TY - JOUR
T1 - Activity in the ventral medial prefrontal cortex is necessary for the therapeutic effects of extinction in rats
AU - Fucich, Elizabeth A.
AU - Paredes, Denisse
AU - Saunders, Madeleine O.
AU - Morilak, David A.
N1 - Funding Information:
This work was supported by National Institute of Mental Health Research Grants MH072672 and MH053851, National Institutes of Health T32 Training Grant NS082145, National Center for Advancing Translational Sciences FellowshipGrantTL1TR001119,U.S.DepartmentofVeteransAffairsBiomedicalLaboratoryResearchandDevelop-ment Program Merit Award 1I01BX003512, and William and Ella Owens Medical Research Foundation, none of which had any role in study design, data collection, analysis or interpretation, nor in the preparation or decision to submit this paper for publication. The contents of this paper do not represent the views of the Department of VeteransAffairsortheU.S.Government.WethankLaurenHatherall,JeriSilva,SuphadaLertphinyowong,andKelly Hohl for technical assistance.
Funding Information:
This work was supported by National Institute of Mental Health Research Grants MH072672 and MH053851, National Institutes of Health T32 Training Grant NS082145, National Center for Advancing Translational Sciences Fellowship Grant TL1 TR001119, U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program Merit Award 1I01BX003512, and William and Ella Owens Medical Research Foundation, none of which had any role in study design, data collection, analysis or interpretation, nor in the preparation or decision to submit this paper for publication. The contents of this paper do not represent the views of the Department of Veterans Affairs or the U.S. Government. We thank Lauren Hatherall, Jeri Silva, Suphada Lertphinyowong, and Kelly Hohl for technical assistance. D.A.M. serves on a Psychopharmacology advisory board for H. Lundbeck A/S and receives research funding from Lundbeck Research USA. These activities have no relation to the work presented in this paper. The remaining authors declare no competing financial interests.
PY - 2018/2/7
Y1 - 2018/2/7
N2 - Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed invmPFCbefore administering chronic unpredictable stress (CUS).vmPFCprojection neurons were then inhibited during extinction treatment by administering clozapine-N-oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reducedmPFCresponsivity, assessed by measuring afferentevoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects.
AB - Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed invmPFCbefore administering chronic unpredictable stress (CUS).vmPFCprojection neurons were then inhibited during extinction treatment by administering clozapine-N-oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reducedmPFCresponsivity, assessed by measuring afferentevoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects.
KW - Behavioral therapy
KW - Cognitive flexibility
KW - Coping behavior
KW - Extinction
KW - Medial prefrontal cortex
KW - Stress
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U2 - 10.1523/JNEUROSCI.0635-17.2017
DO - 10.1523/JNEUROSCI.0635-17.2017
M3 - Article
C2 - 29335360
AN - SCOPUS:85041750842
VL - 38
SP - 1408
EP - 1417
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 6
ER -