During the transition from the awake to the sleep state, neuronal activity in the neocortex is dramatically altered, previously chaotic activity becomes rhythmic and globally synchronous. This so-called slow-wave sleep, which includes sleep spindles and delta rhythms, requires thalamic input to the neocortex via thalamocortical cells. The thalamocortical cells themselves contain specialized ion channels whose voltage-gating properties allow rhythmic membrane potential oscillations. EEG recordings of the hippocampus have revealed that behavioral exploration is marked by theta rhythm, while slow wave sleep and awake immobility are marked by synchronous rhythmic bursts called sharp wave/ripple activity. Individual neurons of hippocampal areas CA1 and CA3 also generate membrane potential oscillations and rhythmic bursts of action potentials. Synchronization of these single neuronal oscillators in the thalamus and hippocampus is thought to occur through GABAergic interneurons. Current models suggest that these membrane potential oscillations and their entrainment by interneurons requires T-type calcium channels. Yet, the lack of specific T-type calcium channel blockers has prevented direct tests of this hypothesis. New technologies for targeted gene knockout and recent cloning of T-type calcium channels now make such work possible. Our laboratory has developed technologies for gene disruption in restricted populations of postmitotic neurons in the murine brain. This method permitted the deletion of NR1, a component of the NMDA receptor, exclusively in pyramidal neurons of hippocampal area CA1. The resulting conditional knockout mice were deficient in hippocampal long term potentiation, hippocampal place cell synchronization, and spatial learning and memory. The results demonstrated a critical role for synaptic plasticity in area CA1 in spatial learning. We propose to employ similar methods to test the hypothesis that T-type calcium channels are required for intrinsic neuronal oscillations in the hippocampal and thalamic neurons using slice electrophysiology. We then propose to examine the role of these oscillations in the production of thalamocortical sleep rhythms, hippocampal theta rhythm, and hippocampal sharp wave/ripple activity using ensemble multielectrode recording techniques. Lastly, we will begin to explore the role of these rhythmic modes of neuronal activity in sleep/wake cycles, attention, motivation, elementary sensory and motor skills, and learning and memory. Such work may also begin to explain the cellular and molecular basis for neuropsychiatric disorders like temporal lobe epilepsy and absence seizures where these physiologic rhythms become pathologic.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZRG1-IFCN-3 (01))
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Desmond, Nancy L
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Beth Israel Deaconess Medical Center
United States
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Anderson, Matthew P; Mochizuki, Takatoshi; Xie, Jinghui et al. (2005) Thalamic Cav3.1 T-type Ca2+ channel plays a crucial role in stabilizing sleep. Proc Natl Acad Sci U S A 102:1743-8