Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex

Neuroscience. 2017 Mar 27;346:284-297. doi: 10.1016/j.neuroscience.2017.01.017. Epub 2017 Jan 26.


Deficits in cognitive flexibility, the ability to modify behavior in response to changes in the environment, contribute to the onset and maintenance of stress-related neuropsychiatric illnesses, such as depression. Cognitive flexibility depends on medial prefrontal cortex (mPFC) function, and in depressed patients, cognitive inflexibility is associated with hypoactivity and decreased glutamate receptor expression in the mPFC. Rats exposed to chronic unpredictable stress (CUS) exhibit compromised mPFC function on the extradimensional (ED) set-shifting task of the attentional set-shifting test. Moreover, CUS-induced ED deficits are associated with dendritic atrophy and decreased glutamate receptor expression in the mPFC. This evidence suggests that impaired glutamate signaling may underlie stress-induced deficits in cognitive flexibility. To test this hypothesis, we first demonstrated that blocking NMDA or AMPA receptors in the mPFC during ED replicated CUS-induced deficits in naïve rats. Secondly, we found that expression of activity-regulated cytoskeleton-associated protein (Arc) mRNA, a marker of behaviorally induced glutamate-mediated plasticity, was increased in the mPFC following ED. We then showed that CUS compromised excitatory afferent activation of the mPFC following pharmacological stimulation of the mediodorsal thalamus (MDT), indicated by a reduced induction of c-fos expression. Subsequently, in vivo recordings of evoked potentials in the mPFC indicated that CUS impaired afferent activation of the mPFC evoked by MDT stimulation, but not the ventral hippocampus. Lastly, glutamate microdialysis showed that CUS attenuated the acute stress-evoked increase in extracellular glutamate in the mPFC. Together, these results demonstrate that CUS-induced ED deficits are associated with compromised glutamate neurotransmission in the mPFC.

Keywords: attentional set-shifting; chronic unpredictable stress; cognitive flexibility; glutamate; medial prefrontal cortex; mediodorsal thalamus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Attention / drug effects
  • Attention / physiology
  • Cognition / drug effects
  • Cognition / physiology*
  • Cytoskeletal Proteins / metabolism
  • Glutamic Acid / metabolism
  • Glutamic Acid / physiology*
  • Hippocampus / physiopathology
  • Male
  • Mediodorsal Thalamic Nucleus / drug effects
  • Mediodorsal Thalamic Nucleus / physiology
  • Nerve Tissue Proteins / metabolism
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiopathology*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / physiology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology*
  • Synaptic Transmission*


  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-jun
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • activity regulated cytoskeletal-associated protein
  • Glutamic Acid