title: Adolescent-onset GABAA α1 silencing regulates reward-related decision making.
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.
authors.affiliation: Graduate Program in Neuroscience, Emory University.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Butkovich
authors.affiliation: Graduate Program in Neuroscience, Emory University.|Department of Pediatrics, Emory University.|Yerkes National Primate Research Center, Emory University.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: DePoy
authors.affiliation: Department of Pediatrics, Emory University.|Yerkes National Primate Research Center, Emory University.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Allen
authors.affiliation: Department of Pediatrics, Emory University.|Yerkes National Primate Research Center, Emory University.|Molecular and Systems Pharmacology, Emory University.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Shapiro
authors.affiliation: Graduate Program in Neuroscience, Emory University.|Department of Pediatrics, Emory University.|Yerkes National Primate Research Center, Emory University.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swanson
authors.affiliation: Graduate Program in Neuroscience, Emory University.|Department of Pediatrics, Emory University.|Yerkes National Primate Research Center, Emory University.|Department of Psychiatry and Behavioral Sciences, Emory University.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
mesh_terms: D000367:Age Factors; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D003657:Decision Making / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D005502:Food; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012646:Self Administration
chemical_list: D018765:Dopamine Uptake Inhibitors; C546241:Gabra1 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D011963:Receptors, GABA-A; D049452:Green Fluorescent Proteins; D003042:Cocaine
keywords: GABAA; addiction; habit; mouse; response-outcome