Optogenetic stimulation of PAG-Nts terminals in the VTA induced robust threat responses including freezing and tail rattle, and simultaneously drove dopamine-dependent operant self-stimulation behavior in mice.
Demonstrates that PAG-Nts neurons form a dual-output circuit that simultaneously drives threat responses and dopamine-dependent reinforcement.
The periaqueductal gray (PAG) is a midbrain structure known to influence responses to both threat and reward. The PAG sends projections to the ventral tegmental area (VTA), a region critical for regulating motivated behavior via dopamine release. We previously identified a population of VTA-projecting PAG neurons that express the peptide neurotensin (Nts), a potent dopamine neuron activator. Here we find that PAG-Nts neurons co-release glutamate and Nts in the VTA to drive dopamine neuron activation. These neurons are activated by threats and threat-predictive cues and are inhibited by entry into a shelter and during reward consumption. Optogenetic stimulation elicits a robust threat response, including freezing and tail rattle, but remarkably can also drive intracranial self-stimulation. This operant reinforcement behavior is dopamine dependent while the threat response is not. Together, these results identify a dual-output circuit that engages the dopamine system, likely to increase the salience of environmental stimuli, while simultaneously driving specific threat response behaviors.
Davis et al. (Tue,) conducted a other in Adult mice (8-20 weeks old) of both sexes with genetically defined neurotensin-expressing neurons in the periaqueductal gray projecting to the ventral tegmental area. Optogenetic stimulation of PAG-Nts neuron terminals in the VTA vs. Control viral vector (AAV-FLEX-YFP), saline or dopamine receptor antagonist flupentixol 0.6 mg/kg intraperitoneal injection was evaluated on Threat response behaviors (freezing, tail rattle) and operant self-stimulation lever pressing. Optogenetic stimulation of PAG-Nts terminals in the VTA induced robust threat responses including freezing and tail rattle, and simultaneously drove dopamine-dependent operant self-stimulation behavior in mice.