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Sex‐Specific Effects of Stress on Respiratory Control: Plasticity, Adaptation, and Dysfunction

Luana Tenorio‐Lopes, Richard Kinkead

10.1002/cphy.c200022

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

As our understanding of respiratory control evolves, we appreciate how the basic neurobiological principles of plasticity discovered in other systems shape the development and function of the respiratory control system. While breathing is a robust homeostatic function, there is growing evidence that stress disrupts respiratory control in ways that predispose to disease. Neonatal stress (in the form of maternal separation) affects “classical” respiratory control structures such as the peripheral O2 sensors (carotid bodies) and the medulla (e.g., nucleus of the solitary tract). Furthermore, early life stress disrupts the paraventricular nucleus of the hypothalamus (PVH), a structure that has emerged as a primary determinant of the intensity of the ventilatory response to hypoxia. Although underestimated, the PVH's influence on respiratory function is a logical extension of the hypothalamic control of metabolic demand and supply. In this article, we review the functional and anatomical links between the stress neuroendocrine axis and the medullary network regulating breathing. We then present the persistent and sex‐specific effects of neonatal stress on respiratory control in adult rats. The similarities between the respiratory phenotype of stressed rats and clinical manifestations of respiratory control disorders such as sleep‐disordered breathing and panic attacks are remarkable. These observations are in line with the scientific consensus that the origins of adult disease are often found among developmental and biological disruptions occurring during early life. These observations bring a different perspective on the structural hierarchy of respiratory homeostasis and point to new directions in our understanding of the etiology of respiratory control disorders. © 2021 American Physiological Society. Compr Physiol 11:2097‐2134, 2021.

Figure 1. Figure 1. Neuroanatomy of the paraventricular nucleus of the hypothalamus (PVH) has numerous anatomical projections onto key structures of the respiratory control system. Top panel: Coronal view of the PVH illustrating its main subdivisions and general projections. Abbreviations: dp, dorsal parvocellular part; lp, lateral parvocellular part; mpd, pv, dorsal and ventral subdivisions of the medial parvocellular part (CRH); pml, pmm, lateral (vasopressinergic) and medial (oxytocinergic) subdivisions of the posterior magnocellular part; mpv, periventricular part. Lower panel: Sagittal view of the rat brain from 432 showing projections from the paraventricular nucleus to key groups of neurons involved in the genesis and regulation of respiratory activity. The colors indicate the predominant transmitters identified. Note that the interaction between the PVH and some nuclei is bidirectional. Abbreviations: PBC, parabrachial complex; NTS, nucleus of the solitary tract; XII, hypoglossal motor nucleus; Pre‐Böt C, Pre‐Bötzinger complex. Created with Biorender.com. Information based on Swanson LW and Sawchenko PE, 1983, 434; Adapted from Swanson LW, 2018 432; Modified, with permission, from Behan M and Kinkead R, 2011 38.
Figure 2. Figure 2. The paraventricular nucleus of the hypothalamus (PVH) augments the hypoxic ventilatory response (HVR). The top panels show results of experiments using a chemogenetic approach to inhibit PVH function in rats. (A) Photomicrographs of coronal PVN sections showing expression of adeno‐associated virus (AAV) 2‐human synapsin promoter (hSyn)‐GFP (top, GFP) or AAV2‐hSyn‐hM4D (Gi)‐mCherry (bottom, GiDREADD‐mCherry). Insets: higher magnification of boxed areas showing GFP‐ and mCherry immunoreactivity (IR) present in neurons and processes. Scale bars = 100 μm. Inset scale bars = 50 μm. Adapted, with permission, from Ruyle BC, et al., 2019 385. (B) Comparison of the minute ventilation response of awake rats to increasing levels of hypoxia measured before (Ctrl; grey circles) and 60 min after animals received an intraperitoneal injection (1 mL) of the selective DREADD agonist C21 (black circles; 1 mg/kg) † versus 21% O2; †† versus 14%, 21% O2; ††† versus 12%, 14%, 21% O2; # versus 10%, 12%, 14%, 21% O2 at P < 0.05. For GiDREADD rats, *C21 versus Ctrl. Adapted, with permission, Ruyle BC, et al., 2019 385. (C) Enhancement of PVH function by early‐life exposure to stress (in the form of NMS, black bars) augments the HVR relative to undisturbed rats (control; white bar). However, inactivation of the PVH by focal microinjection of GABA (1 mM) or the selective GABAA agonist muscimol (1 mM) in the PVH attenuates the HVR, especially in NMS rats. † Different from corresponding control value at P < 0.05; * Different from corresponding vehicle treatment (phosphate‐buffered saline; PBS) value at P < 0.05. Adapted, with permission, from Genest SE, et al., 2007 151.
Figure 3. Figure 3. Endogenous corticosterone secretion is cyclic and pulsatile. (A) and (B) compare representative ultradian (smooth line) and circadian (dashed line) corticosterone release patterns in male and female Sprague Dawley rats, respectively. Blood plasma was collected using automated high‐frequency blood sampling under basal conditions. The gray area indicates the dark, active period of the light/dark cycle. (A) Reused, with permission, from Joëls M, et al., 2012 215. (B) Adapted, with permission, from Windle RJ, et al., 1998 481.
Figure 4. Figure 4. Acute exposure to stress activates numerous brain regions, including A) the forebrain and midbrain and B) “classical” ponto‐medullary structure involved in respiratory control. presents the mean numbers of c‐Fos‐positive cells per section in different brain regions under control conditions (n = 4) and following air puff stress (n = 5). Abbreviations: A5, noradrenergic neurons of the A5 area; BLA, basolateral amygdala; CeA, central amygdala; c, commissural; CVLM, caudal ventrolateral medulla; dm, dorsomedial; di, dorsolateral; DMH, dorsomedial hypothalamus; KF, Kölliker Fuse; LC, locus coeruleus; LH, lateral hypothalamus; m, medial; MeA, medial amygdala; l, lateral; NTS, nucleus of the solitary tract; PAG, periaqueductal gray; PB, parabrachial; PVH, paraventricular nucleus of the hypothalamus; PeF, perifornical area of the hypothalamus; RPa, raphe pallidus; RVLM, rostral ventrolateral medulla; RVMM, rostral ventromedial medulla; v, ventral; vl, ventrolateral. **P < 0.01, *P < 0.05 versus control. This figure is reused, with permission, from Furlong TM, et al., 2014 141.
Figure 5. Figure 5. Gestational stress (GS) delays respiratory control maturation and promotes pathological apneas in newborn rat pups. (A) Box plot of the plasma corticosterone levels measured in gestating dams maintained under standard animal care conditions (control; gray bars) and females subjected to predator odor (GS, black bars). Tail blood samples were taken at 9:20 am on G12. Box boundaries correspond to the 25th and 75th percentiles (top and bottom, respectively); the line within the box indicates the median. Bars above and below show the 90th and 10th percentiles, respectively. Individual points are outside these limits. Effects of GS on circulating levels of corticosterone (B) and testosterone (C) in 4‐days‐old male and female pups. Values are expressed as means ± SEM, which are based on litter averages. These data were obtained from a total of 104 pups (58 controls and 46 stress) originating from 31 litters (16 controls and 15 stress). The numbers underneath the bars indicate the number of litters sampled in each group; the numbers in parentheses indicate the number of animals tested. (D) Effects of gestational stress on apnea frequency during neonatal development (P0‐P4); the right side of the panel presents 30 s segments of plethysmographic recordings illustrating respiratory instability and apneas in newborn pups (P0) born from control (top trace) and stressed (bottom trace) dams. Within the box plots, the numbers indicate the number of litters sampled in each group; the numbers immediately below (in parentheses) indicate the total number of pups used in this group. † p < 0.05 statistically different from corresponding control value. #p < 0.05, statistically different from corresponding female value. (E) Simultaneous recordings of ventilatory activity (plethysmography; top traces), arterial O2 saturation (SpO2), and heart rate (pulse oximetry; bottom traces) in pups born to control dams (left traces) and pups born to dams subjected to GS (right traces). Reused, with permission, from Fournier S, et al., 2013, 138.
Figure 6. Figure 6. Timeline comparing key processes and stages in the perinatal development of rats and humans related to (A) the central nervous system, (B) respiratory motor control, and (C) the lungs. The timeline shows development from conception until end stage of the development process being compared. (A) “Neurodevelopment” depicts neuron, astrocyte, and microglial development and function (e.g., synaptogenesis, myelination). Note that the shaded area represents the period of rapid growth when the central nervous system is most vulnerable to insults. (B) “Respiratory motor control”, depicts the development of respiratory‐related neurons [preBötzinger Complex (preBötC), phrenic motoneurons (PMN)] and the diaphragm and formation/refinement of neuromuscular junctions (NMJ), along with the onset of processes such as respiratory rhythm generation and fetal breathing movements. Although many of those processes are comparable in humans, the precise stage of onset is not always known (e.g., preBötC formation). (C) “Lung development” compares the different stages of lung development from early formation in the fetus to alveolar structure in the lungs between humans and rat. Abbreviations: GD, gestational day; Wk, week; mo, months; yrs, years; PND, postnatal day. Reused, with permission, from Greer JJ, 2012 163; Johnson SM, et al., 2018 216; Mantilla CB and Sieck GC, 2008 290; National_Institute_on_Drug_Abuse, 2000 325; Pilarski JQ, 2019, 353; Schnoll JG, et al., 2019 403; Seaborn T, et al., 2010 405. Created with BioRender.com.
Figure 7. Figure 7. Early life stress (in the form of neonatal maternal separation; NMS) has persistent and sex‐specific effects on the neuroendocrine pathways regulating the stress response. (A) Neonatal maternal separation augments basal levels of c‐Fos mRNA expression in the paraventricular nucleus of the hypothalamus (PVH) of males but not females. This sex‐specific effect is observed downstream from the PVH as indicated by plasma levels of (B) ACTH and (C) corticosterone. Adapted, with permission, from Genest SE, et al., 2004 152; in those experiments (A‐C), pups were subjected to NMS 3 h/day from postnatal days 3 to 12. Controls were undisturbed over the same period. Basal HPA axis function was measured in adulthood (8 to 10 weeks of age). In males, prolonged maternal separation (180 min) augments the rise in plasma (D) ACTH and (E) corticosterone in response to an air startle stress. Reused, with permission, from Lippmann M, et al., 2007 271; in this study, rat pups were either handled and separated from their mother 180 min (3 h; HMS 180), handled and separated from their mother 15 min (HMS 15), or subjected to standard animal facility rearing (AFR). Those protocols were performed each day from postnatal days 2 to 14.
Figure 8. Figure 8. Early life stress (in the form of neonatal maternal separation; NMS) augments cardiorespiratory depression induced by the presence of liquid near the larynx in rat pup. This reflexive response is termed “laryngeal chemoreflex”. The top panels and present original recordings comparing cardiorespiratory responses to by intra‐tracheal water injection (10 μL) between pups subjected to (A) control conditions and (B) neonatal stress. The traces illustrate (from top to bottom): intercostal EMG, SpO2, and heart rate. These recordings were obtained following the third injection in 15‐day‐old male pups. (C) Collage of photomicrographs illustrating the caudal brainstem slice in which whole‐cell recordings were performed in the dorsal motor nucleus of the vagus (DMNV). The area postrema (AP), central canal (CC), commissural region of the nucleus of the solitary tract (NTScom), and hypoglossal motor nucleus (NXII) were used as visual landmarks. The inset shows a patch pipette attached to a cell. (D) Comparison of excitatory postsynaptic currents (EPSCs) recorded in the DMNV of 14‐day‐old male pups that were either raised under standard conditions (black; control) or subjected to the neonatal stress protocol (red). (E) Superimposed average EPSCs (10 min recording) comparing group data in males and females. (F) Cumulative probability plots of EPSC frequencies and amplitudes; in the inset, the histograms show mean data ± SEM for each group. Within each bar, the numbers in parentheses indicate the number of cells that were recorded in each group. Reused, with permission, from Baldy C, et al., 2017 17. Licensed under CC BY 4.0. (G) Photomicrographs of microglia immunolabeled with Iba‐1 (ionized calcium‐binding adaptor protein‐1) from DMNV obtained in medullary sections from 15‐day‐old pups raised in control conditions (top panel) or subjected to neonatal maternal separation. In each panel, the high magnification inset illustrates representative morphology. (H) Comparison of microglial morphological index between control and NMS groups. Data are shown as means + 1 SEM. Numbers in parentheses indicate the number of animals in each group. † Significantly different from control at P < 0.05. Reused, with permission, from Baldy C, et al., 2018 18.
Figure 9. Figure 9. Neonatal maternal separation (NMS) augments the hyperventilatory response to a brief hypoxic episode and promotes respiratory instability during non‐rapid eye movement (non‐REM) sleep. (A) Comparison of the breathing frequency response to hypoxia (90 s) between controls (white circles) and rats previously subjected to NMS (black circles) during non‐REM sleep. The figure also shows the change in frequency during the return to normoxia (recovery: 120 s). The small circles show the fraction of inspired O2 measured in the chamber during the experiment (right‐hand axis). In this panel, data were obtained every 10 s. (B) Correlation between the minute ventilation response to hypoxia (last 20 s of hypoxia expressed as a percentage change from baseline and the coefficient of variation for this variable during the 2.5 h of recording under normoxia. These measurements were obtained during non‐rapid eye movement (non‐REM) sleep. Open circles: control rats (n = 4); black circles: rats previously subjected to NMS (n = 6). Reused, with permission, from Kinkead R, et al., 2009 239.
Figure 10. Figure 10. Neonatal maternal separation (NMS) augments the carotid body's O2 chemosensitivity in males but not females. (A) Photomicrograph of the ex vivo carotid body preparation used to record the change in activity in response to hypoxia; recordings were obtained by placing a suction electrode on the carotid sinus nerve (CSN) from preparations. Neurograms from (B) male and (C) female rats illustrating the rectified carotid sinus nerve activity recorded under baseline condition (95% O2 + 5% CO2) followed by hypoxia (0% O2 + 5% CO2), and return to baseline condition for recovery. Preparations were obtained from adult males raised under control conditions (top) or previously subjected to NMS (bottom; 3 h/day from postnatal days 3‐12). Comparison of (D) male and (E) female mean carotid sinus nerve activity (impulses/sec) over the course of the hypoxic protocol between carotid bodies from control (open squares) and NMS rats (black squares). Hypoxia begins at T = 0 and is maintained until T = 500 s (end of plateau phase), followed by hyperoxic recovery; each data point represents the mean value on a second by second basis. Histograms comparing mean CSN activity of (F) male and (G) female rats for each specific experimental condition between control (white bars) and NMS (black bars) male rats. Data are reported as means ± SD. *indicates a value statistically different from control at P ≤ 0.05. Adapted, with permission, from Soliz J, et al., 2016 422. Licensed under CC‐BY‐4.0.
Figure 11. Figure 11. NMS leads to sex‐specific (female only) augmentation of the hypercapnic ventilatory response in adult rats. The histograms compare the mean increase of the main respiratory variables measured at the end of a 20 min exposure to moderate hypercapnia (FiCO2 = 0.05) between rats raised under control conditions (control, white bars) or subjected to NMS (black bars, 3 h/day from postnatal days 3 to 12). Data were obtained in adult (A) males and (B) females and are expressed as a percent change from baseline ± SEM; the numbers of animals in each group is indicated in the histogram bars. † indicates a value significantly different from control at P < 0.05. # indicates a value significantly different from corresponding female value at P < 0.05. Reused, with permission, from Genest SE, et al., 2007 153.


Figure 1. Neuroanatomy of the paraventricular nucleus of the hypothalamus (PVH) has numerous anatomical projections onto key structures of the respiratory control system. Top panel: Coronal view of the PVH illustrating its main subdivisions and general projections. Abbreviations: dp, dorsal parvocellular part; lp, lateral parvocellular part; mpd, pv, dorsal and ventral subdivisions of the medial parvocellular part (CRH); pml, pmm, lateral (vasopressinergic) and medial (oxytocinergic) subdivisions of the posterior magnocellular part; mpv, periventricular part. Lower panel: Sagittal view of the rat brain from 432 showing projections from the paraventricular nucleus to key groups of neurons involved in the genesis and regulation of respiratory activity. The colors indicate the predominant transmitters identified. Note that the interaction between the PVH and some nuclei is bidirectional. Abbreviations: PBC, parabrachial complex; NTS, nucleus of the solitary tract; XII, hypoglossal motor nucleus; Pre‐Böt C, Pre‐Bötzinger complex. Created with Biorender.com. Information based on Swanson LW and Sawchenko PE, 1983, 434; Adapted from Swanson LW, 2018 432; Modified, with permission, from Behan M and Kinkead R, 2011 38.


Figure 2. The paraventricular nucleus of the hypothalamus (PVH) augments the hypoxic ventilatory response (HVR). The top panels show results of experiments using a chemogenetic approach to inhibit PVH function in rats. (A) Photomicrographs of coronal PVN sections showing expression of adeno‐associated virus (AAV) 2‐human synapsin promoter (hSyn)‐GFP (top, GFP) or AAV2‐hSyn‐hM4D (Gi)‐mCherry (bottom, GiDREADD‐mCherry). Insets: higher magnification of boxed areas showing GFP‐ and mCherry immunoreactivity (IR) present in neurons and processes. Scale bars = 100 μm. Inset scale bars = 50 μm. Adapted, with permission, from Ruyle BC, et al., 2019 385. (B) Comparison of the minute ventilation response of awake rats to increasing levels of hypoxia measured before (Ctrl; grey circles) and 60 min after animals received an intraperitoneal injection (1 mL) of the selective DREADD agonist C21 (black circles; 1 mg/kg) † versus 21% O2; †† versus 14%, 21% O2; ††† versus 12%, 14%, 21% O2; # versus 10%, 12%, 14%, 21% O2 at P < 0.05. For GiDREADD rats, *C21 versus Ctrl. Adapted, with permission, Ruyle BC, et al., 2019 385. (C) Enhancement of PVH function by early‐life exposure to stress (in the form of NMS, black bars) augments the HVR relative to undisturbed rats (control; white bar). However, inactivation of the PVH by focal microinjection of GABA (1 mM) or the selective GABAA agonist muscimol (1 mM) in the PVH attenuates the HVR, especially in NMS rats. † Different from corresponding control value at P < 0.05; * Different from corresponding vehicle treatment (phosphate‐buffered saline; PBS) value at P < 0.05. Adapted, with permission, from Genest SE, et al., 2007 151.


Figure 3. Endogenous corticosterone secretion is cyclic and pulsatile. (A) and (B) compare representative ultradian (smooth line) and circadian (dashed line) corticosterone release patterns in male and female Sprague Dawley rats, respectively. Blood plasma was collected using automated high‐frequency blood sampling under basal conditions. The gray area indicates the dark, active period of the light/dark cycle. (A) Reused, with permission, from Joëls M, et al., 2012 215. (B) Adapted, with permission, from Windle RJ, et al., 1998 481.


Figure 4. Acute exposure to stress activates numerous brain regions, including A) the forebrain and midbrain and B) “classical” ponto‐medullary structure involved in respiratory control. presents the mean numbers of c‐Fos‐positive cells per section in different brain regions under control conditions (n = 4) and following air puff stress (n = 5). Abbreviations: A5, noradrenergic neurons of the A5 area; BLA, basolateral amygdala; CeA, central amygdala; c, commissural; CVLM, caudal ventrolateral medulla; dm, dorsomedial; di, dorsolateral; DMH, dorsomedial hypothalamus; KF, Kölliker Fuse; LC, locus coeruleus; LH, lateral hypothalamus; m, medial; MeA, medial amygdala; l, lateral; NTS, nucleus of the solitary tract; PAG, periaqueductal gray; PB, parabrachial; PVH, paraventricular nucleus of the hypothalamus; PeF, perifornical area of the hypothalamus; RPa, raphe pallidus; RVLM, rostral ventrolateral medulla; RVMM, rostral ventromedial medulla; v, ventral; vl, ventrolateral. **P < 0.01, *P < 0.05 versus control. This figure is reused, with permission, from Furlong TM, et al., 2014 141.


Figure 5. Gestational stress (GS) delays respiratory control maturation and promotes pathological apneas in newborn rat pups. (A) Box plot of the plasma corticosterone levels measured in gestating dams maintained under standard animal care conditions (control; gray bars) and females subjected to predator odor (GS, black bars). Tail blood samples were taken at 9:20 am on G12. Box boundaries correspond to the 25th and 75th percentiles (top and bottom, respectively); the line within the box indicates the median. Bars above and below show the 90th and 10th percentiles, respectively. Individual points are outside these limits. Effects of GS on circulating levels of corticosterone (B) and testosterone (C) in 4‐days‐old male and female pups. Values are expressed as means ± SEM, which are based on litter averages. These data were obtained from a total of 104 pups (58 controls and 46 stress) originating from 31 litters (16 controls and 15 stress). The numbers underneath the bars indicate the number of litters sampled in each group; the numbers in parentheses indicate the number of animals tested. (D) Effects of gestational stress on apnea frequency during neonatal development (P0‐P4); the right side of the panel presents 30 s segments of plethysmographic recordings illustrating respiratory instability and apneas in newborn pups (P0) born from control (top trace) and stressed (bottom trace) dams. Within the box plots, the numbers indicate the number of litters sampled in each group; the numbers immediately below (in parentheses) indicate the total number of pups used in this group. † p < 0.05 statistically different from corresponding control value. #p < 0.05, statistically different from corresponding female value. (E) Simultaneous recordings of ventilatory activity (plethysmography; top traces), arterial O2 saturation (SpO2), and heart rate (pulse oximetry; bottom traces) in pups born to control dams (left traces) and pups born to dams subjected to GS (right traces). Reused, with permission, from Fournier S, et al., 2013, 138.


Figure 6. Timeline comparing key processes and stages in the perinatal development of rats and humans related to (A) the central nervous system, (B) respiratory motor control, and (C) the lungs. The timeline shows development from conception until end stage of the development process being compared. (A) “Neurodevelopment” depicts neuron, astrocyte, and microglial development and function (e.g., synaptogenesis, myelination). Note that the shaded area represents the period of rapid growth when the central nervous system is most vulnerable to insults. (B) “Respiratory motor control”, depicts the development of respiratory‐related neurons [preBötzinger Complex (preBötC), phrenic motoneurons (PMN)] and the diaphragm and formation/refinement of neuromuscular junctions (NMJ), along with the onset of processes such as respiratory rhythm generation and fetal breathing movements. Although many of those processes are comparable in humans, the precise stage of onset is not always known (e.g., preBötC formation). (C) “Lung development” compares the different stages of lung development from early formation in the fetus to alveolar structure in the lungs between humans and rat. Abbreviations: GD, gestational day; Wk, week; mo, months; yrs, years; PND, postnatal day. Reused, with permission, from Greer JJ, 2012 163; Johnson SM, et al., 2018 216; Mantilla CB and Sieck GC, 2008 290; National_Institute_on_Drug_Abuse, 2000 325; Pilarski JQ, 2019, 353; Schnoll JG, et al., 2019 403; Seaborn T, et al., 2010 405. Created with BioRender.com.


Figure 7. Early life stress (in the form of neonatal maternal separation; NMS) has persistent and sex‐specific effects on the neuroendocrine pathways regulating the stress response. (A) Neonatal maternal separation augments basal levels of c‐Fos mRNA expression in the paraventricular nucleus of the hypothalamus (PVH) of males but not females. This sex‐specific effect is observed downstream from the PVH as indicated by plasma levels of (B) ACTH and (C) corticosterone. Adapted, with permission, from Genest SE, et al., 2004 152; in those experiments (A‐C), pups were subjected to NMS 3 h/day from postnatal days 3 to 12. Controls were undisturbed over the same period. Basal HPA axis function was measured in adulthood (8 to 10 weeks of age). In males, prolonged maternal separation (180 min) augments the rise in plasma (D) ACTH and (E) corticosterone in response to an air startle stress. Reused, with permission, from Lippmann M, et al., 2007 271; in this study, rat pups were either handled and separated from their mother 180 min (3 h; HMS 180), handled and separated from their mother 15 min (HMS 15), or subjected to standard animal facility rearing (AFR). Those protocols were performed each day from postnatal days 2 to 14.


Figure 8. Early life stress (in the form of neonatal maternal separation; NMS) augments cardiorespiratory depression induced by the presence of liquid near the larynx in rat pup. This reflexive response is termed “laryngeal chemoreflex”. The top panels and present original recordings comparing cardiorespiratory responses to by intra‐tracheal water injection (10 μL) between pups subjected to (A) control conditions and (B) neonatal stress. The traces illustrate (from top to bottom): intercostal EMG, SpO2, and heart rate. These recordings were obtained following the third injection in 15‐day‐old male pups. (C) Collage of photomicrographs illustrating the caudal brainstem slice in which whole‐cell recordings were performed in the dorsal motor nucleus of the vagus (DMNV). The area postrema (AP), central canal (CC), commissural region of the nucleus of the solitary tract (NTScom), and hypoglossal motor nucleus (NXII) were used as visual landmarks. The inset shows a patch pipette attached to a cell. (D) Comparison of excitatory postsynaptic currents (EPSCs) recorded in the DMNV of 14‐day‐old male pups that were either raised under standard conditions (black; control) or subjected to the neonatal stress protocol (red). (E) Superimposed average EPSCs (10 min recording) comparing group data in males and females. (F) Cumulative probability plots of EPSC frequencies and amplitudes; in the inset, the histograms show mean data ± SEM for each group. Within each bar, the numbers in parentheses indicate the number of cells that were recorded in each group. Reused, with permission, from Baldy C, et al., 2017 17. Licensed under CC BY 4.0. (G) Photomicrographs of microglia immunolabeled with Iba‐1 (ionized calcium‐binding adaptor protein‐1) from DMNV obtained in medullary sections from 15‐day‐old pups raised in control conditions (top panel) or subjected to neonatal maternal separation. In each panel, the high magnification inset illustrates representative morphology. (H) Comparison of microglial morphological index between control and NMS groups. Data are shown as means + 1 SEM. Numbers in parentheses indicate the number of animals in each group. † Significantly different from control at P < 0.05. Reused, with permission, from Baldy C, et al., 2018 18.


Figure 9. Neonatal maternal separation (NMS) augments the hyperventilatory response to a brief hypoxic episode and promotes respiratory instability during non‐rapid eye movement (non‐REM) sleep. (A) Comparison of the breathing frequency response to hypoxia (90 s) between controls (white circles) and rats previously subjected to NMS (black circles) during non‐REM sleep. The figure also shows the change in frequency during the return to normoxia (recovery: 120 s). The small circles show the fraction of inspired O2 measured in the chamber during the experiment (right‐hand axis). In this panel, data were obtained every 10 s. (B) Correlation between the minute ventilation response to hypoxia (last 20 s of hypoxia expressed as a percentage change from baseline and the coefficient of variation for this variable during the 2.5 h of recording under normoxia. These measurements were obtained during non‐rapid eye movement (non‐REM) sleep. Open circles: control rats (n = 4); black circles: rats previously subjected to NMS (n = 6). Reused, with permission, from Kinkead R, et al., 2009 239.


Figure 10. Neonatal maternal separation (NMS) augments the carotid body's O2 chemosensitivity in males but not females. (A) Photomicrograph of the ex vivo carotid body preparation used to record the change in activity in response to hypoxia; recordings were obtained by placing a suction electrode on the carotid sinus nerve (CSN) from preparations. Neurograms from (B) male and (C) female rats illustrating the rectified carotid sinus nerve activity recorded under baseline condition (95% O2 + 5% CO2) followed by hypoxia (0% O2 + 5% CO2), and return to baseline condition for recovery. Preparations were obtained from adult males raised under control conditions (top) or previously subjected to NMS (bottom; 3 h/day from postnatal days 3‐12). Comparison of (D) male and (E) female mean carotid sinus nerve activity (impulses/sec) over the course of the hypoxic protocol between carotid bodies from control (open squares) and NMS rats (black squares). Hypoxia begins at T = 0 and is maintained until T = 500 s (end of plateau phase), followed by hyperoxic recovery; each data point represents the mean value on a second by second basis. Histograms comparing mean CSN activity of (F) male and (G) female rats for each specific experimental condition between control (white bars) and NMS (black bars) male rats. Data are reported as means ± SD. *indicates a value statistically different from control at P ≤ 0.05. Adapted, with permission, from Soliz J, et al., 2016 422. Licensed under CC‐BY‐4.0.


Figure 11. NMS leads to sex‐specific (female only) augmentation of the hypercapnic ventilatory response in adult rats. The histograms compare the mean increase of the main respiratory variables measured at the end of a 20 min exposure to moderate hypercapnia (FiCO2 = 0.05) between rats raised under control conditions (control, white bars) or subjected to NMS (black bars, 3 h/day from postnatal days 3 to 12). Data were obtained in adult (A) males and (B) females and are expressed as a percent change from baseline ± SEM; the numbers of animals in each group is indicated in the histogram bars. † indicates a value significantly different from control at P < 0.05. # indicates a value significantly different from corresponding female value at P < 0.05. Reused, with permission, from Genest SE, et al., 2007 153.
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Article Title: Sex‐Specific Effects of Stress on Respiratory Control: Plasticity, Adaptation, and Dysfunction
 

How to Cite

Luana Tenorio‐Lopes, Richard Kinkead. Sex‐Specific Effects of Stress on Respiratory Control: Plasticity, Adaptation, and Dysfunction. Compr Physiol 2021, 11: 2097-2134. doi: 10.1002/cphy.c200022