Neurobiological Investigation of BLA->NAc Circuit in Motivated Behavior

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DESCRIPTION (provided by applicant): Environmental stimuli that predict reward can acquire biological salience through learned cue-outcome associations. These associations can promote the expression of motivated behaviors and the nucleus accumbens (NAc) plays a key role in this process [1-5]. The NAc is commonly viewed as the limbic-motor interface [6], integrating information from cortical and subcortical structures related to memory, drive and motivation and influencing motor output. The basolateral amygdala (BLA) is one important neural region that sends glutamatergic projections to the NAc and appears to promote goal-seeking behaviors in response to reward-paired cues [7, 8]. While a considerable body of research implicates the highly inter- and intra- connected BLA macrocircuit in the execution of motivated behaviors [14-19], it has been difficult to selectively manipulate the BLA-NAc pathway with available techniques. As such, little is known about how isolated BLA input to the NAc contributes to behavior and NAc cell firing and ultimately drives associative learning related to motivated behaviors. Importantly, a recent study by Stuber and colleagues [20] used optogenetics to selectively inhibit the BLA-NAc pathway and demonstrated a robust disruption of goal-directed actions during reward-predictive cue presentation. Although highly informative, that study did not examine the effects of BLA- NAc inhibition during acquisition versus expression of motivated behavior in separate animals, or behavior to reward-paired versus unpaired (general) cues during BLA-NAc inactivation. Further, although previous studies have shown that nonspecific pharmacological inactivation of the BLA differentially disrupts phasic NAc cell firing to cues during a cued-instrumental task [21], it is not known if this effect was the result of generalized BLA inactivation, or inhibition of specific BLA inputs to the NAc. As such, two specific Aims are proposed in this application to address these issues. Aim 1 will examine the role of the BLA-NAc pathway in the acquisition versus expression of first order conditioning (FOC) using optogenetic tools. Aim 2 will use optogenetic methods coupled with electrophysiological recording procedures to characterize the contribution of BLA afferent inputs to the NAc on NAc cell firing during FOC. The results of the proposed studies will provide critical information into the precise role of BLA inputs to the NAc in discrete aspects of FOC behavior, and in modulating the activity of NAc neurons that encode FOC. Importantly, completion of the proposed studies will also enable my continued training in electrophysiology and optogenetic methods in behaving animals.