Age-related changes in species-typical behaviours in the 5xFAD mouse model of Alzheimer's disease from 4 to 16 months of age.

Alzheimer's disease (AD) patients show age-related decreases in the ability to perform activities of daily living and the decline in these activities is related to the severity of neurobiological deterioration underlying the disease. The 5xFAD mouse model of AD shows age-related impairments in sensory- motor and cognitive function, but little is known about changes in species-typical behaviours that may model activities of daily living in AD patients. Therefore, we examined species-typical behaviours used as indices of exploration (rearing) and compulsivity (grooming) across six tests of anxiety-like behaviour or motor function in female 5xFAD mice from 3 to 16 months of age. Robust decreases in rearing were found in 5xFAD mice across all tests after 9 months of age, although few differences were observed in grooming. A fine-scale analysis of grooming, however, revealed a previously unresolved and spatially restricted pattern of grooming in 5xFAD mice at 13-16 months of age. We then examined changes in species-typical behaviours in the home-cage, and show impaired nest building in 5xFAD mice at all ages tested. Lastly, we examined the relationship between reduced species typical behaviours in 5xFAD mice and the presentation of freezing behaviour, a commonly used measure of memory for conditioned fear. These results showed that along with cognitive and sensory-motor behaviour, 5xFAD mice have robust age-related impairments in species-typical behaviours. Therefore, species typical behaviours in 5xFAD mice may help to model the decline in activities of daily living observed in AD patients, and may provide useful behavioural phenotypes for evaluating the pre-clinical efficacy of novel therapeutics for AD.

Measuring the replicability of our own research.

In the study of transgenic mouse models of neurodevelopmental and neurodegenerative disorders, we use batteries of tests to measure deficits in behaviour and from the results of these tests, we make inferences about the mental states of the mice that we interpret as deficits in "learning", "memory", "anxiety", "depression", etc. This paper discusses the problems of determining whether a particular transgenic mouse is a valid mouse model of disease X, the problem of background strains, and the question of whether our behavioural tests are measuring what we say they are. The problem of the reliability of results is then discussed: are they replicable between labs and can we replicate our results in our own lab? This involves the study of intra- and inter- experimenter reliability. The variables that influence replicability and the importance of conducting a complete behavioural phenotype: sensory, motor, cognitive and social emotional behaviour are discussed. Then the thorny question of failure to replicate is examined: Is it a curse or a blessing? Finally, the role of failure in research and what it tells us about our research paradigms is examined.

Serial reversal learning in an olfactory discrimination task in 3xTg-AD mice.

Male and female 3xTg-AD mice between 5 and 24 mo of age and their B6129F2/J wild-type controls were tested on a series of 18 olfactory discrimination and reversal tasks in an operant olfactometer. All mice learned the odor discriminations and reversals to a criterion of 85% correct, but the 3xTg-AD mice made fewer errors than the B6129F2/J mice in the odor discriminations and in the first six reversal learning tasks. Many mice showed evidence of near errorless learning, and on the reversal tasks the 3xTg-AD mice showed more instances of near errorless learning than the B6129F2/J mice. There was no evidence of an age effect on odor discrimination, but there was a decrease in errorless reversal learning in aged B6129F2/J mice. In long-term memory tests, there was an increase in the number of errors made but no genotype difference. The high level of performance indicates that the mice were able to develop a "learning to learn" strategy. The finding that the 3xTg-AD mice outperformed their littermate controls provides an example of paradoxical functional facilitation in these mice.

Early postnatal development of the MDGA2+/- mouse model of synaptic dysfunction.

Synaptic dysfunction underlies many neurodevelopmental disorders (NDDs). The membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) regulate synaptic development by modulating neurexin-neuroligin complex formation. Since understanding the neurodevelopmental profile and the sex-based differences in the manifestation of the symptoms of NDDs is important for their early diagnosis, we tested a mouse model haploinsufficient for MDGA2 (MDGA2+/-) on a neurodevelopmental test battery, containing sensory, motor, and cognitive measures, as well as ultrasonic vocalizations. When male and female MDGA2+/- and wildtype (WT) C57BL/6 J mice were examined from 2 to 23 days of age using this test battery, genotype and sex differences in body weight, sensory-motor processes, and ultrasonic vocalizations were observed. The auditory startle reflex appeared earlier in the MDGA2+/- than in WT mice and the MDGA2+/- mice produced fewer ultrasonic vocalizations. The MDGA2+/- mice showed reduced locomotion and rearing than WT mice in the open field after 17 days of age and spent less time investigating a novel object than WT mice at 21 days of age. Female MDGA2+/- mice weighed less than WT females and showed lower grip strength, indicating a delay in sensory-motor development in MDGA2+/- mice, which appears to be more pronounced in females than males. The behavioural phenotypes resulting from MDGA2 haploinsufficiency suggests that it shows delayed development of motor behaviour, grip strength and exploratory behaviour, non-social phenotypes of NDDs.

Alternative splicing and heparan sulfation converge on neurexin-1 to control glutamatergic transmission and autism-related behaviors.

Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain, with over a thousand alternatively spliced forms and further structural heterogeneity contributed by heparan sulfate glycan modification. Yet, interactions between these modes of post-transcriptional and post-translational modification have not been studied. We reveal that these regulatory modes converge on neurexin-1 splice site 5 (S5): the S5 insert increases the number of heparan sulfate chains. This is associated with reduced neurexin-1 protein level and reduced glutamatergic neurotransmitter release. Exclusion of neurexin-1 S5 in mice boosts neurotransmission without altering the AMPA/NMDA ratio and shifts communication and repetitive behavior away from phenotypes associated with autism spectrum disorders. Thus, neurexin-1 S5 acts as a synaptic rheostat to impact behavior through the intersection of RNA processing and glycobiology. These findings position NRXN1 S5 as a potential therapeutic target to restore function in neuropsychiatric disorders.

Noncanonical regulation of imprinted gene Igf2 by amyloid-beta 1-42 in Alzheimer's disease.

Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimer's disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1-42 (Aß42) accumulation and epigenetic regulation of the Igf2/H19 gene cluster in cerebrum, liver, and plasma of young and old male and female 5xFAD mice, in frontal cortex of male and female AD and non-AD patients, and in HEK293 cell cultures. We show IGF2 levels, Igf2 expression, histone acetylation, and H19 ICR methylation are lower in females than males. However, elevated Aß42 levels are associated with Aß42 binding to Igf2 DMR2, increased DNA and histone methylation, and a reduction in Igf2 expression and IGF2 levels in 5xFAD mice and AD patients, independent of H19 ICR methylation. Cell culture results confirmed the binding of Aß42 to Igf2 DMR2 increased DNA and histone methylation, and reduced Igf2 expression. These results indicate an age- and sex-related causal relationship among Aß42 levels, epigenomic state, and Igf2 expression in AD and provide a potential mechanism for Igf2 regulation in normal and pathological conditions, suggesting IGF2 levels may be a useful diagnostic biomarker for Aß42 targeted AD therapies.

Abnormal whisker movements in the 3xTg-AD mouse model of Alzheimer's disease.

Alzheimer's disease is the most frequent form of dementia in elderly people. The triple transgenic (3xTg-AD) mouse model of Alzheimer's Disease is important in biomedical research as these mice develop both neuropathological and behavioural phenotypes. However, their behavioural phenotype is variable, with findings depending on the specific task, as well as the age and sex of the mice. Whisker movements show motor, sensory and cognitive deficits in mouse models of neurodegenerative disease. Therefore, we examined whisker movements in 3, 12.5 and 17-month-old female 3xTg-AD mice and their B6129S/F2 wildtype controls. Mice were filmed using a high-speed video camera (500 fps) in an open arena during a novel object exploration task. Genotype and age differences were found in mice exploring the arena prior to object contact. Prior to whisker contact, the 3-month-old 3xTg-AD mice had smaller whisker angles compared with the wildtype controls, suggesting an early motor phenotype in these mice. Pre-contact mean angular position at 3 months and whisking amplitude at 17 months of age differed between the 3xTg-AD and wildtype mice. During object contact 3xTg-AD mice did not reduce whisker spread as frequently as the wildtype mice at 12.5 and 17 months, which may suggest sensory or attentional deficits. We show that whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes, such as the 3xTg-AD mouse model.

A Signal Detection Analysis of Olfactory Learning in 12-Month-Old 5xFAD Mice.

Although Alzheimer's disease is most often studied in terms of memory impairments, olfactory dysfunction begins in the early stages. We tested olfactory learning, sensitivity, and response bias using signal detection methods in 12-month-old male and female 5xFAD mice and their wildtype controls in the operant olfactometer. Odor detection was not reduced in the 5xFAD mice, but learning was, which was worse in female 5xFAD mice than in males. Female mice were more conservative in their response strategy. Signal detection analysis allows us to discriminate between cognitive and sensory deficits of male and female mouse models of AD.

Visuo-spatial learning and memory impairments in the 5xFAD mouse model of Alzheimer's disease: Effects of age, sex, albinism, and motor impairments.

The 5xFAD mouse model of Alzheimer's disease (AD) rapidly develops AD-related neuro-behavioral pathology. Learning and memory impairments in 5xFAD mice, however, are not always replicated and the size of impairments varies considerably across studies. To examine possible sources of this variability, we analyzed the effects of age, sex, albinism due to background genes (Tyrc , Oca2p ) and motor impairment on learning and memory performance of wild type and 5xFAD mice on the Morris water maze, from 3 to 15 months of age. The 5xFAD mice showed impaired learning at 6-9 months of age, but memory impairments were not detected with the test procedure used in this study. Performance of 5xFAD mice was profoundly impaired at 12-15 months of age, but was accompanied by slower swim speeds than wild-type mice and a frequent failure to locate the escape platform. Overall female mice performed worse than males, and reversal learning impairments in 5xFAD mice were more pronounced in females than males. Albino mice performed worse than pigmented mice, confirming that albinism can impair performance of 5xFAD mice independently of AD-related transgenes. Overall, these results show that 5xFAD mice have impaired learning performance at 6-9 months of age, but learning and memory performance at 12-15 months is confounded with motor impairments. Furthermore, sex and albinism should be controlled to provide an accurate assessment of AD-related transgenes on learning and memory. These results will help reduce variability across pre-clinical experiments with 5xFAD mice, and thus enhance the reliability of studies developing new therapeutics for AD.

Age-related deficits in working memory in 5xFAD mice in the Hebb-Williams maze.

The 5xFAD mouse model of Alzheimer's disease (AD) develops age-related neuropathology and sensory, motor, and cognitive impairments. The purpose of this study was to examine whether age-related changes in motor function affected working memory performance in 5xFAD mice in the Hebb-Williams Maze (HWM). At 6 months of age, the 5xFAD mice performed better than the WT (B6SJL) mice on the accelerating rotarod, but much worse at 12 months of age. The 5xFAD and WT mice did not differ in days to acquisition in the HWM at 6 months of age, but the WT mice took longer at 12 months of age. The number of errors increased with maze difficulty and at 6 months of age, the 5xFAD mice made more errors than the WT mice only on difficult problems. At 12 months of age 5xFAD mice made more errors than WT mice at each level of problem difficulty. The latency to solve the problems was higher for the 5xFAD mice than the WT mice in the difficult problems at 6 months of age and in the intermediate problems at 12 months of age. Although body weight had some effect on rotarod performance, there were no systematic effects of motor deficits on either errors or latency measures in the test trials of the HWM. These results indicate that the 5xFAD mice had deficits in working memory in the HWM and that these deficits were not confounded by impaired motor performance.

The Hebb Synapse Before Hebb: Theories of Synaptic Function in Learning and Memory Before , With a Discussion of the Long-Lost Synaptic Theory of William McDougall.

Since the work of Semon was rediscovered by Schacter in 1978, there has been a renewed interest is searching for the "engram" as the locus of memory in the brain and Hebb's cell assembly has been equated with Semon's engram. There have been many theories of memory involving some concept of synaptic change, culminating in the "Hebb Synapse" theory in 1949. However, Hebb said that the idea that any two cells or systems of cells that are repeatedly active at the same time will tend to become "associated," was not his idea, but an old one. In this manuscript we give an overview of some of the theories of the neural basis of learning and memory before Hebb and describe the synaptic theory of William McDougall, which appears to have been an idea ahead of its time; so far ahead of its time that it was completely ignored by his contemporaries. We conclude by examining some critiques of McDougall's theory of inhibition and with a short discussion on the fate of neuroscientists whose ideas were neglected when first presented but were accepted as important many decades later.

Neuroscience education and research in Cameroon: Current status and future direction.

Neurological disorders comprise 20% of hospital admissions in Cameroon. The burden of neurological disorders is increasing, especially in children and the elderly. However, there are very few neurologists, psychiatrists, gerontologists and neuropsychologists trained in the treatment of neurological disorders in Cameroon and there are very few facilities for training in basic and clinical neuroscience. Although non-governmental organizations such as the International Brain Research Organization (IBRO), International Society of Neurochemistry (ISN), and Teaching and Research in Natural Sciences for Development (TReND) in Africa have stepped in to provide short training courses and workshops in neuroscience, these are neither sufficient to train African neuroscientists nor to build the capacity to train neuroscience researchers and clinicians. There has also been little support from universities and the government for such training. While some participants of these schools have managed to form collaborations with foreign researchers and have been invited to study abroad, this does not facilitate the training of neuroscientists in Cameroon. Moreover, the research infrastructure for training in neuroscience remains limited. This is reflected in the low research output from Cameroonian universities in the field. In this review, we describe the burden of neurological disorders in Cameroon and outline the outstanding efforts of local scientists to develop the discipline of neuroscience, which is still an emerging field in Cameroon. We identify key actionable steps towards the improvement of the scientific capacity in neuroscience in Cameroon: (1) develop targeted neuroscience training programs in all major universities in Cameroon; (2) implement a thriving scientific environment supported by international collaborations; (3) focus on the leadership and the mentorship of both local and senior neuroscientists; (4) develop public awareness and information of policy makers to increase governmental funding for neuroscience research.

Age related weight loss in female 5xFAD mice from 3 to 12 months of age.

In addition to cognitive decline, patients with Alzheimer's disease (AD) exhibit sensory, motor, and neuropsychiatric deficits. Many AD patients also show weight loss, suggesting that AD may involve a metabolic syndrome. The 5xFAD mouse model shows age-related weight loss compared to wildtype controls, and thus may exhibit metabolic dysfunction. This longitudinal study measured age-related weight loss in female 5xFAD and B6SJL/JF2 wild-type mice from 3 to 12 months of age, and examines some of the behavioural and physiological phenotypes in these mice that have been proposed to contribute to this weight loss. Because some mice had to be singly housed during the study, we also examined genotype by housing interactions. The 5xFAD mice weighed less and ate less than WT littermates starting at 6 months of age, exhibited less home cage activity, had higher frailty scores, less white adipose tissue, and lower leptin expression. At 9 and 12 months of age, heavier 5xFAD mice performed better on the rotarod, suggesting that metabolic deficits which begin between 6 and 9 months of age may exacerbate the behavioural deficits in 5xFAD mice. These results indicate that the 5xFAD mouse is a useful model to study the behavioural and metabolic changes in AD.

The effect of background strain on the behavioral phenotypes of the MDGA2+/- mouse model of autism spectrum disorder.

The membrane-associated mucin (MAM) domain containing glycosylphosphatidylinositol anchor 2 protein single knock-out mice (MDGA2+/- ) are models of ASD. We examined the behavioral phenotypes of male and female MDGA2+/- and wildtype mice on C57BL6/NJ and C57BL6/N backgrounds at 2 months of age and measured MDGA2, neuroligin 1 and neuroligin 2 levels at 7 months. Mice on the C57BL6/NJ background performed better than those on the C57BL6/N background in visual ability and in learning and memory performance in the Morris water maze and differed in measures of motor behavior and anxiety. Mice with the MDGA2+/- genotype differed from WT mice in motor, social and repetitive behavior and anxiety, but most of these effects involved interactions between MDGA2+/- genotype and background strain. The background strain also influenced MDGA2 levels and NLGN2 association in MDGA2+/- mice. Our findings emphasize the importance of the background strain used in studies of genetically modified mice.

Polysialylated - neural cell adhesion molecule (PSA-NCAM) promotes recovery of vision after the critical period.

Vision loss has long since been considered irreversible after a critical period; however, there is potential to restore limited vision, even in adulthood. This phenomenon is particularly pronounced following complete loss of vision in the dominant eye. Adult neural cell adhesion molecule (NCAM) knockout mice have an age-related impairment of visual acuity. The underlying cause of early deterioration in visual function remains unknown. Polysialylated (PSA) NCAM is involved in different forms of neural plasticity in the adult brain, raising the possibility that NCAM plays a role in the plasticity of the visual cortex, and therefore, in visual ability. Here, we examined whether PSA-NCAM is required for visual cortical plasticity in adult C57Bl/6J mice following deafferentation and long-term monocular deprivation. Our results show that elevated PSA in the contralateral visual cortex of the reopened eye is accompanied by changes in other markers of neural plasticity: increased brain-derived neurotrophic factor (BDNF) levels and degradation of perineuronal nets (PNNs). The removal of PSA-NCAM in the visual cortex of these mice reduced BDNF expression, decreased PNN degradation, and resulted in impaired recovery of visual acuity after optic nerve transection and chronic monocular deprivation. Collectively, our results demonstrate that PSA-NCAM is necessary for the reactivation of visual cortical plasticity and recovery of visual function in adult mice. It also offers a potential molecular target for the therapeutic treatment of cortically based visual impairments.

Donald O. Hebb and the Organization of Behavior: 17 years in the writing.

The Organization of Behavior has played a significant part in the development of behavioural neuroscience for the last 70 years. This book introduced the concepts of the "Hebb synapse", the "Hebbian cell assembly" and the "Phase sequence". The most frequently cited of these is the Hebb synapse, but the cell assembly may be Hebb's most important contribution. Even after 70 years, Hebb's theory is still relevant because it is a general framework for relating behavior to synaptic organization through the development of neural networks. The Organization of Behavior was Hebb's 40th publication. His first published papers in 1937 were on the innate organization of the visual system and he first used the phrase "the organization of behavior" in 1938. However, Hebb wrote a number of unpublished papers between 1932 and 1945 in which he developed the ideas published in The Organization of Behavior. Thus, the concept of the neural organization of behavior was central to Hebb's thinking from the beginning of his academic career. But his thinking about the organization of behavior in 1949 was different from what it was between 1932 and 1937. This paper examines Hebb's early ideas on the neural basis of behavior and attempts to trace the rather arduous series of steps through which he developed these ideas into the book that was published as The Organization of Behavior. Using the 1946 typescript and Hebb's correspondence we can see a number of changes made in the book before it was published. Finally, a number of issues arising from the book, and the importance of the book today are discussed.

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration.

Active whisking in mice and rats is one of the fastest behaviours known in mammals and is used to guide complex behaviours such as exploration and navigation. During object contact, whisker movements are actively controlled and undergo robust changes in timing, speed and position. This study quantifies whisker movements in 6- to 7-month old male and female 5xFAD mice, and their C57/SJL F1 wild-type (WT) controls. As well as genotype, we examined sex differences and the effects of retinal degeneration (rd). Mice were filmed using a high-speed video camera at 500 frames per second (fps), under infrared light while behaving freely in three tasks: object exploration, sequential object exploration and tunnel running. Measures of whisker position, amplitude, speed and asymmetry were extracted and analysed for each task. The 5xFAD mice had significantly altered whisker angular positions, amplitude and asymmetry during object contacts and female 5xFAD mice with rd had lower mean angular positions during object contact. There were no significant effects of genotype on sequential object exploration or on tunnel running but differences due to sex and rd were found in both tasks, with female mice making larger and faster whisker movements overall, and mice with rd making larger and faster whisker movements during object contact. There were sex differences in whisker movements during sequential object exploration and females with rd had higher whisker retraction speeds in tunnel running. These data show that measuring whisker movements can quantify genotype and sex differences and the effects of rd during exploratory behaviour in these mice.

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.

Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.

BACKGROUND: Previous studies have measured whisker movements and locomotion to characterise mouse models of neurodegenerative disease. However, these studies have always been completed in isolation, and do not involve standardized procedures for comparisons across multiple mouse models and background strains. NEW METHOD: We present a standard method for conducting whisker movement and locomotion studies, by carrying out qualitative scoring and quantitative measurement of whisker movements from high-speed video footage of mouse models of Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, Cerebellar Ataxia, Somatosensory Cortex Development and Ischemic stroke. RESULTS: Sex, background strain, source breeder and genotype all affected whisker movements. All mouse models, apart from Parkinson's disease, revealed differences in whisker movements during locomotion. R6/2 CAG250 Huntington's disease mice had the strongest behavioural phenotype. Robo3R3-5-CKO and RIM-DKOSert mouse models have abnormal somatosensory cortex development and revealed significant changes in whisker movements during object exploration. COMPARISON WITH EXISTING METHOD(S): Our results have good agreement with past studies, which indicates the robustness and reliability of measuring whisking. We recommend that differences in whisker movements of mice with motor deficits can be captured in open field arenas, but that mice with impairments to sensory or cognitive functioning should also be filmed investigating objects. Scoring clips qualitatively before tracking will help to structure later analyses. CONCLUSIONS: Studying whisker movements provides a quantitative measure of sensing, motor control and exploration. However, the effect of background strain, sex and age on whisker movements needs to be better understood.

Review of Franz Joseph Gall: Naturalist of the mind, visionary of the brain.

Reviews the book, Franz Joseph Gall: Naturalist of the Mind, Visionary of the Brain by Stanley Finger and Paul Eling (2019). In this book, Finger and Eling describe the rise and fall of phrenology, or organology, the brainchild of Gall. The authors examine the science of mind and brain in the late-18th and early-19th centuries and contextualize his work as the most advanced scientific approach to the study of brain function of his time. Contrary to the way that he is depicted today, Gall is not presented as a charlatan, a quack, or a fraud. He was a physician with a medical degree, a voracious reader, a man familiar with the developments in science and medicine who wanted to develop a science of mankind based on hard facts that others could confirm (p. 122). This book is a reevaluation of Gall's contributions to the science of mind and brain, psychology, and neuroscience, with a focus on the issue of the cerebral localization of function. It also examines Gall's contributions to psychiatry, criminology, and social reform. (PsycINFO Database Record (c) 2019 APA, all rights reserved).