ROLE OF NEUROINFLAMMATION IN THE PANIC-EVOKING EFFECT OF HYPOXIA IN RATS

Abstract Background Exposure to high CO2 or low O2 levels can evoke panic attacks in humans and panic-like escape behavior in rodents1,2. Accumulating evidence indicates that neuroinflammation is a key factor linking environmental stress to the development of psychiatric illness such as post-traumatic stress disorder and depression3. However, the role of neuroinflammation in panic disorder, and more specifically in the genesis of panic attacks, remains unclear. Aims and Objectives We here investigated the effects of exposing rats to hypoxia (7% O2) on microglia activation in two key panic-associated areas, the dorsal periaqueductal gray (dPAG) and dorsal raphe nucleus lateral wings (lwDRN). We also explored the effects of lipopolysaccharide (LPS), a potent immune activator, or minocycline, an inhibitor of microglia activation, on the expression of escape behavior during exposure to hypoxia. LPS was also administered in the neonatal period and its behavioral consequences during the hypoxia challenge was investigated in early adulthood. Methods In experiment 1, immunofluorescence staining for Iba-1 was used to track microglial activation. In experiment 2, LPS (0,1 mg.kg-1, i.p.) or minocycline (30 or 60 mg.kg-1, 5 days, i.p.) were injected 24 hs and 30 min before the hypoxia challenge, respectively. In experiment 3, LPS (0.05 mg.kg-1, ip) was injected on postnatal day 14 (PND 14) and rats were submitted to hypoxia on PND 60. Results Hypoxia exposure caused a marked increase in Iba-1 immunofluorescence both in dPAG and lwDRN and this was observed 6 and 24 hs, but not 1 h after the respiratory challenge. While administration of LPS in the adulthood or on PND14 facilitated the expression of escape response, a panicogenic-like effect, minocycline caused the opposite effect. Discussion and Conclusions The results suggest that neuroinflammatory changes are implicated in pathophysiology of panic-attacks. They also indicate that early hyperactivation of the immune system can increase susceptibility to panic attacks. Acknowledgements Fapesp, CNPq and Faepa, Brazil References 1Spiacci A Jr, Sergio Tde O, da Silva GS, et al. Serotonin in the dorsal periaqueductal gray inhibits panic- like defensive behaviors in rats exposed to acute hypoxia. Neuroscience. 307:191-8, 2015. 2Nardi AE, Valenç a AM, Mezzasalma MA, et al. 35% Carbon dioxide and breath-holding challenge tests in panic disorder: a comparison with spontaneous panic attacks. Depress Anxiety. 23(4):236–44, 2006. 3Pape, K., Tamouza, R., Leboyer, M. Zipp, F. Immunoneuropsychiatry — novel perspectives on brain disorders. Nat. Rev. Neurol. 15, 317–328, 2019.