Gwendolyn G. Calhoon, Ph.D. - US grants

DESCRIPTION (provided by applicant): The ability of an individual to make appropriate choices and enact adaptive behaviors within a dynamic external environment is of crucial importance for his ability to function in society. One must integrate contextual information, previous experience, future planning, and motivational drive, among other points of information, to select the superior course of action among those available. The nucleus accumbens (NA) is a brain region that lies at the confluence of multiple other structures responsible for processing such information, including the prefrontal cortex (PFC) and hippocampus (HP). Activity of neural ensembles in the NA shapes behavioral outputs, and aberrant functioning in this nucleus can lead to the inflexible behaviors characteristic of psychiatric conditions such as drug abuse and schizophrenia. The purpose of the proposed project is to investigate the mechanisms by which the NA integrates inputs from the PFC and HP, and how preferential processing of information arising from either afferent impacts behavior. It is hypothesized that high frequency activity in the PFC shunts excitatory signals from HP afferents in medium spiny neurons (MSNs) via activation of interneurons in the NA. The accumbens is thus able to synchronize with PFC activity such that PFC-dependent behaviors may be enacted. In vivo intracellular electrophysiological techniques will be used in anesthetized rats to evaluate the contribution of accumbens interneurons to the selection of PFC versus HP inputs. MSNs in the NA will be recorded during PFC and HP stimulation in the presence and absence of GABA antagonists. In separate experiments, synchronicity between NA and PFC versus HP local field potentials will be evaluated in behaving animals as a function of correctness of responding in a delayed-nonmatching-to-sample task. NA interneuron signaling will be disrupted via local administration of GABA antagonists to determine whether their contribution to accumbens inputs selection is crucial for response selection. These experiments will be performed in an effort to determine whether NA interneurons activated by burst-activity of the PFC shunt HP responses in MSNs, as well as to determine the relevance of such a mechanism to behavior. Gaining such an understanding of information processing in the NA will be instrumental in recognizing inappropriate activity in this brain region that may underlie maladaptive behaviors in drug abuse and schizophrenia. PUBLIC HEALTH RELEVANCE: The nucleus accumbens is a structure poised to integrate information regarding environmental context, future goals and planning, emotional states, and reward salience to allow adaptive behavior in an ever changing environment. Psychiatric disorders such as schizophrenia and drug addiction are marked by deficits in this type of cognitive flexibility. Through this project, we seek to understand mechanisms of information processing in the nucleus accumbens, thereby providing insight into normal functioning that is disrupted in such psychiatric conditions.