Optogenetics and intersectional genetics manipulation of dorsal raphe nucleus serotonergic projections to the dorsal periaqueductal gray and its role in the mediation of panic-like escape responses

Abstract

Panic disorder (PD) is characterized by the occurence of recurrent panic attacks (PA), with intense fear, sensation of suffocation, and cardiovascular perturbations posing as main symptoms of PD. Both clinical and preclinical data support the dorsal periaqueductal gray (DPAG) as a key brain structure implicated in the pathophysiology of PD. Additional experiments in rodents also indicate that increased serotonergic neurotransmission in the DPAG inhibits panic-like defensive behaviors, such as escape, and that the DPAG receives most of its serotonergic inputs from the lateral wings of the dorsal raphe nucleus (lwDRN). These findings led to the proposal that the dysregulation in the DRN-DPAG pathway can facilitate the occurrence of PA. On the other hand, a second hypothesis supported by clinical data suggests that PA are a misfiring of an evolved suffocating alarm system. This system has been suggested to detect life-threatening situations, such as exposure to high CO2 or low O2 concentrations. However, preclinical evidence is scarce and less supportive when it comes to validating this hypothesis. Given this scenario, the aim of this project is focused on investigating the role of the lwDRN and the DPAG on escape responses of mice and rats eli-cited by hypercapnic or hypoxic environments, respectively. This project will use state-of-the-art techniques, such as optogenetics, intersectional genetics, and specific neurochemical lesioning to selectively manipulate the DPAG-projecting lwDRN serotonergic neurons and evaluate their role on the respiratory challenge-induced panic responses in mice and rats. Lastly, this project will also utilize a rabies virus monosynaptic tracer to uncover the neural substrate that modulates the circuit lwDRN-DPAG, a novel approach never used in Brazil. (AU)