aBLA and pBLA Projections of Cell Type-Specific D1 Neurons from the mPFC Differentially Control Alcohol-Seeking Behavior.

BACKGROUND: Alcohol use disorder (AUD) is characterized by compulsive alcohol-seeking behavior, which is associated with dysregulation of afferent projections from the medial prefrontal cortex (mPFC) to the basal 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 two-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. The electrophysiological method and in vivo optogenetic technique 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 the D1R neurons in the mPFC. Interestingly, we found that two populations of D1R neurons, anterior (aD1R) 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 aD1R neurons in alcohol-drinking mice. Moreover, we observed enhanced glutamatergic transmission and an increase AMPA/NMDA ratio in the mPFC inputs from pD1R neurons to pBLA. Optogenetic long-term depression (LTD) induction of the pD1R-pBLA circuit reduced alcohol-seeking behavior, while optogenetic LTD or long-term potentiation (LTP) induction of the aD1R-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 AUD.