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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.

We investigated interval timing behavior of 10-month-old male and female 3xTg-AD mice compared with their B6129F2/J wild type controls using the peak interval procedure with a 15 s target interval. Multiple parameters reflecting different aspects of timing performance were extracted from steady-state anticipatory nose-poking behavior using two different approaches: single trial analyses and average response curve analyses. These measures can dissociate the differences in performance due to distortions in the interval timing ability or to motivational decline (i.e. apathy); both of which have been reported in Alzheimer patients. We found that the interval timing ability of male and female 3xTg-AD mice did not differ from wild-type controls. However, in measures reflecting motivational state, we found significant sex differences regardless of genotype. Specifically, female mice initiated anticipatory responding later in the trial and had lower response amplitudes than males. Although our findings can also be interpreted in terms of differences in temporal control for response initiation, they more strongly suggest the effect of differential incentive motivation between sexes on timing behavior in these mice.

The membrane-associated mucin (MAM) domain containing glycosylphosphatidylinositol anchor 2 protein single knock-out mice (MDGA2

The APPswe/PS1dE9 mouse (line 85) is a double transgenic model of Alzheimer's disease (AD) with familial amyloid precursor protein and presenilin-1 mutations. These mice develop age-related behavioral changes reflective of the neuropsychiatric symptoms (altered anxiety-like behaviour, hyperactivity) and cognitive dysfunction (impaired learning and memory) observed in AD. The APPswe/PS1dE9 mouse has been used to examine the efficacy of therapeutic interventions on behaviour, despite previous difficulties in replicating behavioural phenotypes. Therefore, the purpose of this study was to establish the reliability of these phenotypes by further characterizing the behaviour of male APPswe/PS1dE9 and wild-type mice between 7 and 14 months of age. Mice were tested on the open-field over 5-days to examine emotionality, locomotor activity and inter-session habituation. Mice were also tested on the repeated-reversal water maze task and spontaneous alternation on the Y-maze to assess working memory. Sensori-motor gating was examined with acoustic startle and pre-pulse inhibition. Lastly contextual and cued (trace) memory was assessed with fear conditioning. The results show that among non-cognitive behaviours, APPswe/PS1dE9 mice have normal locomotor activity, anxiety-like behavior, habituation and sensori-motor gating. However, APPswe/PS1dE9 mice show impaired working memory on the repeated-reversal water-maze and impaired memory in contextual but not trace-cued fear conditioning. These results indicate that the APPswe/PS1dE9 (line 85) mice have deficits in some types of hippocampal-dependent learning and memory and, at the ages tested, APPswe/PS1dE9 mice model cognitive dysfunction but not neuropsychiatric symptoms.

Spatial navigation is a universal behavior that varies depending on goals, experience and available sensory stimuli. Spatial navigational tasks are routinely used to study learning, memory and goal-directed behavior, in both animals and humans. One popular paradigm for testing spatial memory is the Morris water maze, where subjects learn the location of a hidden platform that offers escape from a pool of water. Researchers typically express learning as a function of the latency to escape, though this reveals little about the underlying navigational strategies. Recently, a number of studies have begun to classify water maze search strategies in order to clarify the precise spatial and mnemonic functions of different brain regions, and to identify which aspects of spatial memory are disrupted in disease models. However, despite their usefulness, strategy analyses have not been widely adopted due to the lack of software to automate analyses. To address this need we developed Pathfinder, an open source application for analyzing spatial navigation behaviors. In a representative dataset, we show that Pathfinder effectively characterizes the development of highly-specific spatial search strategies as male and female mice learn a standard spatial water maze. Pathfinder can read data files from commercially- and freely-available software packages, is optimized for classifying search strategies in water maze paradigms, but can also be used to analyze 2D navigation by other species, and in other tasks, as long as timestamped xy coordinates are available. Pathfinder is simple to use, can automatically determine pool and platform geometry, generates heat maps, analyzes navigation with respect to multiple goal locations, and can be updated to accommodate future developments in spatial behavioral analyses. Given these features, Pathfinder may be a useful tool for studying how navigational strategies are regulated by the environment, depend on specific neural circuits, and are altered by pathology.

The 3xTg-AD mouse model of Alzheimer's disease (AD) has both amyloid beta plaque and tau tangle pathology. However, the results of behavioural testing with these mice have been inconsistent due to age- and sex-related differences, as well as differences in the difficulty of the tests used to measure cognitive function. In order to better understand the sex- and age-related spatial working memory deficits in the 3xTg-AD mice compared to their B6129S/F2 wildtype controls, we tested 4 and 7-month-old males and females and 13-month-old females in the Hebb-Williams maze. In the acquisition phase, the 3xTg-AD mice performed better than the WT controls, but the females of both genotypes showed motivational deficits; often returning to the start box and not eating the food reward, thus taking longer than males to meet the criterion for acquisition. The 3xTg-AD mice showed more working memory deficits than WT mice during the test phase, and the difference increased as the problems increased in difficulty. The results of this study indicate that female 3xTg-AD mice may have motivational deficits in tests using food reward and that the cognitive deficits of the 3xTg-AD mice are not apparent when the tests are too easy; the more difficult the task, the more deficits are shown in the 3xTg-AD mice compared to WT controls. Thus, the inconsistency in previous results may result from differences in motivation and in test difficulty and these must be considered when evaluating cognitive deficits in the 3xTg-AD mice.

The neural cell adhesion molecule (NCAM) is involved in developmental processes and age-associated cognitive decline; however, little is known concerning the effects of NCAM in the visual system during aging. Using anatomical, electrophysiological, and behavioral assays, we analyzed age-related changes in visual function of NCAM deficient (−/−) and wild-type mice. Anatomical analyses indicated that aging NCAM −/− mice had fewer retinal ganglion cells, thinner retinas, and fewer photoreceptor cell layers than age-matched controls. Electroretinogram testing of retinal function in young adult NCAM −/− mice showed a 2-fold increase in a- and b-wave amplitude compared with wild-type mice, but the retinal activity dropped dramatically to control levels when the animals reached 10 months. In behavioral tasks, NCAM −/− mice had no visual pattern discrimination ability and showed premature loss of vision as they aged. Together, these findings demonstrate that NCAM plays significant roles in the adult visual system in establishing normal retinal anatomy, physiology and function, and in maintaining vision during aging.

Deficits in odor identification and detection are early symptoms of Alzheimer's disease (AD). Two transgenic mouse models of AD, the 5XFAD and the 3×Tg-AD mice and their wildtype controls, were assessed for olfactory detection with decreasing concentrations of ethyl acetate in a go no-go operant olfactometer task at 6 months of age. For both the 5XFAD and their B6SJLF1 wildtype littermates, females made fewer errors in detecting the ethyl acetate than males on all but the lowest odor concentrations. Female 5XFAD mice performed slightly better than their female wildtype littermates on the higher odor concentrations, though not at the lowest concentration. The 3×Tg-AD females showed decreased olfactory detection compared with their wildtype B6129S1 controls, whereas there was no difference in the males. Therefore, although the 5XFAD mice showed no olfactory detection deficits, female 3×Tg-AD mice had impaired olfactory detection at low odor concentrations but males did not. This difference in odor detection should be considered in studies of olfactory learning and memory, as differences in performance may be due to sensory rather than cognitive factors, though detection seems unimpaired at high odor concentrations.

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.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that causes profound cognitive dysfunction. Deficits in olfactory memory occur in early stages of AD and may be useful in AD diagnosis. The 5xFAD mouse is a commonly used model of AD, as it develops neuropathology, cognitive and sensori-motor dysfunctions similar to those seen in AD. However, olfactory memory dysfunction has not been studied adequately or in detail in 5xFAD mice. Furthermore, despite sex differences in AD prevalence and symptom presentation, few studies using 5xFAD mice have examined sex differences in learning and memory. Therefore, we tested olfactory memory in male and female 5xFAD mice from 3 to 15 months of age using a conditioned odour preference task. Olfactory memory was not impaired in male or female 5xFAD mice at any age tested, nor were there any sex differences. Because early-onset impairments in very long-term (remote) memory have been reported in 5xFAD mice, we trained a group of mice at 3 months of age and tested olfactory memory 90 days later. Very long-term olfactory memory in 5xFAD mice was not impaired, nor was their ability to perform the discrimination task with new odourants. Examination of brains from 5xFAD mice confirmed extensive Aβ-plaque deposition spanning the olfactory memory system, including the olfactory bulb, hippocampus, amygdala and piriform cortex. Overall this study indicates that male and female 5xFAD mice do not develop olfactory memory deficits, despite extensive Aβ deposition within the olfactory-memory regions of the brain.

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.

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.

Motor deficits are some of the most prevalent non-cognitive symptoms of Alzheimer's disease (AD) with patients showing impairments in speech, gait and fine motor skills. We investigated motor behaviour in 16-month-old male and female 3xTg-AD mice and their B6129SF2 wildtype (WT) controls. The 3xTg-AD mice develop extracellular Aβ plaques and tau tangles in the hippocampus and motor cortex between 6 and 9 months of age. Previously we showed that at 6 months of age, 3xTg-AD mice performed better on tests of motor coordination and motor learning than WT mice. The aim of our experiment was to use a battery of motor behaviour tests to determine if this superior motor performance was present in older mice. On the Rotarod, the aged 3xTg-AD mice showed better motor coordination and learning than WT mice. Although females performed better than males, this sex difference was confounded by body weight as females weighed less than males. There were no significant genotype or sex differences on the wire hang or grid suspension tasks, nor in stride length or stride width, but 3xTg-AD mice performed worse than WT mice on the balance beam. In comparison to the 6-month-old mice, an age-related decline in most aspects of motor behaviour was apparent. These results indicate that different sub-domains of motor function are affected differently in the 3xTg-AD mice and that aging does not have the same effect on all motor behaviours.

The lifespan of mice shows genotype, sex and laboratory effects, but little is known about genotype or sex differences in life expectancy of mouse models of Alzheimer's disease (AD). This paper examines the lifespan of males and females of different mouse models of AD and their wildtype strains. Genotype and sex dependent differences in longevity have important implications for designing experiments with Alzheimer's mouse models, comparing genotype and sex differences in aging mouse models, designing drug treatment regimes and the translation of mouse data to human clinical studies. We conclude that the concept of aging and age-related disorders in mice must be reconsidered based on genotype and sex differences in mouse life expectancy data. Use of concepts such as relative age, prospective lifespan and proportion of lifespan remaining should be included in studies of age-related changes in mouse brains and behavior. Finally, measures such as the Frailty Index, which is independent of chronological age might be used to determine a common scale of aging for all mouse strains.

The 3xTg-AD mouse has high validity as a model of Alzheimer's disease (AD) because it develops both amyloid beta plaques and neurofibrillary tangles. Human patients with AD typically develop motor deficits, which worsen as the disease progresses, but 3xTg-AD mice have been reported to show enhanced motor abilities. We investigated the motor behaviour phenotype of male and female 3xTg-AD and B6129SF2 wildtype mice on a battery of motor behaviours at 6 months of age. Compared to wildtype mice, the 3xTg-AD mice had enhanced motor performance on the Rotarod, but worse performance on the grid suspension task. In gait analysis 3xTg-AD mice had a longer stride length and made more foot slips on the balance beam than wildtype mice. There was no overall difference in voluntary wheel-running activity between genotypes, but there was a disruption in circadian activity rhythm in 3xTg-AD mice. In some motor tasks, such as the Rotarod and balance beam, females appeared to perform better than males, but this sex differences was accounted for by differences in body weight. Our results indicate that while the 3xTg-AD mice show enhanced performance on the Rotarod, they have poorer performance on other motor behaviour tasks, indicating that their motor behaviour phenotype is more complex than previously reported. The presence of the P301L transgene may explain the enhancement of Rotarod performance but the poorer performance on other motor behaviour tasks may be due to other transgenes.

Visual impairments and retinal abnormalities occur in patients with Alzheimer's disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1-18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

Brain glucose hypometabolism has been observed in Alzheimer’s disease (AD) patients, and is detected with 18 F radiolabelled glucose, using positron emission tomography. A pathological hallmark of AD is deposition of brain β - amyloid plaques that may influence cerebral glucose metabolism. The five times familial AD (5XFAD) mouse is a model of brain amyloidosis exhibiting AD-like phenotypes. This study examines brain β -amyloid plaque deposition and 18 FDG uptake, to search for an early biomarker distinguishing 5XFAD from wild-type mice. Thus, brain 18 FDG uptake and plaque deposition was studied in these mice at age 2, 5 and 13 months. The 5XFAD mice demonstrated significantly reduced brain 18 FDG uptake at 13 months relative to wild-type controls but not in younger mice, despite substantial β - amyloid plaque deposition. However, by comparing the ratio of uptake values for glucose in different regions in the same brain, 5XFAD mice could be distinguished from controls at age 2 months. This method of measuring altered glucose metabolism may represent an early biomarker for the progression of amyloid deposition in the brain. We conclude that brain 18 FDG uptake can be a sensitive biomarker for early detection of abnormal metabolism in the 5XFAD mouse when alternative relative uptake values are utilized.

We examined measures of locomotor and anxiety-like behavior in male and female mice of 15 inbred strains on the elevated-plus maze, light/dark transition box and open field. Strain differences were found on all measures of locomotor activity and anxiety. Strain means for measures of locomotor activity on the three apparatus were significantly correlated, but strain means for commonly used measures of anxiety were not correlated. Principal component analysis revealed a common locomotor activity factor, which accounted for 28.6 % of the variance, but no common anxiety factor. Species-typical behaviors (defecations, stretch-attend postures, grooming) accounted for smaller proportions (

Most antipsychotics interfere with the dopaminergic system, resulting in extrapyramidal effects. This study compared the extrapyramidal effects of chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res), used as antipsychotics, in mice. Ninety age-matched male CD-1 strain of mice (25–33 g body weight) were divided into 3 groups, each consisting of 5 subgroups (n = 6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) was administered 30 min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6 mg/kg, i.p.) were administered 24 h before testing. Locomotor behaviour (open field test) and motor coordination (acceleratory rotarod) were assessed. Mice were also observed for 10 min for tremor and vacuous chewing movement (VCM). CPZ and Res dose-dependently decreased locomotor behaviour and impaired motor coordination (p < 0.01). RV also decreased locomotor behaviour (4.0 mg/kg; p < 0.05) but had minimal effect on motor coordination. VCM was lower in the RV group (0.17 ± 0.16/10 min) than the Res (6.8 ± 1.36/10 min) and Cpz groups (7.83 ± 1.95/10 min): F(4,25) = 10.703; p < 0.01. The frequency of bouts of tremor was also lower in the RV group (1.17 ± 0.72/10 min) than the Res (21.2 ± 5.63/10 min) and Cpz (7.83 ± 1.59/10 min) groups: F(4,25) = 11.012; p < 0.001. The root bark extract of R. vomitoria, therefore, has great potential in the management of psychotic disorders.

The Barnes maze is a visuo-spatial learning and memory test originally designed for use with rats, and later adapted for use with mice. The Barnes maze design and test procedure vary across studies using mice, but the effects of variation in Barnes maze design and test procedure on learning and memory in mice have not yet been investigated. Therefore the present experiment investigates whether test procedures, such as the number of habituation trials and parameters of the probe trial (correct zone size and trial length) influence learning and memory performance on three Barnes maze designs that differed in size and the presence of a wall with intra-maze visual cues. Performance was compared across the three mazes to determine how apparatus design influences visuo-spatial cue use. The number of habituation trials and parameters of the probe trial had small effects on learning and memory performance. Apparatus design, had little effect on acquisition performance but had a significant effect on memory performance. Mice on a maze with a small diameter, external wall and intra-maze visual cues had very poor visuo-spatial memory relative to mice tested on small and large diameter mazes without a wall or intra-maze visual cues. Assessment of visuo-spatial cue use indicated that mice do not rely on visuo-spatial cues to locate the escape hole on the small-diameter maze with a wall and intra-maze visual cues, but show reliable visuo-spatial cue use on small or large diameter mazes with no wall. These results indicate that apparatus design influences search strategy use and memory performance on the Barnes maze, and that including a wall around the edge of the Barnes maze decreases visuo-spatial cue use.

Semaphorin 5A (Sema5A) expression is reduced in the brain of individuals with autism, thus mice with reduced Sema5A levels may serve as a model of this neurodevelopmental disorder. We tested male and female Sema5a knockout mice (B6.129P2SEMA5A()™(1DGEN)/J) and C57BL/6J controls for emotionality, visual ability, prepulse inhibition, motor learning and cognition. Overall, there were only two genotype differences in emotionality: Sema5a mutant mice had more stretch-attend postures in the elevated plus-maze and more defecations in the open field. All mice could see, but Sema5a mice had better visual ability than C57BL/6J mice. There were no genotype differences in sensory-motor gating. Sema5a mice showed higher levels of activity in the elevated plus-maze and light/dark transition box, and there were sex by genotype differences in the Rotarod, suggesting a sex difference in balance and coordination differentially affected by Sema5a. There were no genotype effects on cognition: Sema5a mice did not differ from C57BL/6J in the Morris water maze, set-shifting or cued and contextual fear conditioning. In the social recognition test, all mice preferred social stimuli, but there was no preference for social novelty, thus the Sema5A mice do not have a deficit in social behavior. Overall, there were a number of sex differences, with females showing greater activity and males performing better in tests of spatial learning and memory, but no deficits in the behavior of Sema5A mice. We conclude that the Sema5a mice do not meet the behavioral criteria for a mouse model of autism.

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.

Aim of the study Since remedies for mental disorders have been sought through both orthodox and traditional medicine this study compared the effects of the antipsychotic, chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res) in mice. Materials and methods Ninety male CD-1 strain of mice (75–80 days old; 30–34 g body weight) were divided into 3 major groups and each consisting 5 subgroups (n = 6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.), was administered 30 min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6 mg/kg, i.p.) were administered 24 h before testing. The open field test was used to assess locomotor and exploratory behaviour, acceleratory rotarod for motor coordination, light/dark box for anxiety. Results CPZ dose-dependently decreased locomotor and exploration behaviour and impaired motor coordination (p

This paper reviews the current work on mouse genetics, brain, and behaviour in my laboratory. It starts with an historical account of our research and shows how certain research themes, such as olfaction, learning, social behaviour, and environmental effects in rodents have led to our current research on behavioural phenotyping of inbred, mutant, knockout, and transgenic mice. We are concerned with finding neural and behavioural sequelae to genetic manipulations in mice and use a battery of tests to detect behaviours that are altered in genetically modified mice. In this way we are working to dissociate neural and behavioural effects of different gene manipulations in mouse models of neurodegenerative diseases. Sensory, motor, cognitive, affective, and social behaviours may all be affected by gene manipulation, thus careful behavioural techniques, with attention to the mice themselves, the apparatus, and procedure, experimenter variables, and environmental effects are necessary in order to determine a reliable and valid mouse behavioural phenotype. As both the genome and the environment have significant effects on the behavioural phenotype, our future research will utilize an epigenetic approach to examine how environmental cues modulate gene expression in the behavioural phenotyping of transgenic mice. Resume Cet article examine les travaux en cours dans mon laboratoire sur la genetique, le cerveau et le comportement de souris. Il debute par un historique de nos recherches et demontre la facon dont certains sujets de recherche comme l'olfaction, l'apprentissage, le comportement social et les effets de l'environnement chez les rongeurs ont mene a notre recherche actuelle sur la determination du phenotype comportemental de souris consanguines, mutantes, deficientes et transgeniques. Nous cherchons a trouver des sequelles neurales et comportementales aux manipulations genetiques des souris. Nous utilisons une panoplie de tests visant a detecter des comportements alteres chez les souris genetiquement modifiees. De cette facon, nous travaillons a dissocier les effets neuraux et comportementaux de diverses manipulations genetiques dans des modeles de souris portant sur des maladies neurodegeneratives. Les comportements sensoriels, moteurs, cognitifs, affectifs et sociaux peuvent tous etre affectes par la manipulation genetique. Ainsi, des techniques comportementales consciencieuses, portant une attention aux souris elles-memes, aux instruments, aux procedures, aux variables de l'experimentateur et aux effets de l'environnement, sont necessaires afin de determiner un phenotype comportemental fiable et valide des souris. Comme le genome et l'environnement ont tous deux des effets importants sur le phenotype comportemental, notre recherche future comportera une approche epigenetique visant a etudier la facon dont les indicateurs environnementaux modulent l'expression genetique dans la determination du phenotype comportemental des souris transgeniques. This paper gives an overview of our research on the behavioural phenotyping of mouse models of neurodegenerative disease. Because this research grew out of previous projects, this paper begins with an historical account of our research program. This shows how one research project grows from another in unexpected ways, the relatedness of seemingly unrelated projects, and the importance of many colleagues and students who have contributed and continue to contribute to our work. Early Research Projects As an undergraduate, I was interested in Robert Rosenthal's work on experimenter effects in behavioural research (Rosenthal, 1966) and in particular on his research on experimenter bias in the training of rats (Rosenthal & Fode, 1963). My honours thesis, completed under the supervision of Dr. Charles W. Tolman at the University of Victoria (Brown, 1970) was on experimenter bias effects on rat maze learning. It is interesting that our current studies of learning and memory in mutant and transgenic mice are still concerned with the problems of experimenter error and experimenter bias (Schellinck, Cyr, & Brown, in press). …

We have previously shown that medial preoptic area (MPOA) lesions disrupt parental behavior in both male and female California mice (P. californicus). In the present study, we compare the effects of lesions in the MPOA, with those in the basolateral amygdala (BA) and nucleus accumbens (NA) on male and female parental behaviors in the biparental California mouse. A male or multiparous female from each male-female pair was given an electrolytic or sham lesion in the MPOA, BA, or NA and tested for parental responsiveness. Since female P. californicus show postpartum estrus, they were likely pregnant during parental testing. MPOA lesions produced deficits in both male and female parental behaviors, and BA lesions disrupted male, and to a lesser extent, female parental behavior. NA lesions produced mild effects on pup-retrieval in males and no effect on parental behavior in females. However, NA lesions incompletely destroyed the NA shell, the region most relevant for maternal behavior in rats, and should be investigated further. These results support a role for the MPOA and BA in both male and female parental behaviors.

Which behavioral test is the most sensitive for detecting cognitive deficits in the 3xTg-AD at 6.5 months of age? The 3xTg-AD mouse model of Alzheimer's disease (AD) has three transgenes (APPswe, PS1M146V, and Tau P301L) which cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits with age. In order to determine which task is the most sensitive in the early detection of cognitive deficits, we compared male and female 3xTg-AD and B6129SF2 wildtype mice at 6.5 months of age on a test battery including spontaneous alternation in the Y-Maze, novel object recognition, spatial memory in the Barnes maze, and cued and contextual fear conditioning. The 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in the novel object recognition task nor was there a genotype difference in cued fear conditioning but females performed better than males. From our results we conclude that the 3xTg-AD mice have mild cognitive deficits in spatial learning and memory and that the Barnes maze was the most sensitive test for detecting these cognitive deficits in 6.5-month-old mice.

Fragile X Syndrome is the most common form of inherited mental retardation. It is also known for having a substantial behavioral morbidity, including autistic features. In humans, Fragile X Syndrome is almost always caused by inactivation of the X-linked FMR1 gene. A single knockout mouse model, fmr1-tm1Cgr, exists. In this report we further characterize the cognitive and behavioral phenotype of the fmr1-tm1Cgr Fragile X mouse through the use of F1 hybrid mice derived from two inbred strains (FVB/NJ and C57BL/6J). Use of F1 hybrids allows focus on the effects of the fmr1-tm1Cgr allele with reduced influence from recessive alleles present in the parental inbred strains. We find that the cognitive phenotype of fmr1-tm1Cgr mice, including measures of working memory and learning set formation that are known to be seriously impacted in humans with Fragile X Syndrome, are essentially normal. Further testing of inbred strains supports this conclusion. Thus, any fmr1-tm1Cgr cognitive deficit is surprisingly mild or absent. There is, however, clear support presented for a robust audiogenic seizure phenotype in all strains tested, as well as increased entries into the center of an open field. Finally, a molecular examination of the fmr1-tm1Cgr mouse shows that, contrary to common belief, it is not a molecular null. Implications of this finding for interpretation of the phenotype are discussed.

To address the role of the parietal pleura in reduction of mesothelial shear stresses during breathing, we measured the stiffness of the parietal pleural surface of mammalian chest walls using microindentation. The pleural surface was indented over ribs and intercostal spaces with rigid flat punches (tip radii of 0.01, 0.02, and 0.1 cm) to probe stiffness at length scales comparable with those of surface asperities. We found a tissue shear modulus of 6,700 dyn/cm2 and pleural membrane tension of 4,900 dyn/cm, with a geometric standard deviation of 0.42. These values are similar to those measured for the lung by Hajji et al., using indentation (Hajji MA, Wilson TA, and Lai-Fook SJ. J Appl Physiol Respirat Environ Exerc Physiol 47: 175–181, 1979). Surprisingly, the pleural surface over ribs and intercostal spaces exhibited similar stiffness. In addition, caudal regions exhibited lower stiffness than cranial regions. In the context of elastohydrodynamic lubrication, these results suggest that shear-induced pressures during breathing deform the chest wall and lung surfaces to a similar extent, promoting spatial uniformity of pleural fluid thickness and reducing shear stresses.

We compared spatial learning and memory in male and female mice of two MHC-congenic strains (C57BL/6J and B6-H-2K) in two versions of the Hebb-Williams Maze. In the food-reward paradigm, males required fewer sessions to learn than females, but there were no strain differences in acquisition. There were no strain or sex differences in the number of errors during the test phase, but the B6-H-2K mice reached the goal box faster than the C57BL/6J mice. In the water-escape paradigm, the C57BL/6J mice required more sessions than the B6-H-2K mice during acquisition. There were no strain or sex differences in the number of errors or in the latency to swim to the goal box in the test phase of the water-escape task. There were no significant correlations between the number of sessions to learn the two mazes; the number of errors made or the latencies to reach the goal box in each maze. These results indicate that these two strains show differences in performance in the Hebb-Williams Maze, but do not differ in cognitive ability.

The objectives of the treatment of mutilating hand injuries are to insure patient's survival, limb survival and ultimately limb function. Initially, patients are stabilized and cleared of other potentially life threatening trauma. The cornerstone to the early intra-operative management of the mangled hand includes irrigation and debribement. Skeletal stabilization, revascularization, replantation or the use of spare parts to restore functions are addressed at the initial surgery. Subsequent second or third look surgeries may be required to procure a clean wound bed. Regional flaps and free tissue transfer provides definitive coverage than soft tissue is required. Secondary procedures such as tenolysis, joint mobilization or toe transfers may be needed to restore dexterity to the healed yet dysfunctional hand. Adherence to sound safe principles help prevent further mobidity while fostering the restoration of hand function to return the patient to gainful activities.

Pup development and behavior in California mice were studied in litters housed with single mothers, or with fathers and mothers living together. Behavior of pups was recorded during a 15-min session every 2 days from 10 to 30 days of age. Physical contact, locomotion, grooming, and physical development indicators were recorded. It was found that the physical contact between siblings was greater and there was a tendency to have more contact between pup and either parent in the group in which the father was present. Finally, it was noted that the presence of the father did not affect either the first appearance of pup behavior during development or physical growth. In conclusion, the results indicate that the presence of the father had a greater influence on social contact between the different members of the litter than on pup behavioral development and physical growth. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 42: 246–251, 2003.

C57BL/6J and DBA/2J inbred mice differ in aspects of maternal behavior and in the morphology of the medial preoptic nucleus (MPO), suggesting a possible association. DBA/2J mice have a compact subnucleus in the MPO, the MPOpc, that is sexually dimorphic and absent in C57BL/6J mice. To determine whether MPOpc cells are activated by maternal behavior, FOS and FOSB immunohistochemistry was performed on brain sections of C57BL/6J and DBA/2J mothers following the return of their pups after a separation of 2 days. In both light and dark phases of the daily cycle, stimulation of DBA/2J mothers evoked an increase in FOS- and FOSB-immunoreactivity in the MPOpc. Stimulated C57BL/6J mice, which lack the MPOpc, did not show an increase in cellular activity in the corresponding MPO region. Cells immediately lateral to the MPOpc were activated by pup stimulation, in both strains. These results suggest that MPOpc cells are active during maternal behavior, and that strain differences in maternal behavior are related to anatomical differences in the MPO.

Methylphenidate hydrochloride (Ritalin, MPH) is frequently prescribed as a treatment for children with attention deficit hyperactivity disorder (ADHD), yet little research has been conducted to determine its potential long-term neurobehavioral effects. We assessed the effects of subchronic MPH administration (2.5, 5, 10, 20, 40, or 80 mg/kg) on male CD-1 mice treated from 26 to 32 days of age. When tested at 33 days of age in the open field and elevated plus maze, there were no significant differences in spontaneous locomotion, exploration, or fear- and anxiety-related behaviors. Testing from 34 to 37 days of age in a water maze task revealed no significant effects of any dose of MPH on learning in this simple paradigm. While it is difficult to extrapolate directly from these results to clinical effects in humans, our results indicate that preexposure of mice to MPH late in the postnatal developmental period does not appear to alter later behavior. We are currently conducting additional studies to further probe the potential effects of MPH administration during development and to examine various contributing factors including stage of development, duration of MPH administration, complexity of the task used to assess behavioral changes, and type of cognitive process being analyzed (attention, nonspatial working memory, etc.).

Doxorubicin is the most common antitumor drug implicated in serious extravasation injuries. Progressive tissue necrosis may lead to intense pain, chronic ulceration, and disfiguring tissue loss. This progressive necrosis is analogous to that seen with brown recluse spider bites, where dapsone is an established mode of therapy, minimizing the area of tissue loss by a proposed antiinflammatory mechanism. The backs of 50 Lewis rats were injected intradermally with 1 mg of doxorubicin in 1 cc of saline to simulate an extravasation injury. The rats were divided into five groups for treatment with oral dapsone 50 mg/kg/day: 10 were controls (no treatment), 10 were started the day before injury, 10 were started the day of injury, 10 were started the day after injury, and 10 were started 1 week after injury. The area of ulceration was calculated by planimetry. The data suggest that dapsone has little positive effect on healing extravasation ulcers.

Impairments in working memory (WM) can predict the shift from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the rate at which AD progresses with age. The 3xTg-AD mouse model develops both Aβ plaques and neurofibrillary tangles, the neuro-pathological hallmarks of AD, by 6 months of age, but no research has investigated the age-related changes in WM in these mice. Using a cross-sectional design, we tested male and female 3xTg-AD and wildtype control (B6129SF2/J) mice between 2 and 15 months of age for reference and working memory errors in the 8-arm radial maze. The 3xTg-AD mice had deficits in both working and reference memory across the ages tested, rather than showing the predicted age-related memory deficits. Male 3xTg-AD mice showed more working and reference memory errors than females, but there were no sex differences in wildtype control mice. These results indicate that the 3xTg-AD mouse replicates the impairments in WM found in patients with AD. However, these mice show memory deficits as early as two months of age, suggesting that the genes underlying reference and working memory in these mice cause deficits from an early age. The finding that males were affected more than females suggests that more attention should be paid to sex differences in transgenic AD mice.

Prefabrication of a latissimus dorsi myocutaneous flap was performed in adult male Landrace pigs. Gelfoam sponges were used as a delivery system for basic fibroblast growth factor (bFGF) at the muscle-subcutaneous tissue interface. Skin survival and angiogenesis were augmented in the growth-factor-treated animals. These data support the use of basic fibroblast growth factor to enhance flap prefabrication.

Free, nonvascularized composite nail grafts have been reported as a successful method to reconstruct nail deformities due to congenital anomalies or traumatic defects. The authors performed a decade review of their experience with nine patients who had had 10 free, nonvascularized composite nail grafts. Patient demographics, mechanism of injury, timing, site of reconstruction, and amount of nail to be replaced were all recorded. Results of nail growth in reconstructed nails were judged as excellent, good, fair, or poor on the basis of the appearance of the nail. The majority of reconstructed nails had half or more of the nail bed replaced. The 10 cases (mean follow-up of 1.8 years) that were reported had two excellent, three good, two fair, and three poor outcomes. There was no apparent relation between the successful outcome of the procedure and patient age, timing of reconstruction, or amount of nail bed replaced. Although the authors' experience suggests the unpredictable nature of this type of graft, it should be considered for patients who desire nail reconstruction and are not candidates for ablative or vascularized nail complex transfer procedures.

Pincer-nail syndrome has been described as distortion in the shape of the nails with excessive transverse curvature of the plate that increases from proximal to distal, leading to pinching and loss of soft tissue in the affected digit, resulting in severe pain. Many treatments have been recommended, but an effective long-term method that preserves the nail matrix has not been described. A method of dermal grafting under the nail matrix is described, and the results of treatment of six digits are reported. Five women and one man with an average age of 52 were treated. The affected digit was the thumb in four patients and the great toe in two patients. Follow-up averaged 25 1/2 months. The results were good in all cases with only one side of one nail remaining slightly curved. Pain was relieved in all cases, and complete adherence of the new nail plate occurred. Dermal grafting seems to provide excellent long-term treatment of the pincer-nail deformity with preservation of the nail matrix.

Cholinergic medial septum neurons express TrkA and p75 nerve growth factor receptor (p75 NGFR ) and interactions between TrkA and p75 NGFR are necessary for high-affinity binding and signaling of nerve growth factor (NGF) through TrkA. In adult p75 NGFR -deficient (− /−) mice, retrograde transport of NGF and other neurotrophins by these neurons is greatly reduced, however, these neurons maintain their cholinergic phenotype and size. Reduced transport of NGF has been proposed to play a role in Alzheimer’s disease. Here, we investigated whether chronic and long-term absence of p75 NGFR (and possibly reduced NGF transport and TrkA binding) would affect the cholinergic septohippocampal system during aging in mice. In young (6–8 months), middle aged (12–18 months), and aged (19–23 months) 129/Sv control mice the total number of choline acetyltransferase-positive medial septum neurons and the mean diameter and cross sectional area of the cholinergic cell bodies were similar. The cholinergic hippocampal innervation, as measured by the density of acetylcholinesterase-positive fibers in the outer molecular layer of the dentate gyrus was also similar across all ages. These parameters also did not change during aging in p75 NGFR −/− mice and the number and size of the choline acetyltransferase-positive neurons and the cholinergic innervation density were largely similar as in control mice at all ages. These results suggest that p75 NGFR does not play a major role in the maintenance of the number or morphology of the cholinergic basal forebrain neurons during aging of these mice. Alternatively, p75 NGFR −/− mice may have developed compensatory mechanisms in response to the absence of p75 NGFR .

The dopamine D(1) receptor agonist, R(+)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297), the dopamine D(2)/D(3) receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3, 4-g]quinoline hydrochloride (quinpirole), and the dopamine D(3) receptor agonist, (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT) all reduced the frequency of isolation-induced infant rat ultrasonic vocalizations and lowered body temperature when compared to saline-injected controls. Ultrasonic vocalization rate was not affected by either the dopamine D(1) receptor antagonist, R(+)-2,3,4, 5-tetrahydro-8-iodo-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (SCH 23390) or the dopamine D(2)/D(3) receptor antagonist, S(-)-raclopride-L-tartrate (raclopride) when given alone, nor did these antagonists block the ultrasonic vocalization reductions caused by the dopamine D(1) receptor agonist or the dopamine D(2)/D(3) receptor agonist. The dopamine D(2)/D(3) receptor antagonist but not the dopamine D(1) receptor antagonist blocked the dopamine D(3) receptor agonist's ultrasonic vocalization reduction. SKF 81297 reduced general activity while quinpirole and 7-OH-DPAT increased activity. Raclopride reversed quinpirole's reduction in body temperature, as well as 7-OH-DPAT's effects on body temperature, ultrasonic vocalizations, and activity. These results indicate that dopamine D(1), D(2)/D(3), and D(3) receptor agonists all reduce ultrasonic vocalizations by as yet undetermined mechanisms.

The incidence of sternal wound infection following median sternotomy is 0.4 to 5 percent. Debridement and closure of the wounds with local and regional muscles, such as a pectoralis or a pedicled rectus abdominis, have been the mainstay of surgical treatment. Often, both pectoralis major muscles and the superior portion of a rectus abdominis muscle must be used to close large sternal wounds. Loss of these major muscles can be both debilitating and cosmetically disfiguring. Free-tissue transfer can be employed to limit the amount of tissue needed to fill the sternal defect. The authors present a series of 12 free-tissue transfers used in 11 patients to close large sternal defects in this subset of patients. Total flap loss occurred in one patient. Partial loss of the skin island was noted in three patients. Two patients developed abdominal hernias after rectus abdominis free flaps. Free-tissue transfer offers the ability to close these large wounds, using one muscle, in those patients where pedicled rectus abdominis flaps are not available.

The odours of adult males, which accelerate the timing of puberty of female mice, activate c-fos in the accessory olfactory bulb (AOB). To test the hypothesis that NMDA receptors are involved in the male odour-induced increase in c-fos expression, we studied the effects of the non-competitive NMDA receptor agonist MK-801 on male odour-induced c-fos expression in the AOB of juvenile female mice. Surprisingly, MK-801 increased FOS-like immunoreactivity (FLI) within the AOB in the absence of male odour and had no effect on male odour-induced c-fos expression. We suggest that MK-801 increases AOB mitral cell activity by disinhibiting GABAergic granule cells, resulting in increased c-fos expression throughout the AOB.

While olfactory delayed matching-to-sample tasks have been used to assess working memory in rats, no such tasks have been tested in mice. Olfactory delayed matching-to-sample learning was assessed in male and female 5XFAD mice, a model of Alzheimer's disease, and their wildtype (B6SJL F1) littermates at 6–7 months of age using an operant olfactometer. All 5XFAD and wildtype mice were able to learn the delayed olfactory matching-to-sample task at 2 and 5 s delays. Fewer mice learned with a 10 s delay and only one mouse learned with a 30 s delay. Female mice showed higher levels of performance on the delayed matching-to-sample task than males, indicative of better working memory. These results demonstrate for the first time that mice are able to learn an olfactory delayed matching to sample task.

Elephants have had to adapt to gravitational stresses imposed on their very large respiratory structures. We describe some unusual features of the elephant's respiratory system and speculate on their functional significance. A distensible network of collagen fibers fills the pleural space, loosely connects lung to chest wall but appears not to constrain lung-chest wall movements. Myriad spaces within the network and its rich supply of capillaries suggest effective local sources and sinks for pleural fluid that may replace the gravity-dependent flows of smaller mammals. The lung is partitioned into approximately equal to 1 cm3 parenchymal units by a system of thick, elastic septa that ramify throughout the lung from origins on the lung's elastic external capsule. Parenchymal units suspended upon the elastic septal system protect dependent alveoli from compression, thereby reducing the usual gravitational gradient of lung expansion. Intra-pulmonary airways are devoid of cartilage, instead they appear to derive resistance to collapse from tethering forces of the attached septa.

A technique of delayed extensor tendon reconstruction and centralization using a palmaris longus tendon graft is presented. The tendon graft is woven through the base of the proximal phalanx and up and over the reconstructed extensor tendon to simulate the natural sagittal bands. As described, the technique allows gliding of the extensor tendon while maintaining its vitally important central location.

We have previously shown that apparatus design can affect visual–spatial cue use and memory performance of mice on the Barnes maze. The present experiment extends these findings by determining the optimal behavioral measures and test procedure for analyzing visuo-spatial learning and memory in three different Barnes maze designs. Male and female C57BL/6J mice were trained with a stable or random escape hole location and the sensitivities (statistical power) of four commonly used measures of learning and three measures of memory to detect differences between these training procedures were compared on each maze design. A maze design with a large diameter and no wall was optimal, because mice showed a reliable use of extra-maze visual cues, visuo-spatial search strategies, and spatial memory. A maze design with a small diameter, surrounding wall, and intra-maze visual cues was the least sensitive for determining visuo-spatial learning and memory, because mice showed little evidence of extra-maze cue use. Errors, distance traveled, and hole deviation scores were more sensitive measures of learning than latency to find the escape hole. Measures based on locating the escape hole (primary measures) were more sensitive than measures based on entering the escape hole (total measures). Measures of memory had similar levels of sensitivity on each maze. This experiment demonstrates that both apparatus design and the behavioral measures used as indicators of learning and memory can influence the ability of the Barnes maze to detect visuo-spatial learning and memory impairments in mice.

Inbred mice of MHC-congenic strains prefer to mate with mice of different MHC types. Mate selection based on MHC-type occurs through the urinary odors specific to each MHC-congenic mouse strain. Both urine and preputial gland odors of male mice have been postulated to act as female attractants and the present study examined the attraction of MHC-congenic female mice (C57BL/6J and B6-AKR.H-2k) to the urine and preputial gland odors of males. Females of both strains showed a greater attraction to the urine odors of intact males of the other MHC type, but did not show a preference for the urine odors of these males after their preputial glands were removed. There was, however, a preference for the preputial fluid of males of the other MHC type. These results indicate that the MHC-specific urinary odors of mice may arise from the preputial glands, and that it is the MHC-specific preputial gland odors of MHC-conspecific males that are used for mate selection by females.

Fifty limited wrist fusions were performed in 47 patients including 24 scaphoid-trapezium-trapezoid, 12 capitate-lunate-triquetrum-hamate, and 13 other limited wrist fusion combinations. Fusions were performed most commonly for rotary subluxation of the scaphoid and follow-up averaged 13.6 months for the chart review and 44 months for the questionnaire. There were 10 major complications in 8 patients, most of which required secondary surgery. There were 3 partial nonunions but no complete nonunions. Two patients later underwent a total wrist fusion. There were 15 minor complications in 10 patients, most of which were managed nonoperatively. A questionnaire was returned on 28 of the 50 fusions. Pain levels decreased from a preoperative level of 8.2 to a postoperative level of 3.0 (scale of 1-10 with 10 being most severe pain ever). All but 3 patients would have the fusion again.