Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks such as deficits in learning, memory and mood. We propose that developmental ethanol (EtOH) exposure may induce long-lasting disruption of neural activity patterns during sleep which are known to be important for memory consolidation and synaptic homeostasis. If so, this would create a situation wherein the normal ability of the nervous system to repair and readjust itself during sleep would be impaired, resulting in a daily insult to nervous system function long after the EtOH exposure ended. In support of this hypothesis, during the past funding cycle we have demonstrated that developmental EtOH 1) disrupts and fragments adult non-REM sleep, 2) the extent of sleep disruption in adults predicts cognitive impairment, 3) the sleep impairment is associated with severe loss of parvalbumin (PV) and somatostatin (SST) expressing GABAergic interneurons which are known to contribute to sleep-wake architecture, 4) disruption of PV cell function through neuropentraxin knock-out replicates some aspects of developmental ethanol but not sleep, and 5) preventing cell loss induced by developmental EtOH with LiCl prevents sleep, anatomical, and cognitive impairments. In this renewal, we plan to further explore the mechanisms of developmental EtOH effects on sleep and waking with cell specific analyses.
Aim 1 will test the hypothesis that selective optogenetic activation of spared GABAergic neurons will restore the deficits in sleep and cognition induced by developmental EtOH in transgenic mice (e.g., SST-Cre;
Aim 1. 1). In the same animals, we will correlate sleep-wake function/dysfunction/repair with anatomical structure of several identified GABAergic circuits (e.g., SST, reelin, vasoactive intestinal peptide (VIP)) in sleep-related regions including basal forebrain nuclei, hippocampus and neocortex. Data will include synaptic interactions of identified cell types using confocal and electron microscopy as well as Golgi analyses (Aim 1.2). Performing the anatomical analyses on animals that we have assayed for sleep/wake and cognitive function will allow us to directly relate structure (e.g., synaptic density) with neurobehavioral function/dysfunction/repair (e.g., slow-wave activity, excitatory/inhibitory [E/I] balance).
Aim 2. 1 examines to what extent PV/SST cells are killed by developmental EtOH, or alternatively have down-regulated phenotypic expression by tracking the fate of fluorescently labeled PV/SST neuron progenitors in Nkx2.1-Cre;Ai9 mice exposed to EtOH. This will provide information needed to guide attempts to restore GABAergic function after EtOH exposure.
Aim 2. 2 will transplant PV/SST interneuron progenitors into EtOH treated mice, to examine if re-populating GABAergic neurons in identified brain regions will restore sleep and/or cortical activity (e.g., slow- wave activity, E/I balance), as well as sleep-related cognitive function and circuit structure. If successful, results from this proposal could open a new window into both understanding and repair of early ethanol-induced neural and cognitive impairment.
Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks such as deficits in learning, memory and mood. Of the many long-lasting consequences of developmental ethanol exposure, sleep disruption has been identified in human and other animal studies, and our previous results indicate that sleep deficits are associated with specific interneuron reduction. Given the importance of sleep in memory consolidation, mood and attention, here we will explore how developmental ethanol affects GABA interneurons and how modifications of the cell numbers or activity improve developmental ethanol-induced sleep disruption, which may help identify treatments for FASD.
