DESCRIPTION (provided by applicant): This grant application is a competing renewal focused on the role of rebound spiking in the generation of spatial coding of neurons in the medial entorhinal cortex, and on the role of modulatory input from the medial septum in regulating spatial coding. This research combines whole cell patch recording of the intrinsic properties of entorhinal neurons with computational modeling of the role of rebound spiking and innovative manipulations of medial septal input to test how modulation of rebound spiking influences unit recording data. Specific Aim #1: This grant will test a model in which rebound spiking regulated by feedback inhibition between stellate cells generates the spatial firing patterns of grid cells. The rebound spiking properties necessary for this model will be tested in whole cell patch clamp recordings that analyze the response to hyperpolarizing current pulses with and without a sinusoidal baseline oscillation. In the model, the speed of transition between firing fields depends upon running speed modulating the magnitude of feedback inhibition. This mechanism will be analyzed by testing the time course of rebound spiking after different magnitudes of hyperpolarizing pulses representing inhibitory input. The model also shows different transitions between firing fields for neurons with different intrinsic resonance properties. We will analyze how neurons with different intrinsic resonance properties generated by h current change their speed of rebound spiking. The intracellular recording data will provide an important test of the regulation of spiking activity dependent upon the cellular properties. Specific Aim #2: The network model of rebound spiking also generates predictions about the network dynamics influencing the pattern of unit recording data. Cellular data from the previous cycle of the grant showed that cholinergic activation of muscarinic receptors reduces the magnitude of h current, which reduces resonance frequency and slows rebound spiking. Unit recordings from medial entorhinal cortex of awake, behaving rats will test the predictions of the model for cholinergic modulatory effects on the relative firing properties of neurons with phase locking to the peak or the trough of the local theta rhythm in medial entorhinal cortex. Experiments will also test predictions of the model about the effects of increased or decreased cholinergic tone (regulated by DREADDs) on the size and spacing between grid cell firing fields. In addition, field potential recordings will test the effects of optogenetic manipulations of cholinergic modulation on the gamma frequency oscillations observed at different phases of theta rhyhm oscillations. Understanding the circuit dynamics of the entorhinal cortex will provide important understanding of the memory deficits associated with both neurological and psychiatric disorders. The entorhinal cortex shows volume reduction in disorders including depression and schizophrenia. The entorhinal cortex also shows the earliest signs and highest final density of neurofibrillary tangle pathology in Alzheimer's disease. Understanding the cellular and circuit dynamics of entorhinal cortex will assist in understanding its vulnerability to these disorders.

PUBLIC HEALTH RELEVANCE: The studies in this grant application focus on the cellular properties of rebound spiking in the entorhinal cortex that might maintain memory for spatial location. Individual experiments and models will analyze the cellular property of neurons in which they rebound from inhibition to generate a spike, will study how these properties could contribute to the spiking of neurons that code spatial location during behavioral tasks, and will determine how modulation of these spiking properties by neurochemicals such as acetylcholine could set appropriate dynamics for memory of spatial location. Understanding these cellular mechanisms may help us understand the breakdown of entorhinal cortex function in Alzheimer's disease and schizophrenia.