Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia

Abstract

Therapeutic hypothermia at 32-34 °C during or after cerebral ischaemia is neuroprotective. However, peripheral cold sensor-triggered hypothermia is ineffective and evokes vigorous counteractive shivering thermogenesis and complications that are difficult to tolerate in awake patients. Here, we show in mice that deep brain stimulation (DBS) of warm-sensitive neurones (WSNs) in the medial preoptic nucleus (MPN) produces tolerable hypothermia. In contrast to surface cooling-evoked hypothermia, DBS mice exhibit a torpor-like state without counteractive shivering. Like hypothermia evoked by chemogenetic activation of WSNs, DBS in free-moving mice elicits a rapid lowering of the core body temperature to 32-34 °C, which confers significant brain protection and motor function reservation. Mechanistically, activation of WSNs contributes to DBS-evoked hypothermia. Inhibition of WSNs prevents DBS-evoked hypothermia. Maintaining the core body temperature at normothermia during DBS abolishes DBS-mediated brain protection. Thus, the MPN is a DBS target to evoke tolerable therapeutic hypothermia for stroke treatment.

Prolonged activation of EP3 receptor-expressing preoptic neurons underlies torpor responses

“…Hence, it will be important to study whether other mammals, including humans, share this same genetic marker and brain circuits to regulate the thermoregulatory system. If so, it may be possible to harness activation of these pathways to modulate Tb for therapeutic proposes 24 in humans.…”

Enhancement of spatial learning by 40 Hz visual stimulation requires parvalbumin interneuron-dependent hippocampal neurogenesis

“…The immunostaining protocol was exactly as we previously described 4,50–52 . Briefly, mice were administered phenobarbital sodium salt (0.1 g/kg) to induce anesthesia.…”

Inhibition of EphA4 reduces vasogenic edema after experimental stroke in mice by protecting the blood-brain barrier integrity

“…The procedures were as we have described previously. 27 Briefly, brains were collected and cut into four coronal slices with 2 mm thickness. After staining with 2% 2,3,5-Triphenyltetrazolium chloride (TTC) solution for 10 min at 37 °C, images of brain slices were immediately captured and analyzed using the Image J software (https://imagej.nih.gov/ij/).…”

“…After 24 h or 72 h reperfusion, mice were evaluated using the neurological deficit score and the forelimb grip strength as previously described. 12,27 The neurological deficit score was assessed as follows: 0, normal motor function; 1, flexion of the contralateral torso and forelimb on lifting the animal by the tail; 2, circling to the contralateral side but normal posture at rest; 3, leaning to the contralateral side at rest; 4, no spontaneous motor activity. The forelimb grip strength test was performed using the Grip Strength Meter from Columbus Instruments (MyNeurolab, St Louis, MO).…”