John K. Chapin - US grants

The experiments proposed here will be carried out as part of a general investigation into the neural mechanisms underlying ethanols disruptive effect on cognitive functions. In particular, selective attention to a sensory stimulus in the presence of distraction is known to be a cognitive skill which is markedly disturbed during intoxication. The PI has developed a relatively simple neurophysiological model for selective sensory processing in the cerebral cortex and is currently using this model in assessments of the effects of acute ethanol intoxication. This model involves recording single units in the primary somatosensory (SI) cortex of rats. Computer techniques are used to measure the gating of cutaneous sensory transmission from the forepaw to these cells during, and in correlation with, link movements to touch the ground in locomotion. Normally, inhibitory controls only allow this sensory information to reach certain cortical cells during precise phases of the step cycle. Ethanol, among other things, appears to reduce or abolish these inhibitory controls in a dose-dependent fashion and thus allow sensory inputs to reach cortical cells in an unfiltered fashion. The experiments proposed here will: 1) investigate these findings in the SI cortex more thoroughly, 2) utilize the Preferring (P) and Non-preferring (NP) rat strains of Li in similar experiments, 3) investigate the possibility that ethanols reduction of inhibitory gating controls may result from disruption of activity in the adjacent motor cortex (one possible source of the gating bias signal) or motor cortical afferents, and 4) develop an operantly controlled behavioral paradigm for "passive" selective attention in which sensory stimuli are made "significant" by pairing it with a reward.

This investigation addresses the need to define the neural circuit mechanisms by which the brain processes different types of somesthetic sensory information during actual behavioral situations, especially during active movements of the limbs. As an example of this, the PI has described a phenomenon in which somatic sensory input to the primary somatosensory cortex of the rat is modified according to the phases of reach-to-touch movements of the forelimb. In this, cutaneous sensory inputs from the forepaw projecting to specific classes of cortical neurons are gated-in or gated-out according to whether the stimulation is delivered during the fast movement of the limb toward a target, or during the touch of the target itself. These studies will continue to define the sites in the somatosensory system at which this sensory gating is occurring, in the context of spontaneous or operantly conditioned movements of the forelimb or the whiskers. The possible role that the motor cortex and other biasing sources may play in this phenomenon will also be examined. New techniques for recording multiple single units at multiple levels of the CNS will be employed in these studies.

The experiments proposed here will be carried out as part of a general investigation into the neural mechanisms underlying ethanols disruptive effect on cognitive functions. In particular, selective attention to a sensory stimulus in the presence of distraction is known to be a cognitive skill which is markedly disturbed during intoxication. The PI has developed a relatively simple neurophysiological model for selective sensory processing in the cerebral cortex and is currently using this model in assessments of the effects of acute ethanol intoxication. This model involves recording single units in the primary somatosensory (SI) cortex of rats. Computer techniques are used to measure the gating of cutaneous sensory transmission from the forepaw to these cells during, and in correlation with, link movements to touch the ground in locomotion. Normally, inhibitory controls only allow this sensory information to reach certain cortical cells during precise phases of the step cycle. Ethanol, among other things, appears to reduce or abolish these inhibitory controls in a dose-dependent fashion and thus allow sensory inputs to reach cortical cells in an unfiltered fashion. The experiments proposed here will: 1) investigate these findings in the SI cortex more thoroughly, 2) utilize the Preferring (P) and Non-preferring (NP) rat strains of Li in similar experiments, 3) investigate the possibility that ethanols reduction of inhibitory gating controls may result from disruption of activity in the adjacent motor cortex (one possible source of the gating bias signal) or motor cortical afferents, and 4) develop an operantly controlled behavioral paradigm for "passive" selective attention in which sensory stimuli are made "significant" by pairing it with a reward.

This investigation addresses the need to define the neural circuit mechanisms by which ethanol disrupts higher-order selective sensory processing in primary and associative areas of the cerebral cortex. As neurophysiological models for such processing, the PI has described several types of sensory modulation in the somatosensory cortex of rats. These include: 1) inhibitory sensory "gating" occurring in phase with forelimb movement, 2) sensory facilitation occurring in arousal, and 3) sensory facilitation occurring in attention and anticipation behaviors. All these phenomena will be investigated using a technique the PI has developed for simultaneous recording from multiple single neurons through arrays of microwire electrodes chronically implanted in precise locations the cortex and thalamus. The major aim will be to test the effects of ethanol on normal circuit interactions exhibited in these recordings. Also, the long term stability of such recordings will allow the same neurons to be recorded over the time course of ethanol chronicity and withdrawal, and over administrations of other drugs of abuse. Finally, genetic models (such as P-NP rats) will be used.

DESCRIPTION: The overall aim of this project is to elucidate the neural circuit mechanisms underlying the brain's ability to control its own sensory input. To address this issue, large number of single neurons (up to 128) will be recorded simultaneously through multi-electrode arrays implanted in multiple processing levels of the trigeminal somatosensory system of awake rates, during immobility and will performing exploratory wwhisking movements. Simultaneous recordings have recently been obtained in the trigeminal ganglion (Vg), principal (PrV) and spinal SpV) trigeminal nuclei, ventral posteromedial (VPM) thalamus, and somatosensory (SI) cortex. Aim #1 is to continue current studies of spatiotemporally distributed "shifting" receptive fields in neurons in the VPM and SI, which appear to be learned through motor experience. Aim #2 is to determine whether active whisker movement produces and "efference copy" which modulates sensory transmission according to the phase and "motor intention" of the movement. Aim #3 is to record from the same neurons in rats trained to discriminate among several tactile objects using active whisking.

This proposal addresses the possibility of utilizing "motor" information extracted from simultaneous neuronal population recordings in the brain to remedy the loss of motor function associated with paralysis, limb amputation and other neurological conditions. This effort is also scientifically significant because it directly addresses the problem of neural population coding in the brain, and the possibility of controlling such coding through biofeedback. We have recently demonstrated in rats and monkeys the feasibility of using simultaneous neuronal population recordings in the motor cortex to control movement of a robot arm. The rats, in particular, were able to utilize their brain activity to accurately position (in one dimension) the robot arm under a water dropper, and then carry the water drop back to their mouths. Moreover, over continued training in this "neuro-robotic" mode, these animals were able progressively decorrelate this neural activity from the overt movements with which they were normally associated. This proposal has three specific aims: I. To utilize chronic neural ensemble recordings in monkeys to directly control multi-directional robot arm movement. The main issue is whether neuro-robotic feasibility be demonstrated for control of movements in multiple directions and under varying load conditions. II. To develop, implement and optimize new methods for transforming neuronal population activity into realtime neuro-robotic control signals. The main issue is whether simple linear neural population coding algorithms can be used to produce optimal neuro-robotic control functions, or whether nonlinear networks will be necessary. III. To investigate the feasibility of neuro-robotic control after sensorimotor denervation. The main question is whether neuro- robotic control is feasible after paralysis. This will be investigated here in rats subject to reversible denervation or amputation of the forelimb.