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

Figures

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  FIGURE 1. KO rats have increased mortality without any sex differences. (a) Survival (% of pups born per genotype) was reduced to ~50% by postnatal (P) day 2 in KO rats which steadily declined with wild‐type survival up to P21. (b) There were no sex differences in survival rates of KO rats. *p < 0.05 by chi‐square test. WT, n = 64; HM, n = 35 (18 F and 17 M)

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  FIGURE 2. Hypoxic and hypercapnic ventilation are reduced in KO rats within specific developmental age ranges. Minute ventilation (ml/min/100g; a), tidal volume (mL/breath/100g; b) and breathing frequency (breaths/min; c) during hypoxic breathing conditions (12% O2) are lower in KO rats (n = 7–11) versus WT rats (n = 8–22) from postnatal days 9–20 driven almost exclusively by lower breathing frequencies (except from P18 to P20 where tidal volume is also lower). Minute ventilation (d), tidal volume (e), and breathing frequency (breaths/min; f) during hypercapnic breathing conditions (7% CO2) are lower in KO rats (n = 5–16) versus WT rats (n = 8–24) from postnatal days 12–16 driven by lower tidal volumes from P12 to P16 and lower breathing frequencies from P14 to P16. Note that hypoxic and hypercapnic ventilation are all lower from P12 to P 16. *p < 0.05, two‐way ANOVA with Sidak post hoc test

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  FIGURE 3. Neurochemicals within the brainstem tissue of KO rats are altered during development. KO rats lack serotonin (5‐HT; a), its metabolite (5‐HIAA; b), and a 5‐HT turnover ratio (c; 5‐HIAA/5‐HT) in brainstem tissue rats aged P7–8 and P20–22. Norepinephrine (NE; d), dopamine (DA; e), and its metabolite, DOPAC (f) are similar between genotypes within P7–8 and P20–22 ages. A metabolite of DA and NE, Homovanillic acid (HVA; g), is significantly greater in KO rats versus WT rats from P7 to P8 but not from P20 to P22. The increase in HVA increased the dopamine turnover ratio (HVA/DA; h). DOPAC/DA ratio is unchanged between genotypes (i). The dopamine turnover ratio inclusive of both dopamine metabolites (HVA +DOPAC/DA) is elevated from P7 to P8 but not P20 to P22 in KO rats (j). *p < 0.05 between genotype within age; +p < 0.05 across age within genotype, two‐way ANOVA

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  FIGURE 4. Apneic‐like metrics measured during room air breathing were greater during two distinct developmental ages in KO rats. The number of apneic‐like events (#; a), average duration (b), and the total duration of apneic‐like events (c) were greater from P1 to P2 and from P12 to P13 or P14 to P16 in KO (n = 14–18) versus WT (n = 15–24) rats. Note, the last 10 minutes from room air ventilation studies were used for analysis. *p < 0.05 between genotype within age, two‐way ANOVA with Sidak post hoc test

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  FIGURE 5. Apneic‐like metrics measured during acute hypoxia were greater during two distinct developmental ages in KO rats. The number of apneic‐like events (#) was greater from P1 to P2 in KO (n = 5–10) versus WT (n = 7–9) rats (a) whereas the average duration (b) and the total duration of apneic‐like events (c) were greater from P12 to P13 or P14 to P16 in KO versus WT rats. Note, the last 5 minutes of acute hypoxic ventilation studies were used for analysis. * p < 0.05 between genotype within age, two‐way ANOVA with Sidak's post hoc test