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PNAS 109 (35): 14224-14229

Copyright © 2012 by the National Academy of Sciences.


Hippocampal nitric oxide contributes to sex difference in affective behaviors

Yao Hua,b, Dan-Lian Wub, Chun-Xia Luob,1, Li-Juan Zhub, Jing Zhangb, Hai-Yin Wub, and Dong-Ya Zhua,b,1

aState Key Laboratory of Reproductive Medicine, and bLaboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing 210029, China

Edited by Jan-Åke Gustafsson, Karolinska Institutet, Huddinge, Sweden, and approved July 20, 2012 (received for review May 3, 2012)

Abstract: Mechanisms underlying the female preponderance in affective disorders are poorly understood. Here we show that hippocampal nitric oxide (NO) plays a role in the sex difference of depression-like behaviors in rodents. Female mice had substantially lower NO production in the hippocampus and were significantly more likely to display negative affective behaviors than their male littermates. Eliminating the difference in the basal hippocampal NO level between male and female mice mended the sex gap of affective behaviors. Estradiol exerted a positive control on hippocampal NO production via estrogen receptor-β–mediated neuronal NO synthase expression. Thus, low estrogen in the female hippocampus accounts for lower local NO than in the male hippocampus. Although estrogen has important significance in modulating affective behaviors, it is not estrogen but NO in the hippocampus that mediates the sex difference of affective behaviors directly, because hippocampal NO was necessary for the behavioral effects of estradiol, and NO was an independent factor in modulating behaviors. Stress promoted hippocampal NO production in males because of glucocorticoid release, thus leading to local NO excess. In contrast, stress suppressed NO production in females because of decreased estrogen, thereby resulting in hippocampal NO shortage. Whereas activating cAMP response element binding protein (CREB) rescued the depression-like effects of the intrahippocampal NO donor diethylenetriamine/nitric oxide adduct (DETA/NONOate), inactivating CREB abolished the antidepressant-like effects of the intrahippocampal NO donor DETA/NONOate. Our findings suggest a molecular mechanism underlying the sex difference of affective behaviors.

Key Words: gender difference • psychiatric disorders • chronic mild stress • depressive behaviors • corticosterone

Author contributions: C.-X.L. and D.-Y.Z. designed research; Y.H., D.-L.W., C.-X.L., L.-J.Z., J.Z., and H.-Y.W. performed research; C.-X.L. contributed new reagents/analytic tools; Y.H. analyzed data; and D.-Y.Z. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

1To whom correspondence may be addressed. E-mail: dyzhu{at} or chunxialuo{at}

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