Sex, hormones, and stress: how they impact development and function of the carotid bodies and related reflexes

Abstract

Progesterone and corticosterone are key modulators of the respiratory control system. While progesterone is widely recognized as an important respiratory stimulant in adult and newborn animals, much remains to be described regarding the underlying mechanisms. We review the potential implication of nuclear and membrane progesterone receptors in adults and in newborns. This raises intriguing questions regarding the contribution of progesterone as a protective factor against some respiratory control disorders during early life. We then discuss our current understanding of the central integration of stressful stimuli and the responses they elicit. The fact that this system interacts with the respiratory control system, either because both share some common neural pathways in the brainstem and hypothalamus, or because corticosterone directly modulates the function of the respiratory control network, is a fascinating field of research that has emerged over the past few years. Finally, we review the short- and long-term consequences of disruption of stress circuitry during postnatal development on these systems.

Fig. 1

Illustration of sex-specific effect of ventilatory control in adult (white area) and pre-pubertal boys and girls (grey area). Alveolar PCO₂ plotted as a function of age. Data taken from Fitzgerald and Haldane (1905).

Fig. 2

(A–D) Normoxic respiratory and metabolic parameters recorded in adult mice – male (M) and female (F), wild type (+/+) or KO (−/−) for the progesterone receptors. (A) Minute ventilation (ml/min/g^0.855), (B) tidal volume (ml/g^1.043), (C) O₂ consumption rate (ml/min/g1.044 ), (D) CO₂ production rate (ml/min/g1.103 ). (E and F) Hypoxic response for minute ventilation (10% O₂ – 30 min) in males (E) and females (F). *p < 0.05 −/− vs. +/+ mice. ^$ p < 0.05 males vs. females. Number of animals for each group: males: (+/+ n = 13; −/− n = 6), females (+/+ n = 13; −/− n = 19).

Fig. 3

Effects of neonatal maternal separation (NMS; black bars) on two indicators or respiratory instability: (A) coefficient of variation (CV) of the breathing cycle and (B) the number of apneic events (apnea index) per unit time. NMS data are compared to that of controls that were undisturbed during the same period. These measurements were obtained in male and female pups under normoxic conditions. The middle panel shows representative plethysmographic recordings from control and NMS pups (males). The white and black arrows indicate a post-sigh and a spontaneous apnea, respectively. Data are presented as means ± 1 SEM. † indicates a mean statistically different from corresponding control value at p < 0.05. From Gulemetova and Kinkead (2011), with permission.

Fig. 4

Correlation between the minute ventilation response to hypoxia (last 20 s of hypoxia expressed as a percentage change from baseline) and coefficient of variation for this variable during the 2.5 h of recording under normoxia. These measurements were obtained during non-REM sleep. Open circles: control rats (n = 5); black circles: rats previously subjected to neonatal maternal separation (NMS; n = 6). From Kinkead et al. (2009), with permission.

Fig. 5

Neonatal maternal separation (NMS) augments GAD65/67 immunostainning in the caudal NTS (bregma −14.3 to −14.6). Representative NTS photomicrographs comparing GAD65/67 immunoreactivity between (A) controls and (B) NMS rats. (C) Comparison of frequency distribution histograms for gray scale GAD65/67 immunoreactive pixel intensities between control (open bars) and NMS rats (gray bars). (D) Comparison of the mean gray scale intensity values between NTS sections from controls and NMS rats. For each section, the gray scale intensity of three circular areas of interests (diameter = 50 μm) positioned within the NTS were analyzed. Note that low gray level values correspond to darker pixels. Data in (D) is expressed as mean ± 1 SEM. From Kinkead et al. (2008), with permission.

Fig. 6

Neonatal maternal separation (NMS) augments c-fos m-RNA expression levels in the caudal NTS of awake rats following exposure to one of three fraction of inspired O₂ level (FiO₂ ) for 20 min: normoxia (FiO₂ = 0.21), moderate hypoxia (FiO₂ = 0.12), or severe hypoxia (FiO₂ = 0.21). Top panels: representative photomicrographs comparing c-fos m-RNA in situ hybridization signal after exposure to severe hypoxia between control rats (left) and rats subjected to neonatal maternal separation (NMS; right). The dotted circle represents the central canal. Lower panel: relationship between the number of c-fos mRNA positive neurons within the NTS, and inspired O₂ level for controls (open circles) and NMS rats (closed triangles) in the caudal NTS. Data are expressed as means ± SEM. Each value represents the mean number of c-fos mRNA-containing perikarya were counted bilaterally from sections corresponding to the rostro-caudal coordinates −14.3 to −14.60 from bregma for each experimental condition. For each rat, a mean number of c-fos positive neurons was obtained by averaging perikarya counted for several sections (the number of sections ranged between 1 and 3). * indicates means that are statistically different from baseline value at p < 0.05. † indicates means that are statistically different from corresponding control value at p < 0.05. Adapted with permission from Kinkead et al. (2008).

Fig. 7

Comparison of ‘resting’ free plasma corticosterone levels in (A) female and (B) male rats following chronic subcutaneous implantation of a “slow release” corticosterone pellets (3 × 100 mg/pellet; active over 21 days). Data were also obtained from rats that received a sham (placebo) implant or no implant (control). For all three groups (corticosterone, placebo, and control) minute ventilation was measured under resting (normoxia) and hypoxic conditions (12% O₂, 20 min) with whole body plethysmography 14 days after implants were placed subcutaneously. For each group, data were obtained in (C) female and (D) male rats. Note that to ensure that ventilatory measurements did not affect “resting” corticosterone levels, blood samples were taken 4 ± 1 days after ventilatory measurements were completed (i.e. 18 ± 1 day post surgery). Data are expressed as means ± 1 SEM. *Value different from corresponding baseline value at p < 0.05. *Value different from corresponding control value at p < 0.05. Redrawn with permission from Fournier et al. (2007).