RESUMEN
BACKGROUND: Neuroimaging studies investigating the behavioral and psychological symptoms of dementia (BPSD)- such as apathy, anxiety, and depression- have linked some of these symptoms with altered neural activity. However, inconsistencies in operational definitions and rating scales, limited scope of assessments, and poor temporal resolution of imaging techniques have hampered human studies. Many transgenic (Tg) mouse models of Alzheimer's disease (AD) exhibit BPSD-like behaviors concomitant with AD-related neuropathology, allowing examination of how neural activity may relate to BPSD-like behaviors with high temporal and spatial resolution. OBJECTIVE: To examine task-dependent neural activity in the medial prefrontal cortex (mPFC) of AD-model mice in response to social and non-social olfactory stimuli. METHODS: We previously demonstrated age-related decreases in social investigation in Tg 5xFAD females, and this reduced social investigation is evident in Tg 5xFAD females and males by 6 months of age. In the present study, we examine local field potential (LFP) in the mPFC of awake, behaving 5xFAD females and males at 6 months of age during exposure to social and non-social odor stimuli in a novel olfactometer. RESULTS: Our results indicate that Tg 5xFAD mice exhibit aberrant baseline and task-dependent LFP activity in the mPFC- including higher relative delta (1-4âHz) band power and lower relative power in higher bands, and overall stronger phase-amplitude coupling- compared to wild-type controls. CONCLUSIONS: These results are consistent with previous human and animal studies examining emotional processing, anxiety, fear behaviors, and stress responses, and suggest that Tg 5xFAD mice may exhibit altered arousal or anxiety.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Masculino , Femenino , Ratones , Humanos , Animales , Enfermedad de Alzheimer/patología , Ratones Transgénicos , Miedo , Ansiedad , Modelos Animales de EnfermedadRESUMEN
Social withdrawal and agitation/aggression are common behavioral and psychological symptoms of dementia presented by Alzheimer's disease (AD) patients, with males exhibiting more aggressive behaviors than females. Some transgenic mouse models of AD also exhibit social withdrawal and aggression, but many of these models only recapitulate the early stages of the disease. By comparison, the 5xFAD mouse model of AD exhibits rapid, progressive neurodegeneration, and is suitable for modeling cognitive and behavioral deficits at early, mid-, and late-stage disease progression. Anecdotal reports suggest that transgenic 5xFAD males exhibit high levels of aggression compared to wild-type controls, but to date, indirect genetic effects in this strain have not been studied. We measured home-cage behaviors in 5xFAD males housed in three different group-housing conditions (transgenic-only, wild-type only, and mixed-genotype) and social approach behaviors when exposed to a novel free-roaming or restrained, wild-type or transgenic conspecific. Transgenic-only home cages required earlier separation due to injuries arising from aggression compared to wild-type-only or mixed-genotype cages, despite no obvious increase in the frequency of aggressive behaviors. Transgenic 5xFAD males and females also spent less time investigating free-roaming conspecifics compared to wild-type controls, but they showed normal investigation of restrained conspecifics; the genotype of the conspecific did not affect approach behavior, and there was no aggression observed in transgenic males. These findings provide evidence in an animal model that amyloid pathology ultimately leads to avoidance of novel social stimuli, and that frequent interactions between individuals exhibiting an AD phenotype further exacerbates aggressive behaviors.
Asunto(s)
Agresión , Enfermedad de Alzheimer , Conducta Animal , Modelos Animales de Enfermedad , Conducta Social , Animales , Femenino , Masculino , Ratones , Ratones TransgénicosRESUMEN
Transgenic mouse models have been used extensively to model the cognitive impairments arising from Alzheimer's disease (AD)-related pathology. However, less is known about the relationship between AD-related pathology and the behavioural and psychological symptoms of dementia (BPSD) commonly presented by patients. This review discusses the BPSD-like behaviours recapitulated by several mouse models of AD-related pathology, including the APP/PS1, Tg2576, 3xTg-AD, 5xFAD, and APP23 models. Current evidence suggests that social withdrawal and depressive-like behaviours increase with progressive neuropathology, and increased aggression and sleep-wake disturbances are present even at early stages; however, there is no clear evidence to support increased anxiety-like behaviours, agitation (hyperactivity), or general apathy. Overall, transgenic mouse models of AD-related pathology recapitulate some of the BPSD-like behaviours associated with AD, but these behaviours vary by model. This reflects the patient population, where AD patients typically exhibit one or more BPSD, but rarely all symptoms at once. As a result, we suggest that transgenic mouse models are an important tool to investigate the pathology underlying BPSD in human AD patients.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Conducta Social , Animales , Ratones , Ratones TransgénicosRESUMEN
In addition to memory impairments, patients with Alzheimer's disease (AD) exhibit a number of behavioural and psychological symptoms that can affect social interactions over the course of the disease. While altered social interactions have been demonstrated in a number of mouse models of AD, many models only recapitulate the initial stages of the disease, and these behavioural changes have yet to be examined over the course of disease progression. By performing a longitudinal study using the 5xFAD mouse model, we have demonstrated that transgenic females exhibit progressive alterations in social investigation compared to wild-type controls. Transgenic females exhibited an age-related reduction in interest for social odours, as well as reduced investigative behaviours towards novel conspecifics in a novel environment. However, transgenic mice exhibited no obvious olfactory deficits, nor any changes in scent-marking behaviour compared to wild-type controls, indicating that changes in investigative behaviour were due to motivation to engage with a social stimulus. This evidence suggests that transgenic 5xFAD females exhibit increased social anxiety in novel environments compared to wild-type controls. Overall, transgenic 5xFAD female mice mimic some features of social withdrawal observed in human AD patients suggesting this strain may be suitable for modelling aspects of the social dysfunction observed in human patients.
Asunto(s)
Factores de Edad , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Conducta Social , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Masculino , Trastornos de la Memoria/fisiopatología , Ratones TransgénicosRESUMEN
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.