Periestropause enhances hypoxia-induced panic and microglial remodelling without altering respiratory control

Perimenopause is characterised by irregular reproductive cycles and hormonal fluctuations, notably decreased estradiol (E₂), which are linked to increased susceptibility to panic disorder and neuroinflammation. We examined whether panic-related respiratory and behavioural responses to respiratory challenges vary across reproductive stages. Female rats with regular estrous cycles (RC), representing reproductive cyclicity, and rats in periestropause (PE), a stage similar to perimenopause, were exposed to normoxia, hypoxia, and hypercapnia. Ventilation (V̇_E) and metabolism (V̇O₂) were measured during diestrus in RC and PE rats. Additionally, to measure levels of neuroinflammation, microglial reactivity in the Locus coeruleus (LC) in response to hypoxia-induced panic-like attacks was assessed. Under normoxia, there were no differences in V̇_E or V̇O₂ between groups. Hypercapnia increased V̇_E in both groups by elevating respiratory frequency (f_R) and tidal volume (V_T), without changing body temperature (Tb). Hypoxia also raised V̇_E in both groups, primarily driven by increased f_R, and hypoxia-induced hypothermia occurred in RC and PE females. Both hypercapnia and hypoxia elevated the V̇_E/V̇O₂ ratio. Exposure to 7% O₂ heightened panic-like behaviours in PE rats. Hypoxia increased LC microglial number, density, and mean soma size, while decreasing arborization area. PE rats also showed a higher microglial morphological index and a shorter nearest neighbour distance (NND). Jump frequency and freezing duration positively correlated with the morphological index and negatively with arborization area. These findings suggest that respiratory regulation remains intact, but behavioural and neuroimmune responses are amplified during the transition to estropause, heightening vulnerability to panic and anxiety-related disorders in ageing females.