Abstract
The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing that MSNs prioritize high-order executive processes information from the PFCx. Importantly, binge alcohol drinking alters this reciprocal inhibition by unilaterally strengthening BLA inhibition of PFCx inputs. In line with this observation, we demonstrate that in vivo optogenetic stimulation of the BLA, but not PFCx, blocks binge alcohol drinking escalation in mice. Overall, our results identify NAc MSNs as a key integrator of executive and emotional information and show that this integration is dysregulated during binge alcohol drinking.
Highlights
Binge drinking is a potentially dangerous pattern of ingesting large quantities of alcohol over a short period of time that effects primarily late adolescents and young adults with roughly 40% of college students in the United States reporting binge drinking (Krieger et al, 2018)
These data suggest that alteration of the processing of prefrontal cortex (PFCx)-driven executive and basolateral amygdala (BLA)-driven emotional information by medium-spiny neurons (MSNs) may be a key cellular mechanism underpinning the role of the nucleus accumbens (NAc) in controlling binge alcohol drinking
In line with this suggestion, optogenetic activation of BLA inputs in the NAc does result in an inhibition of the increase in alcohol drinking behavior observed during the first days of alcohol exposure in mice
Summary
Binge drinking is a potentially dangerous pattern of ingesting large quantities of alcohol over a short period of time that effects primarily late adolescents and young adults with roughly 40% of college students in the United States reporting binge drinking (Krieger et al, 2018). It has been hypothesized that drug addiction develops as a consequence of imbalances in processing of executive (cortical) and emotional (amygdala) information in the NAc (Bechara, 2005), there are currently no data at the cellular level supporting this theory Efforts to test this hypothesis at the cellular level have been hampered by the inability to evoke synaptic responses independently from different pathways converging on NAc MSNs using traditional approaches. When tested in freely behaving mice, optogenetic activation of the BLA, but not PFCx, prevented the escalation of alcohol consumption typically observed in mouse models of binge drinking These data suggest that alteration of the processing of PFCx-driven executive and BLA-driven emotional information by MSNs may be a key cellular mechanism underpinning the role of the NAc in controlling binge alcohol drinking
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