Differential modulation of stress axis by optogenetic stimulation in paraventricular nucleus of the hypothalamus and dentate gyrus

Wei Q, Watson SJ, Seasholtz A, Deisseroth K, Murphy GG, Akil H
Society for Neuroscience. 2013.


Stress-related neuropsychiatric disorders are accompanied by alterations in glucocorticoids. Extremely low or high glucocorticoid levels significantly impair brain development and function, and the normalization of the limbic-hypothalamic-pituitary-adrenal (LHPA) system is thought to be a prerequisite to clinical improvement. The glucocorticoid receptor (GR), a molecule that controls reactivity to stress, plays a critical role in stress responsiveness, emotionality, cognitive function, and addictive behavior. Previous work in our laboratory has shown that constitutive glucocorticoid receptor overexpression (GRov) in forebrain driven by a CaMKIIa promoter results in increased emotional reactivity and an altered neuroendocrine phenotype. In this study, we used optogenetic stimulation to examine the effect of activating the paraventricular nucleus of the hypothalamus (PVN) and the hippocampal dentate gyrus (DG) on LHPA axis activity in both GRov and wild type (WT) mice.

AAV5-CaMKIIa-ChR2(H134R)-eYFP virus or AAV5-CaMKIIa-mCherry control virus was microinjected into PVN, dorsal DG or ventral DG in GRov mice and WT littermates. Activation of opsin ChR2 in PVN or ventral DG while mice explored an open field chamber, led to a significant increase in corticosterone levels in WT mice compared to the control virus group, while activation in dorsal DG during exploration had no significant effect. Moreover, GRov mice, while having comparable basal levels to WT, exhibited significantly lower corticosterone levels in response to ChR2 activation in PVN or ventral DG. This is likely due to ongoing negative feedback by overexpression of GR.

We also evaluated the cFos response following optogenetic stimulation in the same brain areas. Activation of ChR2 in PVN or dorsal DG led to cFos responses in limited brain regions. In contrast, activation in ventral DG resulted in an intensive cFos response in broader areas of the brain. Our findings suggest the distinct contributions of PVN and dentate gyrus to LHPA axis activity and the powerful role of GR in LHPA regulation in these brain areas.