The structural and functional integrity of the basal forebrain (BF) is an absolute requirement for maintaining behavioral and electrographic (EEG) wake. The mechanisms and substrates by which the BF regulates EEG and neurobehavioral arousal remains however poorly understood. A review of the relevant literature reveals that the vast majority of studies on BF circuitry have focused on the corticopetal cholinergic BF system in physiological (EEG and behavioral arousal) and pathophysiological (neurodegenerative disorders) regulation, despite the facts that 1) lesions of the cholinergic BF system produce limited changes in EEG or behavioral wake;and 2) the BF also contains a population of cortically projecting GABAergic neurons that roughly intermingle with the cholinergic neurons. While it has been appreciated for some time that other corticopetal BF neurotransmitter systems may interact or work in parallel with cholinergic neurons in modulating cortical circuitry, the contribution of GABAergic BF neurons, and in particular those projecting to the cortex, to this process remains largely unexplored. In this proposal we seek to determine the in vitro (cellular) and in vivo (system) mechanisms and substrates by which the BF GABAergic neurons contribute to EEG and behavioral arousal, including sleep-wake cycles. We hypothesize that the BF GABAergic population is critically involved in maintaining EEG and behavioral wake and that this influence is mediated primarily by cortically-projecting GABAergic BF neurons and not by BF GABAergic interneurons or BF GABAergic neurons that project to other brain regions, such as the lateral hypothalamus. The experimental dissection of the role of BF GABAergic neurons, and in particular the corticopetal BF GABAergic neurons in EEG and behavioral arousal, has however proven a considerable challenge given the multiple transmitter systems and sub-populations of GABAergic neurons within the BF. We have therefore sought to develop and validate novel viral-based pharmacogenetic and conditional promoter-specific transgene expression systems to test our hypothesis through the selective isolation and manipulation of BF GABAergic neurons. Specifically we will use the so-called DREADD (designer receptors exclusively activated by designer drugs) system to reversibly activate or silence BF GABAergic neurons, including the selective manipulation of cortically-projecting BF GABAergic neurons, both in vitro and in vivo. The results from this experimental work will provide important information regarding the substrates that are necessary to produce and maintain arousal and emphasize the critical contribution of BF GABAergic neurons to these processes in freely behaving, unrestrained animals.
This program seeks to determine the role of GABAergic basal forebrain neurons in the regulation of electrographic and behavioral wakefulness. In addition to revealing the neurobiological role of the basal forebrain GABAergic system in normal function, the results from the proposed studies may provide critical insight into the pathogenesis of a host of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, and the cognitive impairments of normal aging and disorders of consciousness.
