Acute hippocampal brain-derived neurotrophic factor restores motivational and forced swim performance after corticosterone.
BACKGROUND
Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naïve rodents rather than on models that capture the debilitating and protracted feelings of anhedonia and loss of motivation that are core features of depression.


METHODS
In adult male mice, we evaluated persistent effects of oral corticosterone (CORT) exposure on anhedonic-like behavior, immobility in the forced swim test (FST), motivational performance in the progressive ratio task, and later endogenous CORT secretion. After verifying long-term decreases in hippocampal brain-derived neurotrophic factor (BDNF) and cAMP Response Element Binding protein phosphorylation (pCREB), the ability of direct hippocampal BDNF microinfusion after CORT exposure to reverse deficits was investigated.


RESULTS
Prior CORT exposure decreased sucrose consumption, appetitive responding, and FST mobility without long-term effects on water/quinine discrimination and endogenous CORT secretion. Critically, BDNF replacement mimicked chronic antidepressant treatment (ADT) by reversing CORT-induced reductions in instrumental performance and FST mobility.


CONCLUSIONS
Together these findings link persistent alterations in hippocampal BDNF expression and CREB transcriptional activity with a persistent depressive-like state-as opposed to ADT efficacy. These results identify hippocampal BDNF as an essential molecular substrate that bidirectionally regulates appetitive instrumental behavior. Additionally, we suggest this CORT model might provide a powerful tool for future investigation into the neurobiology of complex stress-associated depressive symptoms that persist long after stress exposure itself.
Gourley
Shannon L
SL
Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06508, USA.
Kiraly
Drew D
DD
Howell
Jessica L
JL
Olausson
Peter
P
Taylor
Jane R
JR
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects; D004347:Drug Interactions; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation; D011803:Quinine; D013395:Sucrose / Q000008:administration & dosage; D013550:Swimming
D019208:Brain-Derived Neurotrophic Factor; D013395:Sucrose; D011803:Quinine; D050882:CREB-Binding Protein; D003345:Corticosterone