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. Yet, how circuits that regulate cognition exert direct control over heart physiology remains poorly understood, particularly in primates. Here, we identify a prefrontal-hypothalamic circuit that exerts powerful, bidirectional control over heart rate in monkeys. We show that electrical stimulation of a small ventral subregion within the ventrolateral prefrontal cortex (area 47/12; a12) evokes rapid and robust decreases in heart rate and increases heart rate variability, whereas neighboring prefrontal regions produce weaker or no effects. And a12 neurons are coupled to heart rate on a moment-by-moment basis. Anatomical tracing data reveal projections from a12 to a circumscribed region of lateral hypothalamus (LHA), and stimulation of this LHA target recapitulates the cardiac effects of prefrontal activation. Consistent with a prefrontal-to-hypothalamus system for heart rate control, stimulation of LHA produces faster, stronger, state-independent heart effects, whereas stimulation of a12 produces effects that are sensitive to internal states. Oppositely to its activation, chemogenetic inactivation of a12 or its projections to LHA increases heart rate, demonstrating that this pathway can provide tonic inhibitory control over cardiac function. To make steps towards a more cell-type-specific and minimally invasive causal control of this circuit, we developed a primate sonogenetic approach based on ultrasound activation of CaMKII+ neurons virally transduced with TRPV1. Sonogenetic stimulation of a12 produced increases in heart rate variability, and these effects were attenuated by inactivation of LHA. Finally, we found that sonogenetic and chemogenetic perturbation of the same prefrontal region during a value-based decision-making task bidirectionally alters risky decision making. Together, our 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.