Altered sleep homeostasis after restraint stress in 5-HTT knock-out male mice: a role for hypocretins.


Restraint stress produces changes in the sleep pattern that are mainly characterized by a delayed increase in rapid eye movement sleep (REMS) amounts. Because the serotonin (5-HT) and the hypocretin (hcrt) systems that regulate REMS are interconnected, we used mutant mice deficient in the 5-HT transporter (5-HTT(-/-)) to examine the role of 5-HT and hcrt neurotransmissions in the sleep response to stress. In contrast to wild-type mice, restraint stress did not induce a delayed increase in REMS amounts in 5-HTT(-/-) mice, indicating impaired sleep homeostasis in mutants. However, pharmacological blockade of the hcrt type 1 receptor (hcrt-R1) before restraint stress restored the REMS increase in 5-HTT(-/-) mice. In line with this finding, 5-HTT(-/-) mutants displayed after restraint stress higher long-lasting activation of hypothalamic preprohcrt neurons than wild-type mice and elevated levels of the hcrt-1 peptide and the hcrt-R1 mRNA in the anterior raphe area. Thus, hypocretinergic neurotransmission was enhanced by stress in 5-HTT(-/-) mice. Furthermore, in 5-HTT(-/-) but not wild-type mice, hypothalamic levels of the 5-HT metabolite 5-hydroxyindole acetic acid significantly increased after restraint stress, indicating a marked enhancement of serotonergic neurotransmission in mutants. Altogether, our data show that increased serotonergic -and in turn hypocretinergic- neurotransmissions exert an inhibitory influence on stress-induced delayed REMS. We propose that the direct interactions between hcrt neurons in the hypothalamus and 5-HT neurons in the anterior raphe nuclei account, at least in part, for the adaptive sleep-wakefulness regulations triggered by acute stress.

DOI: 10.1523/JNEUROSCI.3138-09.2009

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@article{Rachalski2009AlteredSH, title={Altered sleep homeostasis after restraint stress in 5-HTT knock-out male mice: a role for hypocretins.}, author={Adeline Rachalski and Chlo{\'e} Alexandre and J. Bernard and Françoise Saurini and Klaus-Peter Lesch and Michel Hamon and Jo{\"{e}lle Adrien and V{\'e}ronique Fabre}, journal={The Journal of neuroscience : the official journal of the Society for Neuroscience}, year={2009}, volume={29 49}, pages={15575-85} }