title: Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction.
abstract: Multiple neuropsychiatric disorders, e.g., depression, are linked to imbalances in excitatory and inhibitory neurotransmission and prefrontal cortical dysfunction, and are concomitant with chronic stress.
  
  
  
  We used electrophysiologic (n = 5-6 animals, 21-25 cells/group), neuroanatomic (n = 6-8/group), and behavioral (n = 12/group) techniques to test the hypothesis that chronic stress increases inhibition of medial prefrontal cortex (mPFC) glutamatergic output neurons.
  
  
  
  Using patch clamp recordings from infralimbic mPFC pyramidal neurons, we found that chronic stress selectively increases the frequency of miniature inhibitory postsynaptic currents with no effect on amplitude, which suggests that chronic stress increases presynaptic gamma-aminobutyric acid release. Elevated gamma-aminobutyric acid release under chronic stress is accompanied by increased inhibitory appositions and terminals onto glutamatergic cells, as assessed by both immunohistochemistry and electron microscopy. Furthermore, chronic stress decreases glucocorticoid receptor immunoreactivity specifically in a subset of inhibitory neurons, which suggests that increased inhibitory tone in the mPFC after chronic stress may be caused by loss of a glucocorticoid receptor-mediated brake on interneuron activity. These neuroanatomic and functional changes are associated with impairment of a prefrontal-mediated behavior. During chronic stress, rats initially make significantly more errors in the delayed spatial win-shift task, an mPFC-mediated behavior, which suggests a diminished impact of the mPFC on decision making.
  
  
  
  Taken together, the data suggest that chronic stress increases synaptic inhibition onto prefrontal glutamatergic output neurons, limiting the influence of the prefrontal cortex in control of stress reactivity and behavior. Thus, these data provide a mechanistic link among chronic stress, prefrontal cortical hypofunction, and behavioral dysfunction.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio; Neuroscience Programe, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: McKlveen
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Morano
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Maureen
authors.initials: M
authors.lastname: Fitzgerald
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zoubovsky
authors.affiliation: Neuroscience Programe, University of Cincinnati, Cincinnati, Ohio; Department of Neurologye, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Cassella
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio; Neuroscience Programe, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Scheimann
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio; Neuroscience Programe, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Ghosal
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Parinaz
authors.initials: P
authors.lastname: Mahbod
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Packard
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Brent
authors.initials: B
authors.lastname: Myers
authors.affiliation: Neuroscience Programe, University of Cincinnati, Cincinnati, Ohio; Department of Anesthesiology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Baccei
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio; Neuroscience Programe, University of Cincinnati, Cincinnati, Ohio; Address correspondence to James P. Herman, Ph.D., Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 East Galbraith Road, ML 0506, Cincinnati, OH 45327. Electronic address: james.herman@uc.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011965:Receptors, Glucocorticoid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: Chronic variable stress; GABA; Glucocorticoid receptor; Prefrontal cortex; Stress; mIPSC