Heat stress attenuates new cell generation in the hypothalamus: A role for miR-138

- New cell generation in the chick hypothalamus occurs in a constitutive manner.
- Excessive heat stress during the critical period reduces hypothalamic newborn cell number.
- Heat stress has a long-term effect on new cell generation in the hypothalamus.
- miR-138 has a modulatory effect on new cell generation in the chick hypothalamus.
- miR-138 can modulate hypothalamic neurogenesis by direct targeting of Reelin.

The anterior hypothalamus (Ant Hyp) of the brain serves as the main regulator of numerous homeostatic functions, among them body temperature. Fine-tuning of the thermal-response set point during the critical postnatal sensory-developmental period involves neuronal network remodeling which might also be accompanied by alterations in hypothalamic cell populations. Here we demonstrate that heat stress during the critical period of thermal-control establishment interferes with generation of new cells in the chick hypothalamus. Whereas conditioning of the 3-day-old chicks under high ambient temperatures for 24 h diminished the number of newborn cells in anterior hypothalamic structures 1 week after the treatment, mild heat stress did not influence the amount of new cells. Phenotypic analysis of these newborn cells indicated a predominant decrease in non-neuronal cell precursors, i.e. cells that do not express doublecortin (DCX). Furthermore, heat challenge of 10-day-old previously high-temperature-conditioned chicks abolished hypothalamic neurogenesis and significantly decreased the number of cells of non-neural origin. As a potential regulatory mechanism for the underlying generation of new cells in the hypothalamus, we investigated the role of the microRNA (miRNA) miR-138, previously reported by us to promote hypothalamic cell migration in vitro and whose levels are reduced during heat stress. Intracranial injection into the third ventricle of miR-138 led to an increase in the number of newborn cells in the Ant Hyp, an effect which might be partially mediated by inhibition of its direct target reelin. These data demonstrate the role of ambient temperature on the generation of new cells in the hypothalamus during the critical period of thermal-control establishment and highlight the long-term effect of severe heat stress on hypothalamic cell population. Moreover, miRNAs, miR-138 in particular, can regulate new cell generation in the hypothalamus.