Anterior and Posterior Basolateral Amygdala Projections of Cell Type-Specific D1-Expressing Neurons From the Medial Prefrontal Cortex Differentially Control Alcohol-Seeking Behavior.

ABSTRACT

BACKGROUND: Alcohol use disorder is characterized by compulsive alcohol-seeking behavior, which is associated with dysregulation of afferent projections from the medial prefrontal cortex to the basolateral amygdala (BLA). However, the contribution of the cell type-specific mechanism in this neuronal circuit to alcohol-seeking behavior remains unclear. METHODS: Mice were trained with 2-bottle choice and operant alcohol self-administration procedures. Anterograde and retrograde viral methods traced the connection between dopamine type 1 receptor (D1R) neurons and BLA neurons. Electrophysiology and in vivo optogenetic techniques were used to test the function of neural circuits in alcohol-seeking behavior. RESULTS: Chronic alcohol consumption preferentially changed the activity of posterior BLA (pBLA) neurons but not anterior BLA (aBLA) neurons and overexcited D1R neurons in the medial prefrontal cortex. Interestingly, we found that 2 populations of D1R neurons, anterior and posterior (pD1R) neurons, separately targeted the aBLA and pBLA, respectively, and only a few D1R neurons innervated both aBLA and pBLA neurons. Furthermore, pD1R neurons exhibited more excitability than anterior D1R neurons in alcohol-drinking mice. Moreover, we observed enhanced glutamatergic transmission and an increased NMDA/AMPA receptor ratio in the medial prefrontal cortex inputs from pD1R neurons to the pBLA. Optogenetic long-term depression induction of the pD1R-pBLA circuit reduced alcohol-seeking behavior, while optogenetic long-term depression or long-term potentiation induction of the anterior D1R-aBLA circuit produced no change in alcohol intake. CONCLUSIONS: The pD1R-pBLA circuit mediates chronic alcohol consumption, which may suggest a cell type-specific neuronal mechanism underlying reward-seeking behavior in alcohol use disorder.