Neonatal stress increases respiratory instability in rat pups

American Journal of Physiology-Regulatory, Integrative and Comp

Gulemetova

Baldy

et al. 2015

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Human and animal studies on sleep-disordered breathing and respiratory regulation show that the effects of sex hormones are heterogeneous. Because neonatal stress results in sex-specific disruption of the respiratory control in adult rats, we postulate that it might affect respiratory control modulation induced by ovarian steroids in female rats. The hypoxic ventilatory response (HVR) of adult female rats exposed to neonatal maternal separation (NMS) is ∼30% smaller than controls (24), but consequences of NMS on respiratory control in aging female rats are unknown. To address this issue, whole body plethysmography was used to evaluate the impact of NMS on the HVR (12% O2, 20 min) of middle-aged (MA; ∼57 wk old) female rats. Pups subjected to NMS were placed in an incubator 3 h/day for 10 consecutive days (P3 to P12). Controls were undisturbed. To determine whether the effects were related to sexual hormone decline or aging per se, experiments were repeated on bilaterally ovariectomized (OVX) young (∼12 wk old) adult female rats. OVX and MA both reduced the HVR significantly in control rats but had little effect on the HVR of NMS females. OVX (but not aging) reduced the anapyrexic response in both control and NMS animals. These results show that hormonal decline decreases the HVR of control animals, while leaving that of NMS female animals unaffected. This suggests that neonatal stress alters the interaction between sex hormone regulation and the development of body temperature, hormonal, and ventilatory responses to hypoxia.

Section: Mating and Neonatal Stress Proceduresmentioning

confidence: 99%

Neonatal stress affects the aging trajectory of female rats on the endocrine, temperature, and ventilatory responses to hypoxia

American Journal of Physiology-Regulatory, Integrative and Comp

Gulemetova

Baldy

et al. 2015

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“…Following birth, litters were randomly assigned to the NMS or control group. The strengths and limitations of using NMS as a stress model have been discussed previously (Behan & Kinkead, 2011;Gulemetova & Kinkead, 2011). The NMS procedures were performed according to protocols used in our previous studies (Genest et al 2004;Fournier et al 2011).…”

Section: Mating and Nms Proceduresmentioning

confidence: 99%

Testosterone potentiates the hypoxic ventilatory response of adult male rats subjected to neonatal stress

Experimental Physiology

Gulemetova

Joseph

et al. 2014

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New Findings r What is the central question of this study?Does testosterone contribute to the enhancement of the hypoxic ventilatory response observed in stressed rats? r What is the main finding and its importance?Castration reduces the hypoxic ventilatory response of stressed rats (but not control rats). Neonatal stress disrupts the gonadotrophic axis and its impact on respiratory control. These results bring new insight into the pathophysiology of sleep-disordered breathing and the sex-based difference in its prevalence.Neonatal stress disrupts development of homeostatic systems. During adulthood, male rats subjected to neonatal maternal separation (NMS) are hypertensive and show a larger hypoxic ventilatory response (HVR), with greater respiratory instability during sleep. Neonatal stress also affects sex hormone secretion; hypoxia increases circulating testosterone of NMS (but not control) male rats. Given that these effects of NMS are not observed in females, we tested the hypothesis that testosterone elevation is necessary for the stress-related increase of the HVR in adult male rats. Pups subjected to NMS were placed in an incubator for 3 h per day from postnatal day 3 to 12. Control pups remained undisturbed. Rats were reared until adulthood, and the HVR was measured by plethysmography (fractional inspired O 2 = 0.12, for 20 min). We used gonadectomy to evaluate the effects of reducing testosterone on the HVR. Gonadectomy had no effect on the HVR of control animals but reduced that of NMS animals below control levels. Immunohistochemistry was used to quantify androgen receptors in brainstem areas involved in the HVR. Androgen receptor expression was generally greater in NMS rats than in control rats; the most significant increase was noted in the caudal region of the nucleus tractus solitarii. We conclude that the abnormal regulation of testosterone is important in stress-related augmentation of the HVR. The greater number of androgen receptors within the brainstem may explain why NMS rats are more sensitive to testosterone withdrawal. Based on the similarities of the cardiorespiratory phenotype of NMS rats and patients suffering from sleep-disordered breathing, these results provide new insight into its pathophysiology, especially sex-based differences in its prevalence.

“…Respiratory measurements performed on 12-day-old rat pups, 2-4 h after the last bout of NMS, show that neonatal stress augments respiratory instability and apnoeas, especially in males (Gulemetova & Kinkead, 2011). More recently, we showed in 14-to 15-day-old rat pups that the apnoeas triggered by stimulating the laryngeal chemoreflex are of longer duration in stressed pups than in control New Findings…”

Section: Introductionmentioning

confidence: 85%

“…Neonatal maternal separation (NMS) is an established and clinically relevant model of stress that disrupts development of the cardiorespiratory control network through sex‐specific effects that persist into adulthood (Kinkead, Guertin, & Gulemetova, ; Kinkead, Tenorio, Drolet, Bretzner, & Gargaglioni, ; Rousseau et al., ). Respiratory measurements performed on 12‐day‐old rat pups, 2–4 h after the last bout of NMS, show that neonatal stress augments respiratory instability and apnoeas, especially in males (Gulemetova & Kinkead, ). More recently, we showed in 14‐ to 15‐day‐old rat pups that the apnoeas triggered by stimulating the laryngeal chemoreflex are of longer duration in stressed pups than in control pups; NMS also augments the concurrent bradycardias and O 2 desaturations, especially in males (Baldy, Chamberland, Fournier, & Kinkead, ).…”

Section: Introductionmentioning

confidence: 99%

The influence of sex and neonatal stress on medullary microglia in rat pups

Baldy

Experimental Physiology

Boisjoly-Villeneuve

et al. 2018

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Neonatal stress has wide-ranging consequences for the developing brain, including the medullary cardiorespiratory network. In rat pups, the reflexive cardiorespiratory inhibition triggered by the presence of liquids near the larynx is augmented by neonatal maternal separation (NMS), especially in males. Sex-specific enhancement of synaptic connectivity by NMS might explain this cardiorespiratory dysfunction. Microglia influence the formation, maturation, activity and elimination of developing synapses, but their role in the wiring of medullary networks is unknown. Owing to their sensitivity to sex hormones and stress hormones, microglial dysfunction could contribute to the abnormal cardiorespiratory phenotype observed in NMS pups. Here, we first used ionized calcium-binding adapter molecule-1 (Iba-1) immunolabelling to compare the density and morphology of microglia in the medulla of male versus female rat pups (14-15 days old) that were either undisturbed or subjected to NMS (3 h day ; postnatal days 3-12). Neonatal maternal separation augmented the density of Iba-1 cells (caudal region of the NTS), increased the size of the soma and reduced the arborization area (especially in the dorsal motor nucleus of the vagus). Sex-based differences were not observed. Given that the actions of microglia are regulated by neuronal fractalkine (CX CL ), we then used western blot analysis to compare the expression of CX CL and its microglial receptor (CX CR ) in medullary homogenates from control and NMS pups. Although CX CR expression was 59% greater in males versus females, NMS had no effect on CX CL /CX CR signalling. Given that an amoeboid morphology reflects an immature phenotype in developing microglia, NMS could interfere with synaptic pruning via a different mechanism.