Altered ventilatory and thermoregulatory control in male and female adult Pet-1 null mice

Abstract

The integrity of the serotonin (5-HT) system is essential to normal respiratory and thermoregulatory control. Male and female transgenic mice lacking central 5-HT neurons (Lmx1bf/f/p mice) show a 50% reduction in the hypercapnic ventilatory response and insufficient heat generation when cooled (Hodges et al. 2008a; Hodges et al. 2008b). Lmx1bf/f/p mice also show reduced body temperatures (Tbody) and O2 consumption (V̇O2), and breathe less at rest and during hypoxia and hypercapnia when measured below thermoneutrality (24°C), suggesting a role for 5-HT neurons in integrating ventilatory, thermal and metabolic control. Here, the hypothesis that Pet-1 null mice, which retain 30% of central 5-HT neurons, will demonstrate similar deficits in temperature and ventilatory control was tested. Pet-1 null mice had fewer medullary tryptophan hydroxylase-immunoreactive (TPH+) neurons compared to wild type (WT) mice, particularly in the midline raphé. Female (but not male) Pet-1 null mice had lower baseline minute ventilation (V̇E), breathing frequency (f), V̇O2 and Tbody relative to female WT mice (P<0.05). In addition, V̇E and V̇E / V̇O2 were decreased in male and female Pet-1 null mice during hypoxia and hypercapnia (P<0.05), but only male Pet-1 null mice showed a significant deficit in the hypercapnic ventilatory response when expressed as % of control (P<0.05). Finally, male and female Pet-1 null mice showed significant decreases in Tbody when externally cooled to 4°C. These data demonstrate that a moderate loss of 5-HT neurons leads to a modest attenuation of mechanisms defending body temperature, and that there are gender differences in the contributions of 5-HT neurons to ventilatory and thermoregulatory control.

Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats

“…5-HT neurons are integrated into the brainstem respiratory network and are thought to influence the control of breathing through two major mechanisms:1) by generating a tonic output of excitatory neuromodulators like 5-HT, substance P and thyrotropin releasing hormone (TRH) to respiratory neurons and/or other central CO 2 /pH chemoreceptors, and 2) through an intrinsic cellular CO 2 /pH chemosensitivity (Richerson 2004). Thus, it could be hypothesized that 5-HT neurons have their greatest influence on ventilatory control via effects on CO 2 sensitivity, consistent with the observations from 5-HT deficient mouse models (Hodges et al 2008b; Hodges et al 2011). These effects likely occur through multiple post-synaptic 5-HT receptors expressed within the respiratory network, or in other sites of central CO 2 /pH chemoreception including the retrotrapezoid nucleus (RTN) (Mulkey et al 2007; Dias et al 2008).…”

“…Genetically modified mouse models of central 5-HT deficiency, such as Pet-1 null and/or conditional Lmx1b f/f/p mice which lack most or all brain 5-HT neurons, demonstrate reduced hypercapnic ventilatory responses (Hodges et al 2008a; Hodges et al 2008b; Hodges et al 2011). The moderate or severe reduction in 5-HT neurons in the Pet-1 null and conditional Lmx1b f/f/p mice, respectively, did not alter eupneic breathing or the ventilatory responses to hypoxia, suggesting a relatively selective effect on ventilatory CO 2 sensitivity similar to the phenotype of the BN rat.…”

Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice

“…Pet-1 null male mice that were ϳ70% depleted in central 5-HT neurons displayed a significantly depressed HCVR confined to reduced frequency responses (24). Lower respiratory frequency also accounted for the depressed HCVR in Lmx1b f/f/p mice that lack 5-HT neurons (25).…”

Central Serotonergic Neurons Activate and Recruit Thermogenic Brown and Beige Fat and Regulate Glucose and Lipid Homeostasis

“…Central serotonergic neurons may be master regulators of whole body energy homeostasis. This role may be intertwined with a larger role integrating metabolism, body temperature and breathing, explaining the contribution of these neurons to central CO 2 chemoreception (Brust et al, 2014; Hodges et al, 2008, 2011; Ray et al, 2011). …”

“…In addition, central administration of para -chlorophenylalanine (PCPA), an inhibitor of 5-HT biosynthesis, inhibits BAT thermogenesis and causes BAT steatosis (Fuller et al, 1987). Further, studies in genetically engineered animals demonstrate an indispensable role for 5-HT neurons in thermogenesis—but not thermosensation or heat conservation—at normal room temperature (Ray et al, 2011), or when exposed to an ambient temperature of 4°C (Hodges et al, 2008, 2011). Most recently, it was demonstrated that lesioning central 5-HT neurons in adult animals with DT causes hypothermia.…”