title: Prefrontal cortical GABAergic signaling and impaired behavioral flexibility in aged F344 rats.
abstract: The prefrontal cortex (PFC) is critical for the ability to flexibly adapt established patterns of behavior in response to a change in environmental contingencies. Impaired behavioral flexibility results in maladaptive strategies such as perseveration on response options that no longer produce a desired outcome. Pharmacological manipulations of prefrontal cortical GABAergic signaling modulate behavioral flexibility in animal models, and prefrontal cortical interneuron dysfunction is implicated in impaired behavioral flexibility that accompanies neuropsychiatric disease. As deficits in behavioral flexibility also emerge during the normal aging process, the goal of this study was to determine the role of GABAergic signaling, specifically via prefrontal cortical GABA(B) receptors, in such age-related deficits. Young and aged rats were trained in a set shifting task performed in operant chambers. First, rats learned to discriminate between two response levers to obtain a food reward on the basis of a cue light illuminated above the correct lever. Upon acquisition of this initial discrimination, the contingencies were shifted such that rats had to ignore the cue light and respond on the levers according to their left/right positions. Both young and aged rats acquired the initial discrimination similarly; however, aged rats were impaired relative to young following the set shift. Among aged rats, GABA(B) receptor expression in the medial prefrontal cortex (mPFC) was strongly correlated with set shifting, such that lower expression was associated with worse performance. Subsequent experiments showed that intra-mPFC administration of the GABA(B) receptor agonist baclofen enhanced set shifting performance in aged rats. These data directly link GABAergic signaling via GABA(B) receptors to impaired behavioral flexibility associated with normal aging.
authors.affiliation: Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States. Electronic address: sofiabeas@ufl.edu.
authors.forename: B S
authors.initials: BS
authors.lastname: Beas
authors.affiliation: Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States. Electronic address: jmcquail@ufl.edu.
authors.forename: J A
authors.initials: JA
authors.lastname: McQuail
authors.affiliation: Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States. Electronic address: cristina.banuelos@nih.gov.
authors.forename: C
authors.initials: C
authors.lastname: Ban Uelos
authors.affiliation: Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychology, University of Florida, Gainesville, FL, United States. Electronic address: setlow@ufl.edu.
authors.forename: B
authors.initials: B
authors.lastname: Setlow
authors.affiliation: Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, United States; Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, United States. Electronic address: bizonj@ufl.edu.
authors.forename: J L
authors.initials: JL
authors.lastname: Bizon
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism* / Q000523:psychology*; D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D001418:Baclofen / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D056344:Executive Function / Q000187:drug effects / Q000502:physiology*; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018080:Receptors, GABA-B / Q000378:metabolism*; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D014796:Visual Perception / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D001418:Baclofen
keywords: GABA(B) receptors; aging; baclofen; behavioral flexibility; prefrontal cortex; rat