Abstract
Background
The nucleus accumbens is a critical mediator of depression-related outcomes to social
defeat stress. Previous studies demonstrate distinct neuroplasticity adaptations in
the two medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D1
versus dopamine receptor D2, in reward and reinforcement leading to opposing roles
for these MSNs in these behaviors. However, the distinct roles of nucleus accumbens
MSN subtypes, in depression, remain poorly understood.
Methods
Using whole-cell patch clamp electrophysiology, we examined excitatory input to MSN
subtypes and intrinsic excitability measures in D1-green fluorescent protein and D2-green
fluorescent protein bacterial artificial chromosome transgenic mice that underwent
chronic social defeat stress (CSDS). Optogenetic and pharmacogenetic approaches were
used to bidirectionally alter firing of D1-MSNs or D2-MSNs after CSDS or before a
subthreshold social defeat stress in D1-Cre or D2-Cre bacterial artificial chromosome
transgenic mice.
Results
We demonstrate that the frequency of excitatory synaptic input is decreased in D1-MSNs
and increased in D2-MSNs in mice displaying depression-like behaviors after CSDS.
Enhancing activity in D1-MSNs results in resilient behavioral outcomes, while inhibition
of these MSNs induces depression-like outcomes after CSDS. Bidirectional modulation
of D2-MSNs does not alter behavioral responses to CSDS; however, repeated activation
of D2-MSNs in stress naïve mice induces social avoidance following subthreshold social
defeat stress.
Conclusions
Our studies uncover novel functions of MSN subtypes in depression-like outcomes. Notably,
bidirectional alteration of D1-MSN activity promotes opposite behavioral outcomes
to chronic social stress. Therefore, targeting D1-MSN activity may provide novel treatment
strategies for depression or other affective disorders.
Keywords
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Article info
Publication history
Published online: July 28, 2014
Accepted:
July 15,
2014
Received in revised form:
July 14,
2014
Received:
May 19,
2014
Identification
Copyright
© 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
