An estimated 39.6 million people, including 8.5 million US Veterans (43%), are elderly and at risk for developing chronic sleep disturbance. Chronic sleep disturbance is associated with a number of negative health outcomes including cognitive decline, increased risk of fall, anxiety, and depressive disorders, contributing to the poor quality of life. The proposed research program will use a multi-disciplinary approach to examine: a) if a physiological decline or dysfunction of the preoptic hypothalamic (POAH) sleep- regulatory systems contribute to chronic sleep disturbance in aging; b) if chronic POAH inflammation and nitrosative stress in aging contribute to sleep-disturbance, by adversely affecting sleep-regulatory systems; and c) if sleep disturbance in aging can be mitigated by anti-inflammatory measures.
Specific aim -1: will determine if the functional activity of sleep-regulatory median preoptic nucleus (MnPN) and ventrolateral preoptic area (VLPO) neurons decline with aging. We will compare in young vs. old rats: a) changes in discharge activity of sleep-active MnPN and VLPO neurons to spontaneous and homeostatic sleep cues (experiment-1); and b) c-Fos expression in VLPO and MnPN GABAergic neurons after different sleep pressures and sleep amounts (experiment-2).
Specific aim -2: will determine if the MnPN and VLPO sleep-regulatory systems exhibit evidence of increased inflammation, nitrosative stress, and neuronal damage with aging. We will compare in young and old rats: a) microglia activation, and expression of TNF-alpha, iNOS, nitrotyrosine (markers of nitrosative stress), and markers of senescence, apoptosis and neuronal damage in the MnPN and VLPO GABAergic neurons, by immunohistochemistry (experiment-3); and b) levels of TNF-alpha, IL-6, iNOS, and nitrotyrosine by quantitative RT-PCR and Western blots as well as NO metabolites (nitrates and nitrites) and cytokine release in the MnPN and VLPO by ELISA and flourometry (experiment-4).
Specific aim -3: will determine if chronic MnPN and VLPO inflammation contribute to sleep disturbance, by adversely affecting their sleep-regulatory neuronal systems. We will quantify: a) if chronic MnPN and VLPO inflammation, induced by local LPS infusion, in young rats produces sleep disturbance and immuno- histochemical changes in GABAergic neurons, that are typical of old age (experiment-5); and b) if chronic suppression of inflammation within the MnPN and VLPO, by focal infusion of minocycline, an inhibitor of microglia activity and a selective scavenger of peroxynitrite, reduces nitrosative stress in GABAergic neurons and improves sleep-wake organization and sleep continuity in aged rats (experiment-6). The proposed research program is conceptually innovative and will generate novel and fundamental data about the functional status of the POAH sleep-regulatory systems in aging. A better understanding of how CNS aging affects sleep-regulatory systems and the mechanism by which inflammation pathologically affects sleep-wake function may contribute to the development of novel preventative and therapeutic options for optimizing sleep health in the elderly including Veterans.
An estimated 39.6 million people, including 8.5 million US Veterans, are elderly and at risk for developing chronic sleep disturbance. Fragmented and poor sleep is one of the most common complaints in elderly and is associated with a number of negative health outcomes including cognitive decline, increased risk of fall, anxiety and depressive disorders, contributing to the poor quality of life. This research program is aimed at examining that if a physiological decline/dysfunction of sleep-regulatory systems contributes to sleep disturbance in aging, if chronic brain inflammatory processes contribute to dysfunction/damage of sleep- regulatory systems in aging, and if sleep disturbance in aging can be mitigated by anti-inflammatory measures. These preclinical studies may help develop novel preventative and therapeutic options to achieve the long-term goal of optimizing sleep health in the elderly including Veterans.
|Alam, Md Noor; McGinty, Dennis (2017) Acute effects of alcohol on sleep are mediated by components of homeostatic sleep regulatory system: An Editorial Highlight for 'Lesions of the basal forebrain cholinergic neurons attenuates sleepiness and adenosine after alcohol consumption' on page 710. J Neurochem 142:620-623|
|Donlea, Jeffrey M; Alam, Md Noor; Szymusiak, Ronald (2017) Neuronal substrates of sleep homeostasis; lessons from flies, rats and mice. Curr Opin Neurobiol 44:228-235|