Neural substrate of cold-seeking behavior in endotoxin shock

Abstract

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 microg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 microg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel ("warmth receptor"). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 ("cold receptor"). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock.

Figure 1. Electrolytic ablation of the POA: histological verification and effects on autonomic thermoregulation.

(A) Bright-field photomicrographs of serial coronal brain sections (50 µm, cresyl violet staining) are shown for a sham-lesioned rat and a POA-lesioned rat. Here and in Figures 2, [3], [7] and [8], the number in the right upper corner of the schematic of each section of the sham-lesioned brain indicates the distance (in mm) between the section's plane and bregma. ac, anterior commissure; f, fornix; LPO, lateral preoptic area; MnPO, median preoptic nucleus; MPA, medial preoptic area; ox, optic chiasm; Sch, suprachiasmatic nucleus; SO, supraoptic nucleus; 3V, third ventricle. (B) The ability of sham-lesioned and POA-lesioned rats to defend their T_b (abdominal) during moderate heat exposure (28°C, 1 h) or mild cold exposure (17°C, 2 h). The rats could not move to a different T_a; therefore, they were forced to regulate their T_b mostly by autonomic mechanisms.

Figure 2. Electrolytic ablation of the PVH: histological verification and effects on autonomic thermoregulation.

(A) Serial coronal brain sections are shown for a sham-lesioned rat and a PVH-lesioned rat. Arc, arcuate hypothalamic nucleus; ME, median eminence; mt, mammillothalamic tract; sox, supraoptic decussation; VMH, ventromedial hypothalamic nucleus. Other abbreviations used are the same as in Figure 1. (B) The ability of sham-lesioned and PVH-lesioned rats to defend their T_b by autonomic mechanisms during moderate heat exposure (28°C, 2 h) or mild cold exposure (17°C, 2 h).

Figure 3. Electrolytic ablation of the DMH: histological verification and effects on autonomic thermoregulation.

(A) Serial coronal brain sections are shown for a sham-lesioned rat and a DMH-lesioned rat. InfS, infundibular stem. Other abbreviations used are the same as in Figures 1 and [2]. (B) The ability of sham-lesioned and DMH-lesioned rats to defend their T_b by autonomic mechanisms during moderate heat exposure (28°C, 2 h) or mild cold exposure (17°C, 2 h).

Figure 4. The effects of LPS (doses indicated) on the selected T_a (top panels) and T_b (bottom panels) of sham-lesioned and POA-lesioned rats.

Figure 5. The effects of LPS (doses indicated) on the selected T_a (top panels) and T_b (bottom panels) of sham-lesioned and PVH-lesioned rats.

Figure 6. The effects of LPS (doses indicated) on the selected T_a (top panels) and T_b (bottom panels) of sham-lesioned and DMH-lesioned rats.

Figure 7. Excitotoxic ablation of the PVH: histological verification and effects on autonomic thermoregulation.

(A) Bright-field photomicrographs of serial coronal brain sections (50 µm, Klüver-Barrera staining) of a sham-lesioned rat and a representative rat with bilateral ibotenic acid lesions of the PVH. The magnification of photomicrographs and the scale vary in different panels. Panels I-VI: ×40 (magnification) and 500 µm (scale bar). Panels VII and VIII: ×100 (magnification) and 200 µm (scale bar). Panels IX and X: ×400 (magnification) and 50 µm (scale bar). (B) The ability of sham-lesioned rats and rats with bilateral ibotenic acid lesions of the PVH to defend their T_b by autonomic mechanisms during moderate heat exposure or mild cold exposure.

Figure 8. Excitotoxic ablation of the DMH: histological verification and effects on autonomic thermoregulation.

(A) Bright-field photomicrographs of serial coronal brain sections (50 µm, Klüver-Barrera staining) of a sham-lesioned rat and a representative rat with bilateral ibotenic acid lesions of the DMH. The magnification and scale of each panel are the same as those of the corresponding panel in Figure 7. (B) The ability of sham-lesioned rats and rats with bilateral ibotenic acid lesions of the DMH to defend their T_b by autonomic mechanisms during moderate heat exposure or mild cold exposure.

Figure 9. The effects of LPS (5,000 µg/kg, i.v.) on the selected T_a and T_b of sham-lesioned rats and rats with bilateral ibotenic acid lesions of either PVH or DMH.