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.
Key Words
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Article info
Publication history
Published online: August 04, 2008
Accepted:
June 22,
2008
Received in revised form:
June 6,
2008
Received:
March 4,
2008
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
