Respiratory control in the newborn : central chemosensitivity, neuropeptides and nicotinic effects
Author: Wickström, Ronny
Date: 2002-11-22
Location: Skandiasalen, Astrid Lindgrens Barnsjukhus, plan 1, Karolinska Sjukhuset
Time: 9.00
Department: Institutionen för kvinnors och barns hälsa / Department of Women's and Children's Health
Abstract
Breathing is regulated by a complex network of neurons located mainly in the brainstem. For the newborn, it is critical for survival that a continuous respiration is established after birth. However, the regulation of respiration also undergoes maturation in the postnatal period. This thesis focuses on some of the systems modulating respiration that may be of great importance for the newborn: central (C02) chemosensitivity and the neuropeptides substance P (SP) and galanin (GAL). We have also examined how perinatal nicotine exposure interferes with these systems.
Areas in the brainstem that contain putative C02 chemoreceptors expressed high levels of c-fos and c-jun mRNA following birth, indicating activation of these areas at this time. Exposure to hypercapnia also evoked expression of c-fos mRNA in several, but not all, of the areas described as chemosensitive in the adult. This may represent a maturational difference in the CO2-sensitivity. Indeed, using flow plethysmography to study the in vivo response to moderate hypercapnia, we found that although a response was present already on postnatal day 1 (P1) this developed during the first 10 postnatal days. We propose that the ventilatory response to hypercapnia develops in a biphasic manner, with a decreasing response until P7 and thereafter an increase, mainly due to increased tidal volumes. Using osmotic minipumps to administer nicotine during gestation we also show that the ventilatory response to moderate hypercapnia was attenuated on P1, possibly reflecting a premature neuronal differentiation.
We further demonstrate that GAL is expressed in the prenatal brainstem and that expression then increases postnatally. Also, we found expression of galanin receptor 1 (GALR- 1) in the brainstem already on embryological day 16, and in increasing amounts during later gestation. Postnatally, GALR-1 expression decreased dramatically in the locus coeruleus. The presence of GAL and GALR-1, and the maturational differences, in respiration-related areas of the brainstem present a theoretical involvement of GAL in respiratory control. We could further demonstrate that mortality increased in P1 mice, perinatally exposed to nicotine, during severe hypoxia. These nicotine-treated mice displayed no increased expression of tyrosine hydroxylase (TH) or GAL mRNA in the locus coeruleus following hypoxia, as was seen in control animals. Furthermore, the basal levels of TH mRNA in the adrenals were decreased following perinatal nicotine, also representing a possible deficiency in the defence against hypoxia.
Levels of SP mRNA increased immediately following birth in the nucleus of the solitary tract, indicating a role for this neuropeptide in the newborn. Using the neurokinin-1 receptor antagonist RP67580 we could demonstrate that intracerebroventricular injection on P5 altered the hypoxic ventilatory response, without affecting basal respiration. This indicates a role for endogenous SP release when increased demands are put on respiration. It also demonstrates that frequency and volume are regulated separately and that volume is affected also by other neurotransmitters and/or other neurokinin receptors. Using c-fos as a marker of neuronal activation, we found that neurons in the rostral ventrolateral medulla may be responsible for the altered response. Perinatal administration of nicotine (3 mg/kg*day) reduced levels of SP in the brainstem and cerebellum, without affecting SP levels in the forebrain or adrenals. Similar increases are seen after intrauterine hypoxia and in human infants that have succumbed to sudden infant death syndrome.
In conclusion, we have demonstrated maturational changes in both the C02-chemosensitive system and the expression patterns of SP and GAL. All these systems were also altered in different ways by perinatal nicotine exposure in the rat and mouse. This supports the idea that perinatal nicotine leads to multiple alterations at a neuronal level, and adds new possible mechanisms underlying the detrimental effect seen following perinatal nicotine exposure.
Areas in the brainstem that contain putative C02 chemoreceptors expressed high levels of c-fos and c-jun mRNA following birth, indicating activation of these areas at this time. Exposure to hypercapnia also evoked expression of c-fos mRNA in several, but not all, of the areas described as chemosensitive in the adult. This may represent a maturational difference in the CO2-sensitivity. Indeed, using flow plethysmography to study the in vivo response to moderate hypercapnia, we found that although a response was present already on postnatal day 1 (P1) this developed during the first 10 postnatal days. We propose that the ventilatory response to hypercapnia develops in a biphasic manner, with a decreasing response until P7 and thereafter an increase, mainly due to increased tidal volumes. Using osmotic minipumps to administer nicotine during gestation we also show that the ventilatory response to moderate hypercapnia was attenuated on P1, possibly reflecting a premature neuronal differentiation.
We further demonstrate that GAL is expressed in the prenatal brainstem and that expression then increases postnatally. Also, we found expression of galanin receptor 1 (GALR- 1) in the brainstem already on embryological day 16, and in increasing amounts during later gestation. Postnatally, GALR-1 expression decreased dramatically in the locus coeruleus. The presence of GAL and GALR-1, and the maturational differences, in respiration-related areas of the brainstem present a theoretical involvement of GAL in respiratory control. We could further demonstrate that mortality increased in P1 mice, perinatally exposed to nicotine, during severe hypoxia. These nicotine-treated mice displayed no increased expression of tyrosine hydroxylase (TH) or GAL mRNA in the locus coeruleus following hypoxia, as was seen in control animals. Furthermore, the basal levels of TH mRNA in the adrenals were decreased following perinatal nicotine, also representing a possible deficiency in the defence against hypoxia.
Levels of SP mRNA increased immediately following birth in the nucleus of the solitary tract, indicating a role for this neuropeptide in the newborn. Using the neurokinin-1 receptor antagonist RP67580 we could demonstrate that intracerebroventricular injection on P5 altered the hypoxic ventilatory response, without affecting basal respiration. This indicates a role for endogenous SP release when increased demands are put on respiration. It also demonstrates that frequency and volume are regulated separately and that volume is affected also by other neurotransmitters and/or other neurokinin receptors. Using c-fos as a marker of neuronal activation, we found that neurons in the rostral ventrolateral medulla may be responsible for the altered response. Perinatal administration of nicotine (3 mg/kg*day) reduced levels of SP in the brainstem and cerebellum, without affecting SP levels in the forebrain or adrenals. Similar increases are seen after intrauterine hypoxia and in human infants that have succumbed to sudden infant death syndrome.
In conclusion, we have demonstrated maturational changes in both the C02-chemosensitive system and the expression patterns of SP and GAL. All these systems were also altered in different ways by perinatal nicotine exposure in the rat and mouse. This supports the idea that perinatal nicotine leads to multiple alterations at a neuronal level, and adds new possible mechanisms underlying the detrimental effect seen following perinatal nicotine exposure.
List of papers:
I. Wickstrom R, Holgert H, Hokfelt T, Lagercrantz H (1999). Birth-related expression of c-fos, c-jun and substance P mRNAs in the rat brainstem and pia mater: possible relationship to changes in central chemosensivity. Dev Brain Res. 112(2): 255-66.
II. Wickstrom R, Hokfelt T, Lagercrantz H (2002). Development of CO(2)-response in the early newborn period in rat. Respir Physiolo Neurobiol. 132(2): 145.
Pubmed
III. Wickstrom R, Holgert H, Lagercrantz H, Hokfelt T (2000). Perinatal distribution of galanin and galanin receptor-1 mRNA in the rat hindbrain. Brain Res Dev Brain Res. 123(1): 53-65.
Pubmed
IV. Wickstrom R, Mas C, Simonneau M, Holgert H, Hokfelt T, Lagercrantz H (2002). Perinatal nicotine attenuates the hypoxia-induced upregulation of tyrosine hydroxylase and galanin mRNA in locus coeruleus of the newborn mouse. Pediatr Res. 52(5): 763-9.
V. Wickstrom R, Berner J, Holgert H, Hokfelt T, Lagercrantz H (2002). Hypoxic response in newborn rat is dependant on NK-1 receptor activation. [Submitted]
VI. Wickstrom R, Berner J, Hokfelt T, Lagercrantz H (2002). Perinatal nicotine alters CO2-response and brainstem substance P levels in newborn rat. [Manuscript]
I. Wickstrom R, Holgert H, Hokfelt T, Lagercrantz H (1999). Birth-related expression of c-fos, c-jun and substance P mRNAs in the rat brainstem and pia mater: possible relationship to changes in central chemosensivity. Dev Brain Res. 112(2): 255-66.
II. Wickstrom R, Hokfelt T, Lagercrantz H (2002). Development of CO(2)-response in the early newborn period in rat. Respir Physiolo Neurobiol. 132(2): 145.
Pubmed
III. Wickstrom R, Holgert H, Lagercrantz H, Hokfelt T (2000). Perinatal distribution of galanin and galanin receptor-1 mRNA in the rat hindbrain. Brain Res Dev Brain Res. 123(1): 53-65.
Pubmed
IV. Wickstrom R, Mas C, Simonneau M, Holgert H, Hokfelt T, Lagercrantz H (2002). Perinatal nicotine attenuates the hypoxia-induced upregulation of tyrosine hydroxylase and galanin mRNA in locus coeruleus of the newborn mouse. Pediatr Res. 52(5): 763-9.
V. Wickstrom R, Berner J, Holgert H, Hokfelt T, Lagercrantz H (2002). Hypoxic response in newborn rat is dependant on NK-1 receptor activation. [Submitted]
VI. Wickstrom R, Berner J, Hokfelt T, Lagercrantz H (2002). Perinatal nicotine alters CO2-response and brainstem substance P levels in newborn rat. [Manuscript]
Issue date: 2002-11-01
Publication year: 2002
ISBN: 91-7349-323-6
Statistics
Total Visits
Views | |
---|---|
Respiratory ...(legacy) | 186 |
Respiratory ... | 119 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Respiratory ... | 1 | 6 | 0 | 0 | 0 | 0 | 0 |
Top country views
Views | |
---|---|
Sweden | 77 |
United States | 44 |
Germany | 43 |
China | 32 |
South Korea | 10 |
Australia | 6 |
Finland | 6 |
Ireland | 6 |
Russia | 4 |
Austria | 3 |
Top cities views
Views | |
---|---|
Kiez | 15 |
Stockholm | 12 |
Seoul | 10 |
Sunnyvale | 9 |
Dublin | 6 |
Kristianstad | 6 |
Beijing | 4 |
Tianjin | 4 |
Ashburn | 3 |
Ballerup | 3 |