Exposure to uncontrollable stress (inescapable tailshocks, IS) produces behavioral changes that do not occur if the stressor is controllable (escapable tailshock, ES), an outcome meditated by greater IS-induced dorsal raphe nucelus (DRN) serotonin (5-HT) activation. It has been proposed that this differential activation occurs because the presence of control leads to top-down inhibition of the DRN from mPFC, not because uncontrollability produces greater excitatory input. Although mPFC inhibitory regulation over DRN 5-HT has received considerable attention, the relevant excitatory inputs that drive DRN 5-HT during stress have not. The lateral habenula (LHb) provides a major excitatory input to the DRN, but very little is known about the role of the LHb in regulating DRN-dependent behaviors. Here, optogenetic silencing of the LHb during IS blocked the typical anxiety-like behaviors produced by IS in male rats. Moreover, LHb silencing blocked the increase in extracellular basolateral amygdala (BLA) 5-HT during IS and, surprisingly, during behavioral testing the following day. We also provide evidence that LHb-DRN pathway activation is not sensitive to the dimension of behavioral control. Overall, these experiments highlight a critical role for LHb in driving DRN activation and 5-HT release into downstream circuits that mediate anxiety-like behavioral outcomes of IS and further support the idea that behavioral control does not modulate excitatory inputs to the DRN.
Significance Statement: Uncontrollable stressors produce dorsal raphe (DRN)-dependent behavioral changes that are prevented if subjects are provided with a controlling response over the stressor. It is proposed that controllable stress is protective because it leads to direct medial prefrontal cortex inhibition of DRN 5-HT neurons rather than reducing excitatory inputs to the DRN. However, the critical excitatory inputs to DRN that mediate the behavioral effects of uncontrollable stress have received little study. Here we show that the lateral habenula (LHb) activation is necessary for mediating the DRN and behavioral outcomes produced by uncontrollable stress. Moreover, excitatory LHb input during the stressor was not reduced by behavioral control.
Authors report no conflict of interest.
HHS | NIH | National Institute of Child Health and Human Development (NICHD) 100000071; HD7289-30; National Institute of Health MH050479