The occurrence of generalized electrographic, behavioral, and autonomic activation during waking is driven by complex interactions between neuromodulatory neurons in the brainstem, hypothalamus, and basal forebrain. These neurons express a variety of neurotransmitters and neuropeptides, such as acetylcholine (ACH), DA, Glu, histamine, serotonin, and oxytocin.
These cells send projections that consolidate wakefulness, and pharmacological and genetic manipulations of these neurons change sleep-wake patterns.
The Hypothalamus
The hypothalamus is a small area in the center of the brain that produces hormones that control body temperature, appetite, sleep-wake cycles, and other physiological processes. It connects the endocrine system with the nervous system, and helps to maintain homeostasis as much as possible (a stable internal state). If the hypothalamus doesn’t work properly, it can cause imbalances in the body that lead to a wide range of rare disorders.
During the Spanish flu pandemic of 1918, Viennese neurologist Baron Constantin von Economo noticed that some patients with influenza developed a severe form of lethargy and would only wake up with intense stimulation. Others didn’t respond to any stimuli, and fell into a deep sleep from which they were not easily awakened. When he autopsied the brains of these patients, he found that those who were comatose had damage to the posterior hypothalamus and rostral midbrain, and that those who had fallen into a prolonged sleep had lesions in the preoptic area.
These findings led Nauta to conclude that there was a sleep center in the brain, and his experiments demonstrated that stimulating inhibitory neurons in the preoptic area could induce awakening from sleep and also suppress the activity of these same neurons during non-sleep periods. More recent studies have shown that generalized electrographic and behavioral activation during waking emerges from neurochemically specified arousal systems in the brain stem, posterior and lateral hypothalamus, and basal forebrain, including neurons that express histamine (HA), serotonin (5HT), noradrenalin (NA), acetylcholine (ACH), glutamate (GLU), dopamine (DA), or hypocretin/orexin (HCT). These neurotransmitter/neuropeptide pathways control various aspects of cognition, behavior, sensory processing, and autonomic function during waking, but they all promote arousal from sleep.
The Pituitary
The pituitary gland is a pea-sized endocrine gland that controls many other endocrine glands and hormone levels in the blood. It is shaped like a slender tube and is kept protected within the skull bone in a cavity called the sella turcica. The anterior pituitary secretes hormones, whereas the posterior pituitary does not synthesize hormones, but stores them in cells known as granules that are packed with pre-hormones (herring bodies). During fetal development, these herring bodies are cleaved into the hormones that control many of the body’s functions, including body temperature, hunger and thirst, urination, heartbeat, sleep, and other aspects of autonomic nervous system activity.
The cells that make these hormones in the hypothalamus are called magnocellular neurosecretory neurons and the neurohypophysial portal system. The axons from these neurons travel down the hypothalamus and through the infundibulum to the posterior pituitary, where they are deposited into storage sites within the posterior pituitary lobes, called the pars distalis, pars intermedia, and pars tuberalis. In response to signals from the hypothalamus, these axons can release the hormones that are stored in their granules.
The hypothalamus also sends messages that promote sleep and arousal to other brain areas. For example, it sends signals to the suprachiasmatic nucleus to promote sleep at night and wakefulness during the day. The SCN is the key to controlling our circadian rhythm, or internal clock. When the SCN is disrupted, as by jet lag or shift work, it can cause insomnia and other disorders.
The Parabrachial Nucleus
Neurons heavily involved in sleep and arousal are located throughout the brainstem, especially the parabrachial nucleus. This cluster of neurons is a major interface between the medullary reflex control mechanisms and central autonomic nervous system, which regulates cortical behavior. Neurons in the PB release neuromodulating substances that diffuse into wide areas of the brain to influence multiple functions simultaneously, such as waking and sleeping states.
This cluster of neurons controls the production and secretion of various hormones, including melatonin, which is responsible for regulation of the circadian clock in the hypothalamus. The PB also sends projections to the locus coeruleus, a key center for arousal. Clonidine and other drugs that act at alpha 1 adrenergic receptors in the locus coeruleus can significantly alter sleep and arousal.
Another important set of arousal-promoting neurons is located in the ventral preoptic area of the midbrain. These neurons produce a neurotransmitter called galanin, which increases the speed of action potentials and decreases their duration. Selective destruction of DA neurons in this nucleus increases daily sleep time by about 20 %, and galanin-immunoreactive neurons within the periaqueductal gray are associated with reduced sleep fragmentation in aging humans.
Moreover, this area also regulates REM sleep, which is characterized by a high-speed cortical activity and rapid eye movements. In the rat, optogenetic stimulation of a subset of Papilio nucleus neurons increases eye movements and elicits a REM-like state.
The Parasympathetic Nervous System
The parasympathetic nervous system helps to calm your body and reduce its activity, a role that’s often summed up in the rhyming phrases “rest and digest” or “feed and breed.” It stimulates glands in your mouth to produce saliva and glands in your nose to produce mucus. It can also cause your pupils to constrict, limiting how much light enters your eyes and helping you see better. It also makes your heart rate and blood pressure decrease.
The neural impulse that travels from the preganglionic neurons to their target organs is conveyed by a chemical called acetylcholine, which acts as a neurotransmitter. After a neuron receives an input from another cell, it releases acetylcholine at the synaptic gap to transmit the signal to a postganglionic neuron. The postganglionic neuron will then travel to the target organ and activate it.
The lateral ventrolateral nucleus (LVN) and pulvinar nucleus (PN) in the thalamus are both involved in arousal, but only LVS signals to the pituitary gland. It’s not clear exactly what causes the PN to send its signal, but a recent study showed that arousal-related brainstem activity occurred in visual regions and was propagated by thalamic circuitry to improve attention. This suggests that the PN plays an important role in our ability to focus on a task, even when we’re stressed or tired.
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