The long term goal of the research is to elucidate the neural and chemical mechanisms generating sleep- wake states and regulating cortical activity and behavior across those states. Such understanding will illuminate how neurological diseases, such as Alzheimer's, or sleep-wake disorders, such as narcolepsy, result in loss of attention and/or the ability to maintain an aroused, waking state. The proposed studies focus upon the role of cholinergic, GABAergic and newly discovered glutamatergic neurons in the basal forebrain (BF). Using juxtacellular labeling of neurons recorded in unanesthetized, head-fixed rats, the discharge of immunohistochemically identified cells will be characterized in association with electroencephalographic (EEG) activity recorded from the cortex and electromyographic (EMG) activity recorded from postural neck muscles across the states of waking, slow wave sleep (SWS) and paradoxical sleep (PS, also known as rapid eye movement sleep, REMS, in humans). Applying newly developed behavioral testing, previously identified W/PS-active, cholinergic BF neurons will be examined for their discharge in association with attention and cortical activation during waking. GABAergic BF neurons will be further studied for their discharge in association with sleep, as SWS or SWS/PS-active cells, and in reciprocal relation to the cholinergic cells in attentional tasks. The unique role of glutamatergic BF neurons will be characterized in relation to cortical activity, behavioral arousal and attention or reinforcement. By neuroanatomical tracing combined with immunohistochemistry for presynaptic vesicular transporter proteins and postsynaptic proteins, projections and synaptic connections of BF cholinergic, GABAergic and glutamatergic neurons will be delineated onto target neurons in the cerebral cortex. Collectively, these studies will elucidate how specific basal forebrain cell groups can promote attention along with cortical activation or behavioral arousal and others reciprocally dampen these processes to evoke drowsiness and sleep. They will provide insight into how imbalances in these systems could lead to deficits in attention and arousal as well as disruption of sleep-wake states.
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