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Saleem NICOLAA Neural Circuit Underlying Dopamine-Mediated Behavior Selection

Abstract :

uman and animal behavior is guided by cues. The brain constantly evaluates new sensory information and adjusts behavior to maximize reward and minimize aversive consequences. Understanding how the brain decides to change behavior based on cues is thus profoundly important for understanding brain function, not least because such an understanding could facilitate the development of treatments for diseases in which cue-elicited behavior selection is aberrant. Drug addiction is such a disease: in response to stimuli that predict drug availability, addicts pursue drug despite grave consequences for themselves and their families. Even addicts who have remained drug-free for months or years are susceptible to relapse in the presence of drug-predictive cues. One common feature of all drugs of abuse is that they cause an increase in the release of dopamine in the nucleus accumbens, the ventral-most portion of the striatum. To better understand how accumbens dopamine contributes to behavior selection in response to cues, we conducted a series of behavioral, pharmacological and electrophysiological studies.

We trained animals to perform a simple task in which they were required to perform an operant response to a cue in order to obtain a sucrose reward. Microinjection of either D1 or D2 dopamine receptor antagonists into the accumbens severely impaired the ability of animals to respond to cues, while having little effect on tasks that did not require cue responding. Thus, both D1 and D2 receptor activation is specifically required to respond to reward-predictive cues. To investigate the mechanism of this effect of dopamine in the accumbens, we recorded the spiking activity of neurons in the accumbens while animals performed a cue-responding task. Subpopulations of neurons were excited or inhibited by presentation of predictive cues. These cue-evoked neuronal responses were abolished by transient inactivation of the ventral tegmental area, the midbrain nucleus containing dopamine neurons that project to the accumbens. Coupled with the finding that dopamine antagonists injected into the accumbens reduce behavioral responding to cues, these results indicate that cue-evoked accumbens firing patterns are dopamine-dependent and drive the behavioral response to cues.

In further behavioral studies, we found that transient inactivation of the accumbens with tetrodotoxin or glutamate receptor antagonists had effects dissimilar to those of dopamine antagonist injection. Instead of reducing cue responsivity, accumbens inactivation increased responding to non-reward predictive cues. These results are consistent with the idea that accumbens neurons both dopamine-dependently promote specific responses to cues and dopamine-independently inhibit responding, perhaps because accumbens neurons influence behavior through direct (activating behavior) and indirect (inhibiting behavior) output pathways.

Selected publications

Nicola SM, Hopf FW and Hjelmstad GO (2004)
Contrast enhancement: a physiological effect of striatal dopamine?
Cell Tissue Res. 318:93-106.
Wakabayashi KT, Fields HL and Nicola SM (2004) Dissociation of the role of nucleus accumbens dopamine in responding to reward-predictive cues and waiting for reward. Behav.
Brain Res. 154:19-30.
Yun IA, Nicola SM and Fields HL (2004) Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue-evoked goal-directed behavior.
Eur. J. Neurosci. 20:249-263.
Yun IA, Wakabayashi KT, Fields HL and Nicola SM (2004) The ventral tegmental area is required for the behavioral and nucleus accumbens neuronal firing responses to incentive cues.
J. Neurosci. 24:2923-2933.

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