2000 — 2002 |
Jones, Barbara E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Basal Forebrain Neurons in Sleep Wake States
The long-term goal of this research is to understand the nerual and chemical mechanisms that generate the different states of the brain and organism: waking (W), slow wave sleep (SWS) and paradoxical sleep (PS or rapid eye movement sleep, REM). During these states, the activity of the cerebral cortex undergoes fundamental changes, which are importantly determined by modulatory inputs from the basal forebrain. In human disease, lesions in this area can result in deficits in cortical activation and arousal, yet also in SWS. The aim of the proposed research is to identify by their anatomical features and neurotransmitters, including acetylcholine, GABA and glutamate, those basal forebrain neurons which are responsible for cortical activation that occurs during W and PS, and those which are reciprocally involved in cortical deactivation that occurs during SWS. Moreover, whether basal forebrain neurons, including cholinergic, GABAergic and possibly glutamatergic cells, modulate cortical activity in a rhythmic manner during cortical activation will be tested according to the thesis that such rhythmic modulation may provide a mechanism for integrated coherent activity across cortical regions. In a first series of experiments, neurons will be recorded by extracellular (or intracellular) technique in urethane-anesthetized rats to be characterized according to their discharge (or membrane) properties in relation to the cortical electroencephalogram (EEG) during undisturbed, irregular slow wave EEG and during stimulus- evoked, activated EEG. The electrophysiologically characterized neurons will be labelled with neurobiotin by juxtacellular (or intracellular) technique, revealed as cholinergic, GABAergic or possibly glutamatergic by dual fluorescent staining and delineated according to their somatodendritic morphology and axonal projections. In a subsequent experimental series, basal forebrain neurons will be recorded by extracellular technique in head-restrained animals to be characterized according to their discharge in relation to the EEG during natural states of W, SWS and PS. Again, they will be labelled by juxtacellular technique for subsequent identification as cholinergic, GABAergic or possibly glutamatergic and for delineation of their efferent projections. These studies will for the first time identify the specific neurons that are critically involved in state determination and reveal the discharge/membrane properties, chemical neurotransmitters and efferent projections by which they modulate cerebral activity across the sleep-wake cycle.
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2003 — 2011 |
Jones, Barbara E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Basal Forebrain Neurons in Sleep-Wake States
DESCRIPTION (provided by applicant): 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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