We propose to undertake computational studies of rhythmic oscillations during quiet sleep in the thalamus and the CA1 hippocampus. Although the thalamic 7-14 Hz spindles and 0.5-5 Hz delta waves, and the hippocampal sharp wave (SPWs) with 200 Hz """"""""ripples,"""""""" occur as rhythmic and stereotyped events, they are also highly complex and display strongly intermittent characteristics (sparse firing of single cells, sparse populations firing patterns). We hypothesize that in both cases, the recurrent synaptic inhibition is central to the genesis and synchronization of the oscillatory phenomena, as well as to the spatio-temporal intermittency. Specific projects include the following. 1. Study in computer simulations the reciprocal connection between inhibitory thalamic reticular (RE) cells and excitatory thalamocortical (TC) relay cells, as a possible mechanism to synchronize the thalamic network oscillations. 2. Formulate and test by modeling the hypothesis that transitions from wakefulness to the spindle sleep state, then to the delta wave sleep state, can be induced by a gradual hyperpolarization of the TC cells via neuromodulatory systems. 3. During spindles the TC cells remain subthreshold for most of the population rhythmic cycles, and fire rebound bursts only intermittently. Our working hypothesis is that this sparse firing phenomenon is produced by an interplay between the synaptic inhibition of the RE origin and an intrinsic property (the hyperpolarization-activated cation (h-type) current) of the TC cells. The modeling is closely related to analysis of intracellular recording data from spindling thalamic slices, provided by Dr. D. A. McCormick. 4. We shall perform statistical analyses of the experimental data provided by Dr. G. Buzsaki's laboratory on hippocampal SPWs, in order to quantitatively characterize the intermittent aspects as well as the oscillatory aspects of this cooperative phenomenon, in CA1 hippocampus. 5. We shall undertake a biophysical modeling of the CA1 network, in order to assess the following ideas. (a) The fast (200 Hz) SPW ripple in CA1 hippocampus are generated by rhythmic firing of interneurons in the strata pyramidale and oriens, and the population synchrony is brought about by synaptic connections between these interneurons. (b) The pyramidal cell population can be synchronized very rapidly during 200 Hz ripples by the divergent projection from interneurons, and the recruiting process as well as the extremely sparse firing patterns in the CA1 network are regulated by the recurrent synaptic inhibitory mechanisms. The proposed research program is designed to elucidate mechanisms underlying normal population oscillations in the thalamus and hippocampus, as well as the pathological petit mal (absence) seizure in the thalamus and focal epilepsy in the hippocampus. St the theoretical level, this work could lead to a general framework to describe ryhthmic, yet strongly intermittent, neuronal cooperative firing patterns.
