70 million Americans suffer from some sort of sleep disorder. Behavior, mood and memory deteriorate with sleep loss and it gets worse with continuing sleep deprivation. Lack of sleep has been linked to Alzheimer?s disease. There is considerable amount of data on the neurons that keep us awake (arousal neurons) whereas very little is known about the neurons that make us fall asleep. Indeed, current network models of sleep-wake regulation list many arousal neuronal populations compared to only one sleep group located in the preoptic area. Better hypnotics will emerge by identifying circuits that directly link specific phenotypes of neurons to sleep. To provide this evidence, we will use the deep-brain imaging method to visualize activity of phenotype specific neurons in the hypothalamus, a part of the brain where neurons regulating sleep and arousal are located.
Aim 1 will image neurons containing melanin concentrating hormone (MCH) based on our evidence published in the last funding period that optogenetic stimulation of these neurons robustly increases both non-REM and REM sleep in mice and rats.
Aim 2 will use new retrograde axon-track tracing tools to insert ChR2 into projection specific MCH neurons to mechanistically demonstrate that driving specific circuits induces sleep. The CLARITY method will be used to visualize the circuit.
In Aim 3, optogenetics will drive these circuits to induce sleep in conditions of high arousal. Solid preliminary data are presented for all aims indicating that these methods are operational in the lab, and that the project will be completed successfully. From a translational perspective these studies are potentially useful in sleep disorders, such as insomnia, where sleep needs to be triggered against a strong arousal drive.
These aims will provide a framework for integrating the sleep-active neurons within an overall model of sleep-wake regulation.
Sleep disturbance is a frequent and common complaint among our Veterans and within the general population. Veterans suffering from post-traumatic stress disorder (PTSD) and depression have severe sleep disorders. In PTSD, there is a marked hyperarousal that makes it difficult for patients to fall asleep. The cause of the insomnia in PTSD is not known because we do not have a clear understanding of the brain circuits that induce sleep. I am using new genetically engineered tools such as optogenetics, pharmacogenetics, deep-brain imaging and CLARITY to identify the brain circuits responsible for specific behaviors, such as sleep. My laboratory is actively engaged in mapping neural circuits, and training a new generation of scientists in the use of cutting-edge neuroscience tools and methods.
|Blanco-Centurion, Carlos; Bendell, Emmaline; Zou, Bingyu et al. (2018) VGAT and VGLUT2 expression in MCH and orexin neurons in double transgenic reporter mice. IBRO Rep 4:44-49|
|Liu, Meng; Blanco-Centurion, Carlos; Shiromani, Priyattam J (2017) Rewiring brain circuits to block cataplexy in murine models of narcolepsy. Curr Opin Neurobiol 44:110-115|
|Shiromani, Priyattam J; Peever, John H (2017) New Neuroscience Tools That Are Identifying the Sleep-Wake Circuit. Sleep 40:|
|Liu, Meng; Blanco-Centurion, Carlos; Konadhode, Roda Rani et al. (2016) Orexin gene transfer into the amygdala suppresses both spontaneous and emotion-induced cataplexy in orexin-knockout mice. Eur J Neurosci 43:681-8|
|Konadhode, Roda Rani; Pelluru, Dheeraj; Shiromani, Priyattam J (2016) Unihemispheric Sleep: An Enigma for Current Models of Sleep-Wake Regulation. Sleep 39:491-4|
|Pelluru, Dheeraj; Konadhode, Roda Rani; Bhat, Narayan R et al. (2016) Optogenetic stimulation of astrocytes in the posterior hypothalamus increases sleep at night in C57BL/6J mice. Eur J Neurosci 43:1298-306|
|Blanco-Centurion, Carlos; Liu, Meng; Konadhode, Roda P et al. (2016) Optogenetic activation of melanin-concentrating hormone neurons increases non-rapid eye movement and rapid eye movement sleep during the night in rats. Eur J Neurosci 44:2846-2857|
|Konadhode, Roda Rani; Pelluru, Dheeraj; Shiromani, Priyattam J (2014) Neurons containing orexin or melanin concentrating hormone reciprocally regulate wake and sleep. Front Syst Neurosci 8:244|
|Blanco-Centurion, Carlos; Liu, Meng; Konadhode, RodaRani et al. (2013) Effects of orexin gene transfer in the dorsolateral pons in orexin knockout mice. Sleep 36:31-40|