Ongoing Projects

Hypothalamic regulation of REM sleep

My research explores the hypothalamic regulation of Rapid Eye Movement (REM) sleep with a focus on the lateral hypothalamus (LH). REM sleep is known to be regulated homeostatically in that REM sleep deprived subjects will later show a rebound to recover this lost sleep state. REM sleep can also be dynamically increased during ambient temperature warming as more REM sleep is expressed while ambient temperatures are increased to the upper limit of the subject’s thermoneutral zone (TNZ). These findings suggest that REM sleep is regulated by several mechanisms, but the specific neuronal population(s) responsible for context-specific REM sleep are yet to be defined. Within the LH, Melanin-concentrating hormone (MCH) neurons fire maximally during REM sleep, and their chemogenic activation increases REM sleep. Mice lacking either the receptor for MCH or during optogenetic silencing of MCH neurons fail to increase REM sleep during ambient temperature warming. However, these mice appear to still demonstrate a normal REM sleep rebound following sleep deprivation. Within the LH, another subpopulation of GABAergic REM active neurons expresses Lim homeobox 6 (Lhx6) and constitute approximately 20% of the neurons activated during REM sleep rebound, whereas chemogenetic activation/inhibition of this neuronal population augments/reduces REM sleep, respectively. Thus, both Lhx6 and MCH neurons represent two separate neuronal populations, among others, that control REM sleep expression.

Given the diversity of inputs received by the LH and its important role in REM sleep regulation, the aim of this research will be to identify the subpopulations of LH neurons implicated in REM sleep control and to determine their respective roles in context-specific REM sleep modulation. Specifically, we aim to determine if the Lhx6 neurons, unlike MCH neurons, may be more likely involved in the homeostatic control of REM sleep in addition to identifying new LH cell populations in REM sleep expression. A second part of this project will be to determine the afferent control of these LH neurons responsible for their activation. Calcium imaging and optogenetic techniques are employed to monitor or manipulate the activity of different LH subpopulations, both in REM sleep rebound conditions following REM sleep deprivation and in ambient temperature warming, to assess the specific role(s) of each subpopulation. A similar approach will be extended to the identified afferents, including the Median preoptic area (MnPO) and the extended ventrolateral preoptic area (eVLPO). Finally, we will also employ TRAP2 mice methodology to specifically target the viral expression of calcium sensor or opsins only in those cells expressing cFos during either REM sleep rebound or temperature warming. This methodology will allow us to determine if the same or different hypothalamic cell populations drive REM sleep expression in a context-specific manner. This project is being carried out in collaboration with Pierre-Hervé Luppi and Patrice Fort from CRNL in Lyon.

Dissociation of REM sleep and cataplexy using ambient temperature manipulation

My PhD project focuses on better understanding the role of the melanin-concentrating hormone (MCH) neurons in increased REM sleep propensity and cataplexy in narcolepsy. MCH neurons are active during REM sleep and they are anatomically intermingled with the wake-promoting orexin/hypocretin (OX/Hcrt) neurons within the lateral hypothalamus. The selective loss of Hcrt-producing neurons causes narcolepsy, a chronic sleep disorder characterized by excessive sleepiness, increased REM sleep propensity and cataplexy. Cataplexy is the sudden loss of muscle tone triggered by strong, positive emotions, but its cause is poorly understood. Interestingly, our data show that MCH neurons are able to dynamically increase REM sleep expression during thermoneutral ambient temperature (Ta) warming in wild type (WT) mice. Although narcoleptic hypocretin-Knockout (Hcrt-KO) mice also increase REM sleep, Ta warming causes a concomitant marked decrease in cataplexy. We hypothesize that the MCH system may play a role in dissociating REM sleep and cataplexy in narcolepsy. Given the reciprocal firing pattern and inhibition between the Hcrt and MCH systems, we hypothesize that loss of Hcrt may disinhibit MCH activity resulting in the increased REM sleep propensity characteristic of narcolepsy, whereas periods of low MCH activity may exacerbate boundary state instability and favor cataplexy. To assess this hypothesis, we combine electrophysiological recordings with optogenetic and imaging techniques in a narcoleptic mouse model in order to dissect the neuronal dynamics of MCH activity across the sleep-wake cycle at both constant Ta and thermoneutral Ta warming. These experimental approaches will allow us to better understand the role of the MCH system in gating or modulating REM sleep and cataplexy expression.

Alterations in thermoregulation and core body temperature in patients with neurodegenerative disorders

Patients suffering from neurodegenerative diseases may exhibit abnormalities in the circadian cycle and thermoregulatory control compared to healthy individuals. For example, Alzheimer’s disease (AD) patients tend to show a phase delay in the circadian cycle with a delayed core body temperature (CBT) acrophase, and also may show an altered circadian autonomic control with a higher distal skin temperature during the day compared to healthy individuals. In patients with Parkinson’s disease (PD), the circadian rhythm of the body temperature is generally preserved, but their basal body temperature is lowered. They also may show a significantly lowered mesor and nocturnal fall in CBT compared to controls and have a phase delay in the sleep-wake-cycle. Narcolepsy patients tend to have an inability to appropriately modulate the thermoregulatory control according to their behavioral state and show a higher distal skin temperature and lower proximal skin temperature while being awake in comparison to healthy individuals. In spite of differences suggested between groups, data in free living conditions are lacking. Finally, narcoleptic patients show episodes of cataplexy, characterized by a complete loss of muscle tone triggered by emotion such as laughing. Recent work from our lab has shown that narcoleptic mice show a markedly reduced expression of cataplexy during ambient temperature warming, but the role of ambient temperature or skin in human cataplexy remains unknown.

For my thesis, I hypothesize that patients with neurodegenerative disorders will show unique circadian and thermoregulatory patterns specific to their neurodegenerative disorders. For this reason, we are investigating three different patient groups, including patients with AD, PD, and narcolepsy. These three groups are each characterized by neurodegeneration of unique neurotransmitter systems, including the cholinergic system for AD, dopamine system for PD and loss of hypocretin neurons in the hypothalamus in narcolepsy. To test this hypothesis, we are measuring different parameters related to thermoregulatory control such as the core body temperature, distal and proximal skin temperature, and heart rate as an indicator of autonomic function over three days in free living conditions. We are also comparing these three patient groups to healthy individuals. In narcolepsy patients, we also monitor cataplexy expression as a function of ambient and skin temperature. Finally, we plan to compare these findings in human narcolepsy with data obtained in a narcoleptic mouse model to better understand the role of ambient or skin temperature in modulating cataplexy expression.