Abstract
Heat acclimation in rats is associated with enhanced neurogenesis in thermoregulatory centers of the hypothalamus. To elucidate the mechanisms for heat acclimation, we investigated the effects of direct mild heat exposure on the proliferation and differentiation of neural stem/progenitor cells (NSCs/NPCs). The NSCs/NPCs isolated from forebrain cortices of 14.5-day-old rat fetuses were propagated as neurospheres at either 37.0°C (control) or 38.5°C (mild heat exposure) for four days, and the effects on proliferation were investigated by MTS cell viability assay, measurement of neurosphere diameter, and counting the total number of cells. The mRNA expressions of heat shock proteins (HSPs) and brain-derived neurotrophic factor (BDNF), cAMP response element-binding (CREB) protein and Akt phosphorylation levels, and intracellular reactive oxygen species (ROS) levels were analyzed using real time PCR, Western blotting and CM-H2DCFDA assay respectively. Heat exposure under proliferation condition increased NSC/NPC viability, neurosphere diameter, and cell count. BDNF mRNA expression, CREB phosphorylation, and ROS level were also increased by heat exposure. Heat exposure increased HSP27 mRNA expression concomitant with enhanced p-Akt level. Moreover, treatment with LY294002 (a PI3K inhibitor) abolished the effects of heat exposure on NSC/NPC proliferation. Furthermore, heat exposure under differentiation conditions increased the proportion of cells positive for Tuj1 (a neuronal marker). These findings suggest that mild heat exposure increases NSC/NPC proliferation, possibly through activation of the Akt pathway, and also enhances neuronal differentiation. Direct effects of temperature on NSCs/NPCs may be one of the mechanisms involved in hypothalamic neurogenesis in heat-acclimated rats. Such heat-induced neurogenesis could also be an effective therapeutic strategy for neurodegenerative diseases.
Highlights
Heat acclimation (HA) is an adaptive physiological process that increases heat tolerance [1, 2]
We demonstrated that larger neurospheres, a greater number of total cells and increased cell viability in a cortical NSC/NPC culture at 38.5 ̊C compared to control, 37.0 ̊C (Fig 1)
These data strongly suggested that mildly elevated culture temperatures can increase the rate of NSC/NPC proliferation
Summary
Heat acclimation (HA) is an adaptive physiological process that increases heat tolerance [1, 2]. Depending on the duration of heat stimuli, the process of heat acclimation is classified into two types, i.e., (1) short-term HA (STHA), and (2) long-term HA (LTHA) [3]. Since LTHA is long lasting, the process might cause functional and morphological changes in the hypothalamic thermoregulatory centers to achieve such persisting effect. The ratio of hypothalamic thermosensitive to thermo-insensitive neurons is changed after heat exposure, suggesting a considerable plasticity exist in thermoregulatory centers [15]. Such plasticity could be involved in establishing LTAHAHhhHA, the exact cause that changes the ratio of neuronal types is unknown
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