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Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.

ABSTRACT: Serotonin (5-HT) influences brain development and has predominantly excitatory neuromodulatory effects on the neural respiratory control circuitry. Infants that succumb to sudden infant death syndrome (SIDS) have reduced brainstem 5-HT levels and Tryptophan hydroxylase 2 (Tph2). Furthermore, there are age- and sex-dependent risk factors associated with SIDS. Here we utilized our established Dark Agouti transgenic rat lacking central serotonin KO to test the hypotheses that CNS 5-HT deficiency leads to: (1) high mortality in a sex-independent manner, (2) age-dependent alterations in other CNS aminergic systems, and (3) age-dependent impairment of chemoreflexes during post-natal development. KO rat pups showed high neonatal mortality but not in a sex-dependent manner and did not show altered hypoxic or hypercapnic ventilatory chemoreflexes. However, KO rat pups had increased apnea-related metrics during a specific developmental age (P12-16), which were preceded by transient increases in dopaminergic system activity (P7-8). These results support and extend the concept that 5-HT per se is a critical factor in supporting respiratory control during post-natal development.

SUBMITTER: Mouradian GC

PROVIDER: S-EPMC8259800 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.

Mouradian Gary C GC Kilby Madeline M Alvarez Santiago S Kaplan Kara K Hodges Matthew R MR

Physiological reports 20210701 13

Serotonin (5-HT) influences brain development and has predominantly excitatory neuromodulatory effects on the neural respiratory control circuitry. Infants that succumb to sudden infant death syndrome (SIDS) have reduced brainstem 5-HT levels and Tryptophan hydroxylase 2 (Tph2). Furthermore, there are age- and sex-dependent risk factors associated with SIDS. Here we utilized our established Dark Agouti transgenic rat lacking central serotonin KO to test the hypotheses that CNS 5-HT deficiency le ...[more]

PMID: 34228894

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Project description:The present study was designed to explore whether the depletion of serotonin (5-HT) in the central nervous system (CNS5-HT) leads to systolic and diastolic dysfunction and whether this dysfunction is exacerbated by sex, age and spinal cord injury. Echocardiographic assessment of systolic and diastolic function was completed in young and old male and female tryptophan hydroxylase 2 knockout (TPH2-/-) and wild-type (TPH2+/+) mice with intact spinal cords, as well as in C2 spinal cord hemisected young TPH2-/- and TPH2+/+ mice. In addition, lumbar sympathetic nervous system activity was recorded in elderly male and female intact TPH2-/- and TPH2+/+ mice. Systolic and diastolic dysfunction was evident in young TPH2-/- mice, including a higher left ventricular mass (P < 0.001), left ventricular outflow parameters (e.g. peak velocity) and E/A (P < 0.001). Reductions in ejection fraction and fractional shortening were also evident (P < 0.001), although stroke volume and cardiac output were maintained. The assessed dysfunction was exacerbated by age and spinal cord injury, resulting in reductions in cardiac output (P ≤ 0.01). The dysfunction was accompanied by increases in sympathetic burst height (P = 0.038) and incidence (P = 0.001). Reductions in CNS5-HT are coupled to systolic and diastolic dysfunction, which is exacerbated by age and spinal cord injury. This dysfunction is coupled to increases in sympathetic nervous system activity in elderly mice. Our findings are an initial step toward determining whether reductions in CNS5-HT are a unifying mechanism that links central sleep apnoea, sympathoexcitation and heart failure in intact and spinal cord injured individuals. KEY POINTS: Reductions in central nervous system serotonin (CNS5-HT) may contribute to systolic and diastolic dysfunction. This dysfunction may be linked to increases in sympathetic nervous system activity and exacerbated by sex, age and spinal cord injury. Echocardiographic assessment of systolic and diastolic function was completed in young and old male and female intact TPH2+/+ and TPH2-/- mice, as well as in C2 spinal cord hemisected young mice. Lumbar sympathetic nervous system activity was also recorded in elderly male and female intact TPH2+/+ and TPH2-/- mice. Systolic and diastolic dysfunction was evident in young TPH2-/- mice. This dysfunction was exacerbated by age and spinal cord injury. The cardiac dysfunction was accompanied by increases in lumbar sympathetic nervous system activity. Our findings are an initial step toward determining whether reductions in CNS5-HT is a unifying mechanism that links central sleep apnoea, sympathoexcitation and heart failure in intact and spinal cord injured individuals.

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Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.

Publications

Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.

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