Circadian rhythms are daily fluctuations in physiology and behavior that regulate many important aspects of daily life. Although there has been tremendous progress elucidating the molecular mechanisms responsible for the workings of the master clock of the suprachiasmatic nucleus (SCN) and those of multiple extra-SCN oscillators, most of the work with mammals has used traditional laboratory species, which are nocturnal. Little is known of the mechanisms that support a diurnal profile of activity in species like our own. Many humans with neurological disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), and other dementia related neurological disorders exhibit circadian rhythm dysfunction. Specifically, many of these patients exhibit increased levels of nocturnal activity, aberrant sleep and body temperature rhythms, and disrupted masking responses to light. The neural mechanisms that support diurnal activity and species specific masking responses are not yet known, thus limiting the use of animal models for understanding the etiologies of the disruptions in these functions that accompany AD and other neurological pathologies. Here, we take advantage of a diurnal mammalian model, the grass rat (Arvicanthis niloticus), to examine this issue. We have new data suggesting that the retinorecipient intergeniculate leaflet (IGL) is a key brain area critical for the display of normal patterns of daily activity in grass rats. Specifically, diurnal grass rats with IGL lesions reverse their activity profiles to become night-active, and after the phase reversal, they respond to acute presentations of light similarly to nocturnal animals. I propose to use diurnal grass rats to test the hypothesis that brain circuitry involving the IGL is critical for the expression of diurnal behavior and physiology, and plays an important role in masking responses to light. Here, in Aim I-1, we examine to what extent the IGL contributes to the coordination of many aspects of circadian behavior and physiology, including daily activity patterns, sleep, wakefulness, temperature regulation, and stress.
Aim I -2 will test the hypothesis that the IGL, and structures downstream of the IGL, play an important role in the acute effects of light. Using neural tracing and pharmacological manipulations, Aims II and III look more closely at the mechanism by which these effects are mediated (via Neuropeptide Y or Enkephalin). Altogether, the proposed work will lead to an improved understanding of the neural mechanisms underlying diurnality, and has implications for the understanding of neurological disorders, such as Alzheimer's Disease, that involve disrupted circadian patterns of activity and aberrant responses to light.
Many individuals with neurological disorders such as Alzheimer's Disease, Parkinson's Disease, and other dementia related disorders have disrupted circadian patterns of activity. The proposed work will elucidate the mechanisms involved in these disruptions. This may, ultimately, have an enormous impact on the health and quality of life for millions of Americans who are suffering from such neurological disorders.
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