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

Abstract

Panic Disorder (PD) is characterized by the presence of recurrent Panic Attacks (PA), with intense fear, sensation of suffocation, and cardiovascular perturbations posing as main symptoms of PD. Both clinical and pre-clinical data support the Dorsal Periaqueductal Gray (DPAG) as a key brain structure implicated in the pathophysiology of PD. Additional exper-iments in rodents also indicate that increased serotonergic neurotransmission in the DPAG can inhibit panic-like defensive behaviors, such as escape, and that the DPAG receives most of its serotonergic inputs from the lateral wings within the Dorsal Raphe Nucleus (lwDRN). These findings led different authors to propose a hypothesis that the dysregulation in the DRN-DPAG pathway can facilitate the occurrence of PA. On the other hand, a second hy-pothesis 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 low O2 or high CO2 environments. However, pre-clinical evidences are 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 lateral wings within the DRN and the DPAG on escape responses elicited by the CO2 exposure test in mice. This project will use state-of-the-art technologies, such as optogenetics, intersectional genetics, and specific lesioning techniques to selectively manipulate the DPAG-projecting lwDRN serotonergic neurons and evaluate their role on the 20% CO2 challenge-induced panic responses. Lastly, this project will also utilize a rabies virus monosynaptic tracer to anatomically and functionally interrogate unidentified pathways that modulate the circuit lwDRN-DPAG, a novel approach in the field never used in Brazil. (AU)