains in the protein may be the main pathologic feature of apoE4. To test this hypothesis, we used Arg-61 mice, a model of apoE4 domain interaction, by introducing the domain interaction feature of human apoE4 into native mouse apoE. We carried out hippocampus-dependent learning and memory tests and related cellular and molecular assays on 12- and 3-month-old Arg-61 and age-matched background C57BL/6J mice. Learning and memory task performance were impaired in Arg-61 mice at both old and young ages compared with C57BL/6J mice. Surprisingly, young Arg-61 mice had more mitotic doublecortin-positive cells in the subgranular zone; mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB were also higher in 3-month-old Arg-61 hippocampus compared with C57BL/6J mice. These early-age neurotrophic and neurogenic (proliferative) effects in the Arg-61 mouse may be an inadequate compensatory but eventually detrimental attempt by the system to “repair” itself. This is supported by the higher cleaved caspase-3 levels in the young animals that not only persisted, but increased in old age, and the lower levels of doublecortin at old age in the hippocampus of Arg-61 mice. These results are consistent with human apoE4-dependent cognitive and neuro-pathologic changes, supporting the principal role of domain interaction in the pathologic effect of apoE4. Domain interaction is, therefore, a viable therapeutic/prophylactic target for cognitive impairment and AD in apoE4 subjects.     

Strain differences in activity and emotionality do not account for differences in learning and memory performance between C57BL/6 and DBA/2 mice

This study examined emotionality, activity, learning and memory, as well as the influence of emotionality and activity on learning and memory performance in C57BL/6 and DBA/2 mice using a mouse-test battery. DBA/2 mice performed more poorly than C57BL/6 mice in complex learning tasks such as the water maze and object recognition tasks. In contrast, C57BL/6 mice showed attenuated habituation to novelty in the open field apparatus and poorer performance in the step-down passive avoidance task. The C57BL/6 mice were less exploratory and more anxious than the DBA/2 mice. The anxiety score (open arm entries in the elevated plus maze) was significantly correlated with all measures of learning and memory in the object recognition task, and some measures in the passive avoidance and water maze tasks. Analysis of covariance (with open arm entries as a covariate) revealed that some measures on trial 1 of the object recognition task, but not the memory scores on trial 2, were confounded by anxiety. No confounding factors of anxiety were found in the water maze or passive avoidance tasks. Similar results were obtained with the activity scores (line crossing and rearing in the open field). In conclusion, strain differences in activity and anxiety did not account for strain differences in learning and memory performance of C57BL/6 and DBA/2 mice. Nonetheless, the importance of using complete behavioural test batteries should be stressed to ensure that strain differences in learning and memory tasks are not confounded by non-cognitive factors.     

Analysis of sensory, motor and cognitive functions of the coloboma (C3Sn.Cg-Cm/J) mutant mouse

The coloboma mutant mouse (C3Sn.Cg-Cm/J) has been proposed as an animal model of attention-deficit hyperactivity disorder (ADHD) because of excessive locomotion in the open field, yet few studies have looked at other behavioral measures in these mice. We analyzed activity levels of male and female Cm mice and their littermate controls (C3H) in two different types of open field, as well as their hearing (acoustic startle) and sensorimotor gating (prepulse inhibition), pain responsiveness (tail flick and hot plate), motor control (balance beam), motor learning (Rotarod), hippocampal working memory (spontaneous alternation in a Y-maze) and olfactory learning and memory (conditioned odor preference). We found hyperactivity and a lack of habituation in the small and large open fields and a deficit in prepulse inhibition in these mice, as well as a learning deficit in male Cm mice in conditioned odor preference but no deficits in pain perception or spontaneous alternation. Results from the rotarod and balance beam tasks indicate that Cm mice have severe motor co-ordination and balance problems compared to their C3H littermates, suggesting that Cm mice may be a more suitable model of ataxia than ADHD.     

Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice

Olfactory bulbectomized (OBX) mice showed significant impairment of learning and memory-related behaviors 14 days after olfactory bulbectomy, as measured by passive avoidance and Y-maze tasks. We here observed a large impairment of hippocampal long-term potentiation (LTP) in the OBX mice. Concomitant with decreased acetylcholinesterase expression, protein kinase C (PKC)alpha autophosphorylation and NR1(Ser-896) phosphorylation significantly decreased in the hippocampal CA1 region of OBX mice. Both PKCalpha and NR1(Ser-896) phosphorylation significantly increased following LTP in the control mice, whereas increases were not observed in OBX mice. Like PKC activities, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in the hippocampal CA1 region of OBX mice as compared with that of control mice. In addition, increased CaMKII autophosphorylation following LTP was not observed in OBX mice. Finally, the impairment of CaMKII autophosphorylation was closely associated with reduced pGluR1(Ser-831) phosphorylation, without change in synapsin I (site 3) phosphorylation in the hippocampal CA1 region of OBX mice. Taken together, in OBX mice NMDA receptor hypofunction, possibly through decreased PKCalpha activity, underlies decreased CaMKII activity in the post-synaptic regions, thereby impairing LTP induction in the hippocampal CA1 region. Both decreased PKC and CaMKII activities with concomitant LTP impairment account for the learning disability observed in OBX mice.     

Correlation between a learning disorder and elevated brain-reactive antibodies in aged C57BL/6 and young NZB mice

Previous studies have indicated an increase in brain-reactive antibodies (BRA) in sera of aging mammals and an autoimmune disorder underlying senescence has been suggested. Since New Zealand Black (NZB) mice have a shorter lifespan and greater propensity for autoimmune diseases than C57BL/6 mice, various age groups from both strains of mice were investigated for simultaneous occurrence of BRA serum titer and deficits in learning. NZB mice exhibited a marked learning deficit as well as higher BRA levels at all ages. C57BL/6 mice showed increased BRA and a learning deficit only at advanced ages. The findings of "precocious" BRA titers along with marked learning deficits, both occurring at young ages in NZB mice and both similar to defects seen in the normal mice at senescence and in patients with senile-dementia, suggest that NZB mice may serve as a useful animal model of pre-senile dementia.     

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf ^im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf ^im on motor function, suggesting that Dysf ^im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.     

Olfaction in Three Genetic and Two MPTP-Induced Parkinson’s Disease Mouse Models

Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson’s disease (PD) mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs) and an olfactory behavior test (cookie-finding test). We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated α-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated α-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium.     

Cognitive Dysfunction Precedes the Onset of Motor Symptoms in the MitoPark Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by progressive loss of dopamine neurons, leading to loss of motor coordination. However, PD is associated with a high rate of non-motor neuropsychiatric comorbities that often develop before the onset of movement symptoms. The MitoPark transgenic mouse model is the first to recapitulate the cardinal clinical features, namely progressive neurodegeneration and death of neurons, loss of motor function and therapeutic response to L-DOPA. To investigate whether MitoPark mice exhibit early onset of cognitive impairment, a non-motor neuropsychiatric comorbidity, we measured performance on a spatial learning and memory task before (∼8 weeks) or after (∼20 weeks) the onset of locomotor decline in MitoPark mice or in littermate controls. Consistent with previous studies, we established that a progressive loss of spontaneous locomotor activity began at 12 weeks of age, which was followed by progressive loss of body weight beginning at 16–20 weeks. Spatial learning and memory was measured using the Barnes Maze. By 20 weeks of age, MitoPark mice displayed a substantial reduction in overall locomotor activity that impaired their ability to perform the task. However, in the 8-week-old mice, locomotor activity was no different between genotypes, yet MitoPark mice took longer, traveled further and committed more errors than same age control mice, while learning to successfully navigate the maze. The modest between-day learning deficit of MitoPark mice was characterized by impaired within-day learning during the first two days of testing. No difference was observed between genotypes during probe trials conducted one or twelve days after the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited impaired novel object recognition when compared to control mice. Together, these data establish that mild cognitive impairment precedes the loss of motor function in a novel rodent model of PD, which may provide unique opportunities for therapeutic development.