Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO2 inhalation in a female rat model of panic disorder

Abstract

Panic disorder (PD) is ~2 times more frequent in women. An excessive ventilatory response to CO2 inhalation is more likely during the premenstrual phase. While ovarian hormones appear important in the pathophysiology of PD, their role remains poorly understood as female animals are rarely used in pre-clinical studies. Using neonatal maternal separation (NMS) to induce a “PD-like” respiratory phenotype, we tested the hypothesis that NMS disrupts hormonal regulation of the ventilatory response to CO2 in female rats. We then determined whether NMS attenuates the inhibitory actions of 17-β estradiol (E2) on orexin neurons (ORX). Pups were exposed to NMS (3 h/day; postnatal day 3–12). The ventilatory response to CO2-inhalation was tested before puberty, across the estrus cycle, and following ovariectomy. Plasma E2 and hypothalamic ORXA were measured. The effect of an ORX1 antagonist (SB334867; 15 mg/kg) on the CO2 response was tested. Excitatory postsynaptic currents (EPSCs) were recorded from ORX neurons using whole-cell patch-clamp. NMS-related increase in the CO2 response was observed only when ovaries were functional; the largest ventilation was observed during proestrus. SB334867 blocked this effect. NMS augmented levels of ORXA in hypothalamus extracts. EPSC frequency varied according to basal plasma E2 levels across the estrus cycle in controls but not NMS. NMS reproduces developmental and cyclic changes of respiratory manifestations of PD. NMS disrupts the inhibitory actions of E2 on the respiratory network. Impaired E2-related inhibition of ORX neurons during proestrus is a novel mechanism in respiratory manifestations of PD in females.

Isoflavone and Antioxidant of Instant Cream Soup Made from Pumpkin and Tempeh and Their Active Compound in Ovariohysterectomy Rat-Induced Alzheimer’s Disease

“…The decrease in estradiol in the body causes changes in gene transcription that result in an increased risk of cognitive impairment [ 37 ]. More significant effects such as decreased memory and learning function may occur when decreased estradiol is present in postmenopausal women [ 38 , 39 ].…”

Neuroimmune mechanisms in fear and panic pathophysiology

“…As described in preceding sections, homeostatic triggers that promote acid-base imbalance such as low-dose, non-hypoxic CO 2 inhalation induce intense fear, anxiety, physiological responses and panic attacks in PD subjects (18,19,34,38,41,47,56). Several investigators including our laboratory, have used CO 2 inhalation to simulate panic-relevant behavior and physiology in mice and rats (48,65,94,(125)(126)(127)(128)(129)(130)(131)(132)(133). The partial pressure of CO 2 in the blood and CNS increases following CO 2 inhalation challenge.…”

Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

“…Pups are placed in an incubator where the temperature and humidity are kept constant (35°C and 45% RH, respectively). Pups are isolated from each other by acrylic (Genest et al, 2007;Fournier et al, 2015;Tenorio-Lopes et al, 2020). As discussed elsewhere (Lehmann and Feldon, 2000;Gulemetova and Kinkead, 2011), animals that are undisturbed during that period and remain in their nest are the best control groups for this type of research (males WT: n = 9 and Tg21: n = 7; females WT: n = 6 and Tg21: n = 8).…”

“…One neural system of considerable interest is the neural system regulating breathing because pathology in this homeostatic control system underlies important clinical disorders, such as sleep apnea (SA; Dempsey et al, 2010;White and Younes, 2012;Eckert, 2018). Early life stress comes in many forms, and basic and clinical studies consistently show that adverse conditions, such as low socioeconomic status or poor parental care, can compromise the respiratory control system at various life stages (Genest et al, 2004;Spilsbury et al, 2006;Kinney and Thach, 2009;Boss et al, 2011;D' Amato et al, 2011;Fournier et al, 2013;Battaglia et al, 2014;Guglielmi et al, 2019;Tenorio-Lopes and Kinkead, 2021). In humans, these stressors are often associated with significant confounding factors related to maternal health and lifestyle thus compromising our ability to conclude on the link between stress and respiratory control dysfunction.…”

“…NMS also disrupts the function of the stress pathways by affecting the paraventricular nucleus of the hypothalamus (PVH; Liu et al, 1997;Genest et al, 2007;Ulrich-Lai and Herman, 2009;Gulemetova et al, 2013). Owing to its direct projections into structures generating the respiratory rhythm, integrating respiratory stimuli, and motoneurons controlling the diaphragm and upper airways, the PVH exerts a "top down" influence on respiratory function (Tenorio-Lopes and Kinkead, 2021).…”