Thomas C. Chou

The sleep switch: hypothalamic control of sleep and wakefulness

More than 70 years ago, von Economo predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting region in the preoptic area. Recent studies have dramatically confirmed these predictions. The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior lateral hypothalamus contains orexin/hypocretin neurons that are crucial for maintaining normal wakefulness. A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Disruption of wake- or sleep-promoting pathways results in behavioral state instability.

The Need to Feed: Homeostatic and Hedonic Control of Eating

Feeding provides substrate for energy metabolism, which is vital to the survival of every living animal and therefore is subject to intense regulation by brain homeostatic and hedonic systems. Over the last decade, our understanding of the circuits and molecules involved in this process has changed dramatically, in large part due to the availability of animal models with genetic lesions. In this review, we examine the role played in homeostatic regulation of feeding by systemic mediators such as leptin and ghrelin, which act on brain systems utilizing neuropeptide Y, agouti-related peptide, melanocortins, orexins, and melanin concentrating hormone, among other mediators. We also examine the mechanisms for taste and reward systems that provide food with its intrinsically reinforcing properties and explore the links between the homeostatic and hedonic systems that ensure intake of adequate nutrition.

Melanopsin in cells of origin of the retinohypothalamic tract

All known eukaryotic organisms exhibit physiological and behavioral rhythms termed circadian rhythms that cycle with a near-24-hour period; in mammals, light is the most potent stimulus for entraining endogenous rhythms to the daily light cycle. Photic information is transmitted via the retinohypothalamic tract (RHT) to the suprachiasmatic nucleus (SCN) in the hypothalamus, where circadian rhythms are generated, but the retinal photopigment that mediates circadian entrainment has remained elusive. Here we show that most retinal ganglion cells (RGCs) that project to the SCN express the photopigment melanopsin.

Contrasting Effects of Ibotenate Lesions of the Paraventricular Nucleus and Subparaventricular Zone on Sleep–Wake Cycle and Temperature Regulation

The suprachiasmatic nucleus (SCN), the circadian pacemaker for the brain, provides a massive projection to the subparaventricular zone (SPZ), but the role of the SPZ in circadian processes has received little attention. We examined the effects on circadian rhythms of sleep, body temperature, and activity in rats of restricted ibotenic acid lesions of the ventral or dorsal SPZ that spared the immediately adjacent paraventricular hypothalamic nucleus (PVH) and the SCN. Ventral SPZ lesions caused profound reduction of measures of circadian index of sleep (by 90%) and locomotor activity (75% reduction) but had less effect on body temperature (50% reduction); dorsal SPZ lesions caused greater reduction of circadian index of body temperature (by 70%) but had less effect on circadian index of locomotor activity (45% reduction) or sleep (<5% reduction). The loss of circadian regulation of body temperature or sleep was replaced by a strong ultradian rhythm (period ∼3 hr). Lesions of the PVH, immediately dorsal to the SPZ, had no significant effect on any circadian rhythms that we measured, nor did the lesions affect the baseline body temperature. However, the fever response after intravenous injection of lipopolysaccharide (5 μg/kg) was markedly decreased in the rats with PVH lesions (66.6%) but not dorsal SPZ lesions. These results indicate that circadian rhythms of sleep and body temperatures are regulated by separate neuronal populations in the SPZ, and different aspects of thermoregulation (circadian rhythm and fever response) are controlled by distinct anatomical substrates.

Effects of adenosine on gabaergic synaptic inputs to identified ventrolateral preoptic neurons

The ventrolateral preoptic nucleus (VLPO) is a key regulator of behavioral state that promotes sleep by directly inhibiting brain regions that maintain wakefulness. Subarachnoid administration of adenosine (AD) or AD agonists promotes sleep and induces expression of Fos protein in VLPO neurons. Therefore, activation of VLPO neurons may contribute to the somnogenic actions of AD. To define the mechanism through which AD activates VLPO neurons, we prepared hypothalamic slices from 9 to 12-day-old rat pups and recorded from 43 neurons in the galaninergic VLPO cluster; nine neurons contained galanin mRNA by post hoc in situ hybridization. Bath application of AD (20 microM) to seven of these neurons had no direct effect but caused a significant decrease in the frequency of spontaneous miniature inhibitory postsynaptic currents in the presence of tetrodotoxin, indicating a presynaptic site of action. We conclude that AD-mediated disinhibition increases the excitability of VLPO neurons thus contributing to the somnogenic properties of AD.

Lateral hypothalamic acetylcholinesterase-immunoreactive neurons co-express either orexin or melanin concentrating hormone

The lateral hypothalamic area (LHA) contains a large population of neurons that express the enzyme acetylcholinesterase (AChE), but are not themselves cholinergic. Some of these neurons have been shown to contain melanin-concentrating hormone (MCH), a neuropeptide implicated in regulating feeding, but the identities of the remaining neurons are unknown. We now report that nearly all AChE-immunoreactive neurons in the LHA express immunoreactivity for either MCH or for orexin, a peptide implicated in regulating wakefulness. Furthermore, most orexin neurons and MCH neurons appear to contain AChE. AChE immunoreactivity appears to be a key feature of nearly all of the diffusely-projecting cortical systems.