DESCRIPTION (provided by applicant): Our lab is focused on understanding mechanisms by which sleep enhances plastic processes in brain. We have shown that sustained sleep fragmentation (SF) strongly inhibits adult hippocampal dentate gyrus (DG) neurogenesis, including both cell proliferation and maturation, and that this inhibition is not due to stress. We now propose to study a mechanism underlying the pro-neurogenic effects of sleep. The proposed studies focus on DG 3-aminobutyric acid (GABA)-ergic neuronal activation during sleep as a mechanism by which sleep can promote adult neurogenesis. We will test the following general theses: Sustained sleep strongly activates intrinsic DG GABAergic mechanisms and thereby promotes hippocampal neurogenesis, particularly enhancing survival and maturation of post-mitotic cells. The effects of exercise on neurogenesis and subsequent spatial learning depend on GABAergic activation during sustained sleep. We will assess the following specific hypotheses: 1. Hippocampal DG GABAergic neurons are activated during sleep. By manipulating NREM and REM sleep, we will determine what properties and stages of sleep are maximally associated with GABAergic neuronal activation and if SF diminishes sleep-related DG GABAergic neuronal activation. GABAergic neuronal activation will be identified by double-labeling for c-Fos protein, a marker of neuronal activation, and a GABA neuronal marker [glutamic acid decarboxylase (GAD)}]. We developed a well-controlled method for SF. 2. DG GABA release is increased during consolidated sleep, and sleep fragmentation will reduce the sleep- enhanced release of GABA in DG. DG GABA release will be measured by in vivo microdialysis. We will examine changes in GABA release during specific sleep events, including NREM sleep-associated sharp waves (SPWs) and REM-associated theta bursts. 3. Exercise increases GABAergic processes during subsequent sleep. We will determine effects of exercise on GABA release, and NREM SPWs and REM-associated theta bursts. Sleep fragmentation will block the GABAergic activation during sleep resulting from exercise. 4. Exercise increases post-mitotic cell survival and maturation and expression of a critical trophic factor, Brain-Derived Neurotrophic Factor (BDNF) identified immunostaining for markers of BDNF, cell survival (bromo-deoxyuridine, BrdU) and maturation (doublecortin, DCX). Sleep fragmentation will block the effects of exercise. 5. The beneficial effects of exercise on hippocampal-dependent cognitive performance and novelty- suppressed feeding depend on sustained sleep. Hippocampal-dependent function following exercise will be assessed using the Barnes maze. Insomnia, particularly sleep fragmentation, predicts subsequent major depressive disorder (MDD) and recurrence of MDD in remitted patients. In preclinical studies, antidepressant treatments progressively facilitate DG neurogenesis and require neurogenesis. The efficacy of antidepressant treatment may depend on sustained sleep. In humans, initial antidepressant treatment has low efficacy. We propose that MDD treatment is best understood as a multi-stage process that requires sustained sleep as one element. Exercise facilitates neurogenesis and has antidepressant effects in animals and humans. We will determine if these effects of exercise depend on sustained sleep.

Major depressive disorder (MDD) and depression spectrum disorders are prevalent in veterans. Many other neuropathological disorders are also associated with sleep fragmentation. Response to initial drug treatment of MDD in humans is inconsistent, but there is evidence that adjunctive treatment of insomnia in MDD patients with a GABA agonist greatly enhances antidepressant treatment response. Antidepressant treatment can depend on hippocampal adult neurogenesis, and adult neurogenesis is facilitated by GABA agonists. There is no specific neurological rationale for coincident management of sleep disorders and MDD or other disorders. By linking antidepressant treatment, sustained sleep, and adult neurogenesis, proposed work could provide a specific neurochemical rationale for development of treatment protocols which include management of sleep disorders.