J. Wayne Aldridge - US grants

DESCRIPTION (Adapted from applicant's abstract): The goal of this project is to understand the neuronal mechanisms of the basal ganglia that mediate sequences of behavior. Studies in humans indicate that sequence control, especially the control of movement sequences, may be a fundamental property of the basal ganglia. Motor disorders of the basal ganglia, such as Parkinson's disease and Huntington's disease, are associated with a profound loss of the ability to organize and execute sequences of movement. Furthermore, cognitive disorders of the basal ganglia such as the uncontrollable repetition of spoken words in Tourette's syndrome and the tormenting habits and thoughts of obsessive compulsive disorder suggest that sequential control mechanisms may be a fundamental property of the basal ganglia. In this project, the correlates and properties of single neurons related to instinctive, stereotyped sequences of behavioral actions will be studied. The long term goals of this project are designed to answer the following questions: How does the brain and in particular, the basal ganglia coordinate behavioral sequences? Are there basic principals for sequential organization? What are the computational properties of sequence-related neuronal assemblies in the basal ganglia? A key hypothesis to be tested in this study is that neuronal activity of a subset of cells in the basal ganglia will be related to movements within the context of rule-governed behavioral sequences and not related to these movements when they occur on their own or in irregular, less organized sets of movements. Previous experiments have shown that rats exhibit highly structured (i.e., syntactical) sequences of grooming bouts that follow strict rules for their temporal organization and that these syntactical sequences are disrupted by damage to the basal ganglia. Rats also execute comparable grooming movements in isolation and in other randomly organized patterns of movements. Our method will be to record and compare the activity of single neurons in rats during both syntactical and non-syntactical grooming sequences. It is anticipated that neuronal activity will be preferentially linked to movements in the context of stereotyped syntactical sequences. We will evaluate the anatomical location of neurons related to grooming movements to test the idea that the functional organization is related to the proposed cortico-striatal loops in the basal ganglia. We will evaluate the hypothesis that neostriatal neurons mediate sequences by modulating sensorimotor responsiveness. Finally, we will test the idea that Dl dopamine receptor activation will enhance neuronal activity related to sequential movements and the dopaminergic lesions will produce the opposite effect. It is hoped that new information about the neuronal network properties related to the organization of behavioral sequences will lead to a better understanding of the pathophysiology of basal ganglia diseases and eventually contribute to better treatments for these brain disorders.

DESCRIPTION (provided by applicant): In this study, we will investigate possible neural coding mechanisms for reward liking and wanting, which are important to drug addiction as well as motivation for natural rewards. We will focus on neural firing in the ventral pallidum (VP), which is a primary target of brain mesolimbic circuits involved in wanting and liking rewards. We will test the idea that neural activity in the ventral pallidum encodes stimuli that are hedonic rewards, such as sucrose taste, and encodes also conditioned incentive stimuli that predict rewards, such as Pavlovian-trained sounds. We will record activity of single neurons in rats trained to discriminate a tone (CS+) that predicts a sucrose reward (UCS) from a tone that predicts nothing (CS-). We anticipate finding that VP neurons have population codes and firing rate codes both for hedonic UCS receipt and for predictive CS+s. To find out whether such codes reflect the value of these reward stimuli or else more stable properties (sensory features or prior associations), we will test VP firing after manipulations that change CS or UCS reward values (e.g., neural sensitization, taste aversion conditioning). Based on preliminary work, we anticipate that VP neuronal firing rates will code CS and UCS reward values independently of other features, providing neural bases for integrating reward liking and wanting. Our findings could lead to a better understanding of the pathophysiology of reward and new therapeutic tactics for drug abuse.

PROJECT SUMMARY (See instructions): Cues associated with food and drug rewards acquire 1) predictive properties, and the ability to evoke conditioned responses, and 2) incentive properties, and thus the ability to attract, reinforce, and motivate behavior. These latter properties may be especially important in the development of compulsive behavioral disorders, including addiction. However, predictive cues do not necessarily have the ability to act as incentive stimuli. In fact, there are substantial individual differences in the ability of cues to influence behavior. For example, while some people are able to use drugs casually throughout their lifetime, others become addicted, having difficulty remaining abstinent, especially in the presence of people, places, and other cues associated with drug-taking. By examining the behavioral responses to food cues, we have identified rats that attribute incentive value to these cues (sign-trackers), and are more sensitive to the effects of drug cues on drug-taking behavior and relapse. In contrast, goal-trackers do not attribute incentive value to food cues and are unaffected by drug cues. Studies of cue-evoked changes in brain activity have found that ventral regions of the basal ganglia (including the nucleus accumbens [NAcc] and ventral pallidum [VP]) process information related to both food and drug cues. However, until recently, it has been difficult to delineate what aspects (i.e., predictive or incentive) of these cues are processed, and whether the processsing of incentive value is altered by abused drugs. The experiments described within this proposal will utilize individual differences of sign- and goal-trackers to determine whether the NAcc and VP process incentive vs. predictive properties of food cues in sign- and goal-trackers, and to what extent the neurochemical dopamine is involved. To this end, we will measure the neural response to cues in Pavlovian and drug self-administration experiments using in-vivo single-unit recordings. Our overall hypothesis is that VP and NAcc neurons will be more responsive to the incentive properties than to the predictive properties of reward cues when presented within these experiments.