Changes in thermoregulation and monoamine release in freely moving rats during cold exposure and inhibition of the ventromedial, dorsomedial, or posterior hypothalamus

Abstract

The hypothalamus is critical for regulating thermogenesis, but the role of monoamines in specific hypothalamic subregions in thermogenesis is not thoroughly established. The purpose of this study was to confirm changes of body temperature (T ) and thermoregulatory parameters upon inhibition of neural activity in hypothalamic subregions in freely moving rats. In addition, the pattern of monoamine release in these nuclei was measured during active thermoregulation using microdialysis. Tetrodotoxin (TTX) was perfused into the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), or posterior hypothalamus (PH) at two different ambient temperatures (5 or 23 °C). Using telemetry, we continuously measured the T and the heart rate (HR) as an index of heat production as well as locomotor activity (Act). Tail skin temperature (T ) was also continuously measured as an index of heat loss. Although the perfusion of TTX into hypothalamic subregions had no effect on any of the measured thermoregulatory parameters at an ambient temperature of 23 °C, it induced significant T decrease under cold conditions only when perfused into the DMH and the PH. In contrast, the HR decreased only after perfusion of TTX into the PH during cold conditions, while the T and Act remained unchanged. Serotonin (5-HT) in the DMH and dopamine (DA) metabolite 3,4-Dihydroxyphenylacetic acid in the PH, but not noradrenaline, increased significantly during exposure to cold temperatures. Our results indicate that the DMH and the PH, but not the VMH, are particularly involved in heat production under cold conditions. In addition, 5-HT in the DMH and DA in the PH may be involved in thermogenesis.

Pivotal mental states

“…Antagonism of the 5-HT2AR also reduces body temperature (Pawlyk et al, 2006) and blocks hyperthermic response to social defeat (Sinh and Ootsuka, 2019). Some evidence suggests that exposure to heat or cold increases 5-HT levels (Hale et al, 2011; Ishiwata and Greenwood, 2018; Kelly et al, 2011; Myers and Beleslin, 1971), but other studies found no relationship between temperature manipulations and brain 5-HT levels (Ishiwata et al, 2004; Nakagawa et al, 2016; Saito et al, 2005). We are not aware of any direct evidence showing that body temperature manipulation influences 5-HT2AR activity (Zamfir et al, 1992), but given the intentional manipulation of body temperature in spiritual and therapeutic practice (see below), there are logical reasons to suspect there may be a relationship.…”

“…As discussed in previous sections, certain types of stress upregulate 5-HT2AR expression and activity (see Table 1 for a review of the relevant literature). Moreover, evidence that acute stress causes the release of 5-HT is compelling (Adell et al, 1997; Amat et al, 1998, 2005; Bastani et al, 2017; Beitia et al, 2005; Bland et al, 2003; Cohen et al, 2015; Ferres-Coy et al, 2013; Fuenmayor and Garcia, 1984; Fujino et al, 2002; Gardner et al, 2005; Hale et al, 2011; Higuchi et al, 2019; Ishida et al, 1997; Ishiwata and Greenwood, 2018; Johnson et al, 2005; Keeney et al, 2006; Kelly et al, 2011; Li et al, 2015; Myers and Beleslin, 1971; Nakajima et al, 2009; Neugebauer, 2020; Paul et al, 2011; Rex et al, 2005; Yoshioka et al, 1995) and it is logical to surmise that increased endogenous 5-HT release will engage the 5-HT2AR system, an assumption backed up by evidence of increased 5-HT2AR associated responses with drug-induced 5-HT release (Kuypers et al, 2018; Liechti et. al., 2000; Pitts et al, 2017; van Wel et al, 2012).…”

“…We place special focus on the serotonin system and its 2A receptor (5-HT2AR) subtype in particular, which has been shown to be particularly implicated in biology x environment interactions (Chang et al, 2017; Dressler et al, 2016; Fiocco et al, 2007; Jiang et al, 2016; Jokela et al, 2007; Lebe et al, 2013; Mellman et al, 2009; Parade et al, 2017; Salo et al, 2011). Various acute stressors appear to be reliable and robust inducers of serotonin release (Adell et al, 1997; Amat et al, 1998, 2005; Bastani et al, 2017; Beitia et al, 2005; Bland et al, 2003; Cohen et al, 2015; Ferres-Coy et al, 2013; Fuenmayor and Garcia, 1984; Fujino et al, 2002; Gardner et al, 2005; Hale et al, 2011; Higuchi et al, 2019; Ishida et al, 1997; Ishiwata and Greenwood, 2018; Johnson et al, 2005; Keeney et al, 2006; Kelly et al, 2011; Li et al, 2015; Myers and Beleslin, 1971; Nakajima et al, 2009; Neugebauer, 2020; Paul et al, 2011; Rex et al, 2005; Yoshioka et al, 1995) and different types of stressor, such as sleep deprivation (Elmenhorst et al, 2012; Maple et al, 2015; Zhao et al, 2019), hypoxia (Anju et al, 2011), chronic tryptophan depletion (Cahir et al, 2007), inflammation (Zhang et al, 2001), tonic pain (Kupers et al, 2009), repeated forced swim (Takao et al, 1995), repeated shock (Dwivedi et al, 2005), administration of stress hormones (Jitsuiki et al, 2000; Kuroda et al, 1992, 1994), amygdala stimulation (…”

Hypothalamic control of energy expenditure and thermogenesis

“…The VMH is another important nucleus involved in cold-induced thermogenesis, as the activation of the VMH induces BAT thermogenesis in cold-exposed rats 203 and increases oxygen consumption and shivering in rabbits 204 , and chemical lesioning of the VMH causes cold intolerance in rats 205 . Takayuki Ishiwata and colleagues proposed that the VMH is not involved in thermogenesis under cold conditions, with evidence that extracellular noradrenaline, serotonin, and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the VMH are not changed during cold exposure 206 . However, the data showed that body temperature increase and sympathetic output were reflected through heart rate, while the cold challenge was blocked with the perfusion of tetrodotoxin into the VMH 206 .…”

“…Takayuki Ishiwata and colleagues proposed that the VMH is not involved in thermogenesis under cold conditions, with evidence that extracellular noradrenaline, serotonin, and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the VMH are not changed during cold exposure 206 . However, the data showed that body temperature increase and sympathetic output were reflected through heart rate, while the cold challenge was blocked with the perfusion of tetrodotoxin into the VMH 206 . In addition, it is debatable whether microdialysis at the level of the lateral VMH can fully demonstrate neurotransmitter release from VMH neurons to downstream target regions, as the VMH does not directly innervate BAT 207 .…”