A prefrontal cortex-hypothalamus circuit for heart rate control in non-human primates

Humans exhibit changes in heart rate during cognitive and emotional events, and dysregulation of this brain-heart coupling is a hallmark of many psychiatric disorders. However, how cognition-regulating circuits directly control heart physiology has remained poorly understood, especially in primates.

Using electrical stimulation in monkeys, the authors identified a small ventral subregion of ventrolateral prefrontal cortex (area 47/12; a12) that evokes rapid, robust decreases in heart rate and increases in heart-rate variability. Neighboring prefrontal regions produced weaker or no cardiac effects, and a12 neurons were coupled to heart rate on a moment-by-moment basis.

Anatomical tracing showed projections from a12 to a circumscribed region of lateral hypothalamus (LHA), and stimulating this LHA target recapitulated the cardiac effects of prefrontal activation. LHA stimulation produced faster, stronger, state-independent heart effects, whereas a12 stimulation produced effects sensitive to internal states.

Oppositely to activation, chemogenetic inactivation of a12 or its projections to LHA increased heart rate, demonstrating that this pathway provides tonic inhibitory control over cardiac function.

To move toward more cell-type-specific and minimally invasive causal control, the team developed a primate sonogenetic approach using ultrasound activation of CaMKII+ neurons virally transduced with TRPV1. Sonogenetic stimulation of a12 increased heart-rate variability, and these effects were attenuated by inactivation of LHA.

Finally, sonogenetic and chemogenetic perturbation of the same prefrontal region during a value-based decision-making task bidirectionally altered risky decision making. Together, the work identifies how a12 regulates heart rate and cognition, revealing a mechanistic substrate for brain-body interactions and a potential therapeutic target for disorders of cognitive-autonomic dysregulation.