Enhanced emotional reactivity to optogenetic stimulation of the hippocampus in mice overexpressing the glucocorticoid receptor in forebrain

Wei Q, Moore S, Li F, Watson SJ, Deisseroth K, Murphy GG, Akil H
Society for Neuroscience. 2017.


Vulnerability to mood disorders involves enhanced reactivity to environmental adversity, resulting from the interplay of genetic and developmental factors. Genes that modify the organism’s ability to cope with environmental demands likely play a key role in the causation and expression of these disorders. A key question is whether a given gene can simultaneously set the threshold for negative or positive affect and modulate the dynamics of affective responsiveness. This is particularly important in bipolar disorder, where the dysregulation manifests as affective lability or the propensity to shift mood states. The glucocorticoid receptor (GR) is a gene that plays a critical role in stress responsiveness and has been directly implicated in human mood disorders. Previous work in our laboratory has shown that GR overexpression (GRov) in forebrain leads to increased anxiety behavior coupled with greater affective lability. Thus, this model captures some key features of bipolar illness. In the present study, we used optogenetic stimulation to examine the effects of activating the ventral or dorsal hippocampus (V-HC or D-HC) on anxiety behavior in both GRov and WT mice. In the elevated plus maze (EPM), activation of D-HC or V-HC induced a rapid and robust anxiolytic response in both GRov and WT mice, accompanied by increased total exploration. In the open field test, mild optogenetic stimulation of the D-HC induced an acute and reversible anxiolytic response in both GRov and WT mice with normal exploration. By contrast, activation in V-HC elicited the anxiolytic effect in the open field only in GRov but not in WT mice. Interestingly, the greater affective reactivity of the GRov mice could be discerned with optogenetic stimulation. Thus, activation of V-HC or D-HC readily abolished the increased basal anxiety in GRov mice, rendering them indistinguishable from controls while the laser was on. More remarkable is that the anxiolytic response to stimulation in V-HC of GRov mice was prolonged after the termination of stimulus. Thus, the optogenetic activation rapidly shifted the GRov emotional status from being more anxious to being less anxious than WT mice. We also evaluated the cFos response following optogenetic stimulation in these brain areas. Activation in D-HC led to a cFos response in limited brain regions. In contrast, activation in V-HC resulted in an intensive cFos response in broader areas of the brain. This body of work demonstrates that modulating the activity of a single gene can profoundly alter emotional reactivity, modifying both the magnitude and the duration of responsiveness to a stimulus and altering the nature and duration of affective states.