Enhanced slow-wave EEG activity and thermoregulatory impairment following the inhibition of the lateral hypothalamus in the rat.

Matteo Cerri,Marco Mastrotto,Flavia Del Vecchio,Giovanni Zamboni,Roberto Amici,Marco Luppi,Domenico Tupone,Emanuele Perez,Davide Martelli,Andrej A Romanovsky

doi:10.1371/journal.pone.0112849

Abstract

Neurons within the lateral hypothalamus (LH) are thought to be able to evoke behavioural responses that are coordinated with an adequate level of autonomic activity. Recently, the acute pharmacological inhibition of LH has been shown to depress wakefulness and promote NREM sleep, while suppressing REM sleep. These effects have been suggested to be the consequence of the inhibition of specific neuronal populations within the LH, i.e. the orexin and the MCH neurons, respectively. However, the interpretation of these results is limited by the lack of quantitative analysis of the electroencephalographic (EEG) activity that is critical for the assessment of NREM sleep quality and the presence of aborted NREM-to-REM sleep transitions. Furthermore, the lack of evaluation of the autonomic and thermoregulatory effects of the treatment does not exclude the possibility that the wake-sleep changes are merely the consequence of the autonomic, in particular thermoregulatory, changes that may follow the inhibition of LH neurons. In the present study, the EEG and autonomic/thermoregulatory effects of a prolonged LH inhibition provoked by the repeated local delivery of the GABAA agonist muscimol were studied in rats kept at thermoneutral (24°C) and at a low (10°C) ambient temperature (Ta), a condition which is known to depress sleep occurrence. Here we show that: 1) at both Tas, LH inhibition promoted a peculiar and sustained bout of NREM sleep characterized by an enhancement of slow-wave activity with no NREM-to-REM sleep transitions; 2) LH inhibition caused a marked transitory decrease in brain temperature at Ta 10°C, but not at Ta 24°C, suggesting that sleep changes induced by LH inhibition at thermoneutrality are not caused by a thermoregulatory impairment. These changes are far different from those observed after the short-term selective inhibition of either orexin or MCH neurons, suggesting that other LH neurons are involved in sleep-wake modulation.

Highlights

The lateral hypothalamus (LH) is a complex network of several different kinds of neurons involved in many functions [1]
Effects on sleep The 6-h inhibition of the LH neurons was characterized by a significant increase in the amount of NREM sleep at both Ta 24uC and Ta 10uC (Figure 2)
The results of the present study show that, as previously described [5], in the rat kept at normal laboratory temperature (Ta, 24uC) the prolonged inhibition of LH neurons produced a pronounced increase in NREM sleep and a total suppression of rapid eye movement (REM) sleep

Summary

Introduction

The lateral hypothalamus (LH) is a complex network of several different kinds of neurons involved in many functions [1]. The pharmacological activation of LH neurons has been shown to promote active behaviour and locomotion [2], and to coherently induce an increase in sympathetic outflow [3]. Both effects can be the consequence of the activation of a subpopulation of LH neurons producing orexin [4]. It has been shown that the inhibition of LH neurons prevented rats from producing rapid eye movement (REM) sleep [5]. Optogenetic inhibition of MCH neurons did not produce a significant reduction in REM sleep duration [6]

Methods

Results

Conclusion