Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Neurons in the hypothalamus regulate internal states, such as thirst and circadian rhythmicity, and send projections to the extended amygdala to influence defensive responses, including fear and anxiety-like behaviors. Two hypothalamic hormones and neuromodulators, oxytocin (OT) and arginine-vasopressin (AVP) modulate parturition and lactation, water and electrolyte balance and as well as circadian rhythmicity. Neurons of the bed nucleus of the stria terminalis (BNST) express both oxytocin (OTR) and vasopressin receptors and mediates defensive behaviors, including fear- and anxiety behaviors. Here we show that both OT and AVP directly excite BNST neurons via oxytocin receptor (OTR) transmission. These excitatory effects are also confirmed by specifically recording excitability of fluorescent OTR-neurons from OTR-Cre transgenic male rats after application of AVP or selective OTR agonist, TGOT. Considering the well-established role of BNST in avoidance and fear-related behaviors, we used chemogenetics in OTR-Cre rats and demonstrate that silencing of OTR-BNST neurons significantly reduces exploration of open arms of the elevated plus-maze and increases cue-induced vigilance measured in the fear-potentiated startle. We demonstrate how OTR-BNST neurons exited by hypothalamic OT and AVP play a major role in regulating BNST excitability, overcoming threat avoidance, and reducing fear responses to ambiguous threats. Using neuronal tracing studies and peptide optogenetics we demonstrate that distinct populations of hypothalamic OT and AVP neurons send projections to the BNST. Therefore, changes in the activity of internal state-sensitive hypothalamic nuclei will directly impact OTR neuron excitability in the BNST via hypothalamic inputs to shape appropriate, physiologically relevant levels of defensive behaviors.

Learning Objectives:

1. Describe the impact of hypothalamic hormones (oxytocin, vasopressin) on the extended amygdala activity and defensive behaviors. 

2. Explain how chemogenetic manipulations of BNST neurons affect fear- and anxiety-like behaviors.

3. Explain which hypothalamic neurohypophysial neurons innervate the bed nucleus of the stria terminalis (BNST).