Participation of noradrenergic neurons of Locus coeruleus in behavioral and cardiorespiratory manifestations to CO2 induced panic attack

Abstract

Locus coeruleus (LC) is a sexually dimorphic noradrenergic nucleus that sends projections to the entire brain and it is the main source of central noradrenaline controlling several physiological functions, including central chemoreception. It is well described that imbalances in the modulation of noradrenergic neurotransmission are responsible for several psychiatric disorders, including panic disorder. Patients with such a disorder are more sensitive to changes in CO2 concentrations/H+, and therefore are more likely to experience the "suffocation false alarm" which, in turn, triggers the panic attack. It is known that the brain detects acid for several reasons besides ventilatory control, and the association between hypercapnia and panic disorders is quite strong. Therefore, this project aims to investigate the participation of noradrenergic neurons in LC in CO2 induced panic attack. To this end, male and female knockout mice with the absence of catecholaminergic neurons in the A6 region (En1Cre; DbhcKO) will be exposed to severe hypercapnia and ventilation, autonomic responses and behavior will be evaluated. Additionally, some studies have suggested heterogeneity of the LC cell population, therefore, we will investigate whether the population of noradrenergic cells in the LC activated by moderate (7% CO2) and severe (20% CO2) hypercapnia receive different efferent projections from the Pre-Botzinger neurons, region involved with breathing control, and the central nucleus of the amygdala, the region involved with behavior. To this end, retrograde tracers will be injected into the Pré-Botzinger complex and the central nucleus of the amygdala of male and female non-mutant mice, to ascertain their projections for the LC. (AU)