Threat-dependent cardiac interoceptive signalling by glycinergic periaqueductal grey neurons

Interoception, the process through which afferent information reaches the brain to report the body's physiological state, is a critical element in adapting responses to potential threats. Cardiac interoceptive information has been shown to play a crucial role in these adaptive defensive processes. Neuronal circuits within the periaqueductal grey (PAG) play a pivotal role in controlling heart function, yet it remains unknown how PAG circuits process interoceptive signals as part of a defensive reaction to threats. Employing trans-synaptic retrograde tracing, we demonstrate that glycinergic neurons of the ventrolateral PAG receive projections from cardiac regulatory areas, such as the nucleus of the solitary tract. In vivo calcium-imaging further revealed that glycinergic vlPAG neuronal activity followed heart rate increases under threat conditions. Under low threat conditions, optoactivation resulted in short-lasting bradycardia without eliciting anxiety-like behavior. In these mice, we additionally observed cFos activation in key brain regions for processing of internal states, such as the hypothalamus (a main output region of glycinergic interoceptive neurons) and the insular cortex (a central hub of interoception). Conversely, during high fear states, activation of PAG-glycinergic neurons altered cardiac micro- and macrostate dynamics, and affected subsequent anxiety-like behaviours, accompanied by a decrease in cFos activity in the hypothalamus and insular cortex. In conclusion, our data strongly support the notion that vlPAG-glycinergic neurons threat-dependently regulate defensive states via cardiac interoception, a process that plays a major role in fear, anxiety and related disorders.