Cold-Induced Thermogenesis and Inflammation-Associated Cold-Seeking Behavior Are Represented by Different Dorsomedial Hypothalamic Sites: A Three-Dimensional Functional Topography Study in Conscious Rats

Abstract

In the past, we showed that large electrolytic lesions of the dorsomedial hypothalamus (DMH) promoted hypothermia in cold-exposed restrained rats, but attenuated hypothermia in rats challenged with a high dose of bacterial lipopolysaccharide (LPS) in a thermogradient apparatus. The goal of this study was to identify the thermoeffector mechanisms and DMH representation of the two phenomena and thus to understand how the same lesion could produce two opposite effects on body temperature. We found that the permissive effect of large electrolytic DMH lesions on cold-induced hypothermia was due to suppressed thermogenesis. DMH-lesioned rats also could not develop fever autonomically: they did not increase thermogenesis in response to a low, pyrogenic dose of LPS (10 μg/kg, i.v.). In contrast, changes in thermogenesis were uninvolved in the attenuation of the hypothermic response to a high, shock-inducing dose of LPS (5000 μg/kg, i.v.); this attenuation was due to a blockade of cold-seeking behavior. To compile DMH maps for the autonomic cold defense and for the cold-seeking response to LPS, we studied rats with small thermal lesions in different parts of the DMH. Cold thermogenesis had the highest representation in the dorsal hypothalamic area. Cold seeking was represented by a site at the ventral border of the dorsomedial nucleus. Because LPS causes both fever and hypothermia, we originally thought that the DMH contained a single thermoregulatory site that worked as a fever–hypothermia switch. Instead, we have found two separate sites: one that drives thermogenesis and the other, previously unknown, that drives inflammation-associated cold seeking.SIGNIFICANCE STATEMENT Cold-seeking behavior is a life-saving response that occurs in severe systemic inflammation. We studied this behavior in rats with lesions in the dorsomedial hypothalamus (DMH) challenged with a shock-inducing dose of bacterial endotoxin. We built functional maps of the DMH and found the strongest representation of cold-seeking behavior at the ventral border of the dorsomedial nucleus. We also built maps for cold-induced thermogenesis in unanesthetized rats and found the dorsal hypothalamic area to be its main representation site. Our work identifies the neural substrate of cold-seeking behavior in systemic inflammation and expands the functional topography of the DMH, a structure that modulates autonomic, endocrine, and behavioral responses and is a potential therapeutic target in anxiety and panic disorders.

Pre-exercise exposure to the treadmill setup changes the cardiovascular and thermoregulatory responses induced by subsequent treadmill running in rats

“…Additional evidence suggesting that these physiological changes are stress-related responses is the fact that dorsomedial hypothalamic nucleus lesions attenuate the increase in T CORE induced by placing an animal on a treadmill (Wanner et al, unpublished observations); the same lesions also attenuated hyperthermia following handling and injection of intraperitoneal saline in rats. 41 Of note, monosynaptic excitatory neurotransmission from the dorsomedial hypothalamus to sympathetic premotor neurons in the rostral medullary raphe region drives brown adipose tissue thermogenesis and tachycardia, leading to the development of psychological stress hyperthermia. 42 Our findings indicate that the increase in T CORE we observed was a long-lasting response to being placed on the treadmill, unlike the increases in cardiovascular parameters.…”

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

“…This set‐up permitted simultaneous recording of deep (colonic) T b and tail‐skin temperature (an indicator of vasomotor tone) in restrained rats that were either desensitized with RTX (see Intra‐abdominal desensitization of TRPV1 channels) or sham‐desensitized. The thermocouple set‐up used has been described in detail previously . The T a was set to 27°C, which is slightly subneutral for rats in this set‐up …”

“…The thermocouple set‐up used has been described in detail previously . The T a was set to 27°C, which is slightly subneutral for rats in this set‐up …”

“…For example, the same dose of the psychostimulant 3,4‐methylenedioxymethamphetamine, bioactive phospholipid platelet‐activating factor or bacterial lipopolysaccharide (LPS) can either increase or decrease T b in the same species, depending on the ambient temperature ( T a ). In the case of LPS, its opposite effects on T b have been shown to be mediated by different mechanisms, that is to involve different receptors, different enzymes, different brain structures and, at least in some cases, different thermoeffectors . Another example of a substance with a dual (hyper‐ and hypothermic) thermoregulatory action is cholecystokinin (CCK) octapeptide.…”

Neurons in the rat ventral lateral preoptic area are essential for the warm‐evoked inhibition of brown adipose tissue and shivering thermogenesis

“…| 1 of 22 regulation of brown adipose tissue (BAT) thermogenesis 1 and cutaneous vasoconstriction, 2 and through the activation of muscle shivering 3 and thermodefensive behaviours. 4,5 Preoptic area neurons project to the dorsomedial hypothalamus (DMH) and to the rostral raphe pallidus (rRPa) 6 to influence the activity of thermogenesis-promoting and thermogenesis premotor neurons respectively. [7][8][9] In particular, during warm exposure, inhibitory GABAergic inputs to DMH neurons from the medial preoptic area (MPA), 1,10,11 as well as the ventral medial preoptic area (VMPO), including the median preoptic nucleus (MnPO), 11 are proposed to suppress thermogenesis by reducing the excitatory drive to BAT sympathetic and to shivering somatic premotor neurons in the rRPa.…”