Jon C. Horvitz - US grants

DESCRIPTION: (Applicant's Abstract) Dopamine (DA) activity is strongly implicated in the reinforcing properties of drugs of abuse. The reinforcing properties of such drugs appear to result from pharmacological activation of DA substrates which mediate natural reinforcement processes. Critical gaps exist in the experimental literature, however, regarding the precise function(s) of DA in reinforcement, particularly within specific brain target sites. Humans acquire associations between A) their behaviors and reward events (response-reward) and B) between environmental stimuli and rewards (CS-reward); rats acquire similar associations. Is DA involved in the acquisition of response-reward, CS-reward, and/or stimulus-response associations during reinforcement? What is the precise role of DA within these associative mechanisms at different brain target sites? In light of recent information from single-unit and dialysis studies of DA activity in behaving animals, the studies in this application examine the precise nature of DA's role in the acquisition of CS-reward associations, within three brain target structures, the nucleus accumbens, caudate, and prefrontal cortex. The studies will examine, for each brain target site, whether DA disruption of CS-reward learning is dependent upon the intensity of the CS, the time interval between CS and reward, and whether DA disruptions impair aversive as well as appetitive CS-outcome associations under varying intensities of the aversive outcome.

[unreadable] DESCRIPTION (provided by applicant): A key to understanding addiction and other compulsive behaviors will be to reveal the means by which environmental cues (conditioned stimuli, CS) associated with primary rewards (palatable food or addictive drugs) come to generate both approach responses to the location where reward is expected and more complex operants associated with reward procurement. In order to understand the dysfunction of these processes, it is critical to understand their neural bases under normal conditions. The nucleus accumbens is anatomically connected as an interface between limbic motivational circuitry and the motor system, and has been strongly implicated in reward processes. However, it remains unclear 1) whether accumbens processing of a reward-paired CS and behavioral responses can be localized to the two anatomically and functionally distinct accumbens subregions, the core and shell; 2) whether individual accumbens neurons associated with the CS and behavioral response also encode the strength of the animal's reward expectation. 3) how levels of DA transmission interact with reward expectation strength to determine whether or not an approach response will be generated. Here, single-neuron recordings in the accumbens core or shell will be obtained in parallel with intra-accumbens microinjections of DA antagonists, employing identical behavioral paradigms. Reward expectation will be manipulated by presenting CSs that predict food delivery with varying probability or magnitude. Another set of experiments will ask whether accumbens responses code for the specific behavioral act, the specifc reward expected, and/or the behavior/reward conjunction. It is predicted that 1) neurons in the medial shell will be more responsive to the CS than neurons in the core; while neurons in the core will show greater firing during the behavioral response than neurons in the medial shell; 2) these cells will reflect the strength of the animal's reward expectation, 3) D1 receptor blockade will increase the threshold for CSs signaling varying levels of reward expectation to trigger approach responses, and 4) populations of accumbens neurons will be found to encode specific response-reward relationships. Regardless of the direction of results, the findings will contribute to a clearer neurobiological understanding of accumbens shell and core involvement in reward processes, without which the current state of knowledge may not lead to the development of effective strategies for treating addictions.Relevance [unreadable] [unreadable] The proposed experiments will shed light upon the neurobiological mechanisms underlying addiction and compulsive behaviors. Past research strongly suggests that the nucleus accumbens is a key site in the brain circuits by which natural rewards (such as food) as well as drug rewards (such as cocaine) acquire the ability to powerfully control human behavior. These studies, which examine the responses of neurons in this brain area to environmental stimuli associated with natural reward, will provide key insights regarding the manner in which reward-associated environmental stimuli produce normal and abnormal reward-driven behaviors. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): By the time individuals enter a clinical setting for treatment of a dysfunctional habit - whether directed toward food, gambling, drugs of abuse, or sex - the behavior has not only been acquired, but overlearned. In order to treat such behaviors, it is not sufficient to understand the neurobiological circuits controlling acquisition nd expression of behavior during early stages of learning. The long-term objective of this work is to understand the changes that occur within brain circuits mediating reward-directed behavior as it becomes over-learned. Preliminary data show that dopamine D1 receptor transmission within the nucleus accumbens core mediates cued approach to a reward location during early stages of learning, but not after the behavior has been well acquired. In this proposal we test the hypotheses that neural substrates mediating the reward-directed behavior A) remain in the accumbens while the role of dopamine transmission in the region diminishes (the accumbens early and late model), or B) no longer involves the accumbens (substrate shift model). Three specific aims attack these two hypotheses by 1) examining the cued approach response following blockade of dopamine receptors within the accumbens core or shell during either early or extended stages of training, 2) examining the effect of accumbens core or shell deactivation during early vs late stages of training, and 3) examining how individual neurons in the accumbens core and shell respond during the behavior after extended training. Unique sets of results will distinguish the two models above, as well as a third (hybrid) model in which the accumbens continues to mediate the learned behavior while additional parallel circuits come to mediate the response as well.