Anterior hypothalamic parvalbumin neurons are glutamatergic and promote escape behavior

The anterior hypothalamic area (AHA) is a critical structure for defensive responding. Here, we identified a cluster of parvalbumin-expressing neurons in the AHA (AHA(PV)) that are glutamatergic with fast-spiking properties and send axonal projections to the dorsal premammillary nucleus (PMD). Using in vivo functional imaging, optogenetics, and behavioral assays, we determined the role of these AHA(PV) neurons in regulating behaviors essential for survival. We observed that AHA(PV) neuronal activity significantly increases when mice are exposed to a predator, and in a real-time place preference assay, we found that AHA(PV) neuron photoactivation is aversive. Moreover, activation of both AHA(PV) neurons and the AHA(PV) -> PMD pathway triggers escape responding during a predator-looming test. Furthermore, escape responding is impaired after AHA(PV) neuron ablation, and anxiety-like behavior as measured by the open field and elevated plus maze assays does not seem to be affected by AHA(PV) neuron ablation. Finally, whole-brain metabolic mapping using positron emission tomography combined with AHA(PV) neuron photoactivation revealed discrete activation of downstream areas involved in arousal, affective, and defensive behaviors including the amygdala and the substantia nigra. Our results indicate that AHA(PV) neurons are a functional glutamatergic circuit element mediating defensive behaviors, thus expanding the identity of genetically defined neurons orchestrating fight-or-flight responses. Together, our work will serve as a foundation for understanding neuropsychiatric disorders triggered by escape such as post-traumatic stress disorder (PTSD).

Automated summary

The study identified a cluster of glutamatergic parvalbumin-expressing neurons in the anterior hypothalamic area (AHA) that play a critical role in regulating defensive behaviors, including escape responses. Activation of these AHA(PV) neurons increased during exposure to a predator and triggered aversive responses. Neurotransmission between AHA(PV) neurons and the dorsal premammillary nucleus (PMD) was found to be involved in escape responses. The ablation of AHA(PV) neurons impaired escape responses but had no effect on anxiety-like behavior. Whole-brain metabolic mapping revealed activation of downstream areas such as the amygdala and substantia nigra. This study expands our understanding of the neuronal circuits underlying fight-or-flight responses and has important implications for studying neuropsychiatric disorders like post-traumatic stress disorder (PTSD).