How the brain regulates states of consciousness is not known, but first-order circuits detailing interactions between wake-active and sleep-active neurons have been proposed. Here we focus on a portion of the wake circuit that involves the basal forebrain (BF) and link it to the neuropeptide hypocretin (HCRT). The basal forebrain (BF) has been implicated in regulating wakefulness (Szymusiak, 2000), and contains neurons that are preferentially wake/REM-active or sleep-active (Szymusiak, 2000). The sleep-active neurons are GABAergic (Manns et al., 2003) and could oppose the wake-active neurons (Jones, 2004). The wake-active neurons are thought to be driven by ascending influences from other arousal populations (Semba, 2000), and are hypothesized to shut-off by the localized build-up of adenosine (AD) (Porkka-Heiskanen et al., 1997). Although in the BF adenosine levels rise with wakefulness and then fall with sleep, would adenosine levels rise with prolonged waking if the cholinergic neurons were absent? This is an important question that surprisingly has never been investigated, but which can easily be answered by using 192-lgG-saporin to lesion the BF cholinergic neurons and measuring adenosine in the BF that is devoid of cholinergic neurons. Here we propose four aims utilizing overlapping methodologies and transgenic rats to test a specific circuit.
Aim 1 will test the hypothesis that in the absence of the BF cholinergic neurons adenosine will not build in the BF in response to waking.
Aim 2 will test the hypothesis that in the absence of the BF cholinergic neurons adenosine or the adenosine A1 receptor agonist CHA will not induce sleep.
Aim 3 will link the HCRT system with the BF cholinergic system by demonstrating that ascending influences from this prominent arousal system drives the BF. We will directly test this possibility by demonstrating that in 192-lgG sap lesioned rats HCRT will be less effective in evoking wakefulness.
In aim 4 we will utilize the ataxin-HCRT transgenic rats to test this circuit. We will measure AD levels in the BF of the transgenic rats and hypothesize that in response to prolonged waking they will be lower compared to wild-type control rats, since the HCRT neurons are lost and not driving the BF neurons. Then 192-lgG saporin will be used in the transgenic rats to lesion the BF cholinergic neurons and we hypothesize that with both the BF cholinergic and HCRT neurons lost, the rats should have more sleep compared to single lesions. ? ? ?
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