Synaptic routing and feed-forward neuropeptide network in the threat connectome

Mental disorders account for 30% of worldwide disease burden with anxiety disorders being the most frequent group of psychiatric disorders. Compared to men, women have twice the risk to develop anxiety disorders. Threat-processing and fight-or-flight networks have crucial role in the pathophysiology of developing anxiety disorders.
The periaqueductal gray matter is an evolutionary conserved key center for integrating emotional behaviors, such as anxiety and defensive reactions. Its dorsal aspect (dPAG) is critical for processing threatful and panicogenic stimuli. The anterior hypothalamic nucleus (AHN) is a hub of the hypothalamic defense circuitry that responds to exposure of threats such as the proximity of predators. The ventromedial hypothalamus (VMH) provides strong excitatory input both to dPAG to promote freezing and to the AHN to promote escape in rodents and induce. Interestingly, the VMH, the dPAG but and the inputs of the VMH such as the medial amygdala (MeA) are highly expressing neuropeptides and its receptors.
However, the circuit motifs, neuronal types and synaptic mechanisms that respond to the VMH inputs and process the threatful information are poorly understood. We probe connectivity and synaptic plasticity with high-throughput all-optical voltage imaging and we use Voltage-Seq to reveal the identity of protagonist neurons within the crucial circuit motifs. We also aim to understand the role of feed-forward neuromodulation by investigation of excitatory and inhibitory circuit re-routing modulated by neuropeptides that contributes to the long-term changes in threat-processing circuits of dPAG, AHN and VMH. We compare male and female networks in the VMH-PAG-AHN postsynaptic connectome and the synaptic plasticity. Neuronal cell types and their connectivity are highly conserved in mammals and can successfully be used as targets in the treatment of mood disorders.