Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala.
The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections.SIGNIFICANCE STATEMENTThe vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic structures that regulate alcohol intake, it has been difficult to disentangle how separate projections between them may control different aspects of these complex behaviors. Here, we demonstrate a new approach for noninvasively ablating each of these pathways and testing their necessity for both extinction and relapse. We show that inputs to the nucleus accumbens from medial prefrontal cortex and amygdala regulate alcohol-seeking behaviors differentially, adding to our understanding of the neural control of alcoholism.
Department of Psychiatry, Division of Molecular Psychiatry.|Interdepartmental Neuroscience Program, and.
Colby R
0000-0001-5086-1456
CR
Keistler
Department of Psychiatry, Division of Molecular Psychiatry.
Emma
0000-0001-5347-3926
E
Hammarlund
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425.
Jacqueline M
0000-0002-1176-5397
JM
Barker
Department of Psychiatry, Division of Molecular Psychiatry.|Interdepartmental Neuroscience Program, and.
Colin W
CW
Bond
Department of Psychiatry, Division of Molecular Psychiatry.|Interdepartmental Neuroscience Program, and.
Ralph J
RJ
DiLeone
Department of Psychiatry, Division of Molecular Psychiatry.|Interdepartmental Neuroscience Program, and.|Department of Psychology, Yale University, New Haven, Connecticut 06510, and.
Christopher
0000-0003-2117-9321
C
Pittenger
Department of Psychiatry, Division of Molecular Psychiatry, jane.taylor@yale.edu.|Interdepartmental Neuroscience Program, and.|Department of Psychology, Yale University, New Haven, Connecticut 06510, and.
Jane R
JR
Taylor
D000437:Alcoholism / Q000503:physiopathology* / Q000523:psychology*; D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D000431:Ethanol / Q000494:pharmacology; D005108:Extinction, Psychological; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence
D000431:Ethanol
alcohol; basolateral amygdala; extinction; medial prefrontal cortex; nucleus accumbens; reinstatement