Adolescent-onset GABA(A)1 silencing regulates reward-related decision making

• Type of Material: Article
• Authors: Laura M. Butkovich, Emory University; Lauren M. DePoy, Emory University; Amanda G. Allen, Emory University; Lauren P. Shapiro, Emory University; Andrew M. Swanson, Emory University; Shannon Gourley, Emory University
• Language: English
• Date: 2015-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
• Final Published Version (URL): http://dx.doi.org/10.1111/ejn.12995
• Title of Journal or Parent Work: European Journal of Neuroscience
• ISSN: 0953-816X
• Volume: 42
• Issue: 4
• Start Page: 2114
• End Page: 2121
• Grant/Funding Information: The Yerkes National Primate Research Center is supported by the Office of Research Infrastructure Programs/OD P51OD11132.; This work was supported by the Emory University Research Council, DA015040 (PI: Kuhar), and DA034808 (PI: Gourley).; The Emory Viral Vector Core is supported by an NINDS Core Facilities grant, P30NS055077.
• Keywords: IN-UTERO; habit; PRENATAL COCAINE EXPOSURE; GABA(A); RECEPTOR ALPHA-1; Science & Technology; response-outcome; EXPRESSION; RATS; INSTRUMENTAL ACTION; mouse; Neurosciences; MICE; MEDIAL PREFRONTAL CORTEX; addiction; Neurosciences & Neurology; BEHAVIORAL PLASTICITY; PRELIMBIC CORTEX; Life Sciences & Biomedicine
• Research Categories: Biology, Molecular; Psychology, Behavioral; Biology, Neuroscience

Abstract

The GABAA receptor mediates fast, inhibitory signaling, and cortical expression of the α1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABAA α1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABAA α1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral-mediated gene silencing of Gabra1. Adolescent-onset Gabra1 knockdown delayed the acquisition of a cocaine-reinforced instrumental response but spared cocaine seeking in extinction and in a cue-induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action-outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent-onset knockdown, although not adult-onset knockdown, delayed the expression of goal-directed response strategies in this task, resulting instead in inflexible habit-like modes of response. Thus, the maturation of medial prefrontal cortex GABAA α1 systems during adolescence appears necessary for goal-directed reward-related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity.