Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20714-9. doi: 10.1073/pnas.1208342109. Epub 2012 Nov 26.

Abstract

Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affect / drug effects
  • Affect / physiology
  • Amitriptyline / pharmacology
  • Animals
  • Antidepressive Agents, Tricyclic / pharmacology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Brain-Derived Neurotrophic Factor / antagonists & inhibitors
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / physiology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Corticosterone / pharmacology
  • Corticosterone / physiology
  • Dendritic Spines / drug effects
  • Dendritic Spines / physiology
  • Gene Knockdown Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mifepristone / pharmacology
  • Motivation / drug effects
  • Motivation / physiology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / physiology*
  • Stress, Physiological

Substances

  • Antidepressive Agents, Tricyclic
  • Brain-Derived Neurotrophic Factor
  • Receptors, Glucocorticoid
  • Amitriptyline
  • Mifepristone
  • Corticosterone