Wyoming Sensory Biology COBRE

摘要

Abstract Women are much more likely than men to develop Alzheimer’s disease (AD) and related dementias, which are associated with progressive disruption of circadian rhythms. Additionally, women are more likely than men to develop circadian disorders, such as sleep disorders, and one particular feature of circadian dysfunction in patients with AD and related dementias is “sundowning syndrome”, a poorly understood clinical phenomenon characterized by agitation, aggression, and delirium during the early evening hours. Sundowing symptoms have a major impact on the quality of life for both the patient and their caregivers, who are also more likely to be women, and often lead to the decision to seek institutionalization. The neurobiology of sundowning remains unknown, however the temporal periodicity of sundowning symptoms suggests a possible disturbance in the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, or in the pathways by which the SCN modulates particular rhythms. Rhythms of sleep-wake and locomotor activity (LMA) are regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). Additionally, we recently demonstrated that the propensity for behavioral aggression also follows a daily rhythm that is regulated by the SCN, via an additional pathway through the SPZ, to the ventromedial hypothalamus (VMH). Importantly, disrupting this SCNSPZVMH pathway led to increased aggression during the early resting phase (the light period for nocturnal mice), which is temporally analogous to when AD and dementia patients who experience sundowning display increased agitation and aggression. This suggests that the function of certain structures within this circuit may be compromised in AD and dementia. Interesting, women have also been shown to have a particular profile of inflammatory markers in AD, however these differences have never been examined directly in areas associated with circadian regulation. We have begun examining circadian rhythms in the TAPP mouse model, which develops amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology), and our preliminary results suggest that these mice exhibit increased early resting period aggression and disrupted LMA at very early ages of AD pathology. In this proposal, we will examine whether sex-differences in specific inflammatory markers are associated with sex differences in increased aggression during the early resting phase and disrupted LMA rhythms in female and male TAPP mice, and in their female and male wild-type controls. We will focus our analysis in a circuit-based and region-specific manner, by specifically examining lysates from dissected hypothalamic tissue containing the SCN and SPZ, and dissected midbrain tissue containing areas which we know project to the circadian system and which display heavy phosphorylated tau pathology at later ages.