Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input

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Alzheimer’s disease (AD) and related dementias are associated with progressive disruption of circadian rhythms. 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. The neurobiology of sundowning remains unknown, however the temporal periodicity of it 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. Intrinsically photosensitive retinal ganglion cells (RGCs), that express the photopigment melanopsin, project to the SCN via the retinohypothalamic tract (RHT) and entrain its activity the daily lightdark cycle. Dr. Clifford Saper’s lab has shown that sleep-wake and locomotor activity (LMA) rhythms are regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). More recently, my work postdoctoral work in Dr. Saper’s lab revealed that aggression propensity in male mice also follows a daily rhythm that is regulated by GABAergic SPZ neurons. This work further demonstrated that these SPZGABA neurons receive functional input from the SCN, are active in a phase-dependent manner, and project to neurons within the ventromedial hypothalamus (VMH) that drive attack behavior, altogether suggesting a novel pathway by which the central circadian clock gates aggression propensity across the 24h day. Importantly, I found that disrupting the 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 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 related dementias, and that this pathway may be a promising therapeutic target for treating circadian dysfunction and aggression in patients who display sundowning. I began testing this hypothesis by examining circadian rhythms in TAPP mice (also known as APPSwe-Tau), which develop amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology). I found that these mice exhibit increased early resting period aggression and blunted active period LMA at ages shortly after they are known to develop AD-related neuropathology. In this proposal, I seek to expand on this work by examining brain tissue from these mice for a-beta and tau in the SCN, the SPZ, and their output targets the VMH and the DMH. It has been hypothesized that circadian dysfunction associated with sundowning may instead result from AD-related disturbances to areas that provide input to the circadian system, such as serotoninergic and cholinergic pathways, and I will also examine AD-related neuropathology in such areas. I will also assess cell loss in all of these pathways, as well as in the retina (specifically RGCs that project to and entrain the SCN). Finally, I seek to determine the effects of manipulating SPZ and RGC activity (using chemogenetic activation) on increased aggression and blunted circadian sleep-wake rhythms in TAPP mice, and on the patterns of AD neuropathology. While sundowning is an important clinical problem, there has been little work focused on how the circadian system effects agitation and aggression, and almost none on how such circuits are affected by AD. Interrogating such circuits, and determining whether manipulation of their neuronal activity can ameliorate AD-related behavioral disturbances in mice, may point to an eventual therapy that could greatly improve quality of life for AD patients and their caregivers.