![]() This observation provides the main rationale for treating cataplexy with antidepressants that increase brain levels of norepinephrine and serotonin. With loss of hypocretins, levels of these two neurotransmitters may be lower, permitting paralysis to occur even during wakefulness. These paralysis circuits are normally blocked by norepinephrine and serotonin during wakefulness. During REM sleep, most muscles are paralyzed by circuits in the lower brainstem and spinal cord. As a consequence, people with narcolepsy can be fully alert at times, but have great difficulty sustaining this alertness for long periods of time.Ĭataplexy and sleep paralysis are unusual states in which the brain circuits that produce paralysis during REM sleep become active during wakefulness. In narcolepsy, the loss of hypocretins may result in reduced or inconsistent activity in these target neurons. ![]() These neurons include those that produce key neurotransmitters such as norepinephrine, serotonin, and dopamine. Many researchers theorize that the sleepiness of narcolepsy is a consequence of “sleep state instability,” a condition in which the thresholds between wake and sleep are easily crossed, resulting in both fragmented wakefulness during the daytime and fragmented sleep at night.ĭuring normal wakefulness, hypocretin neurons send signals that produce long-lasting increases in the activity of many other neurons essential for sustaining alertness and wakefulness. In addition to revealing the normal role of hypocretin neurons in the brain, research has provided many insights into how a loss of hypocretin signaling causes sleepiness and cataplexy. (See Key discoveries below for more on some of the studies that have shed light on the role of hypocretins in narcolepsy.) Most likely, it is caused by less severe injury to the hypocretin neurons, resulting in fewer and less severe symptoms. Though much has been learned about narcolepsy with cataplexy, considerably less is known about the cause of narcolepsy without cataplexy. In fact, REM sleep can become so poorly regulated that the paralysis or dreaming that normally occurs only in REM sleep can mix into wakefulness, causing cataplexy and dreamlike hallucinations. The consequent lack of hypocretins results in lasting sleepiness and poor control of REM sleep. In people who have narcolepsy with cataplexy, most of the hypocretin-producing neurons die off. In individuals without narcolepsy and whose sleep is well regulated, hypocretins are released during wakefulness and increase activity in target neurons that promote wakefulness and suppress rapid-eye-movement (REM) sleep. ![]() (This website uses the term “hypocretins,” as this name is preferred by clinicians.) 1, 2 One group named them hypocretin-1 and -2, and the other group named them orexin-A and -B. Hypocretins were first discovered in 1998 when two research groups independently identified them in the brain. Hypocretins are released from these neurons during wakefulness and bind to specific hypocretin receptors on target neurons, which increases the activity of these neurons. Of the billions of neurons in the brain, only about 100,000–200,000 produce hypocretins. Hypocretins are only produced by a small cluster of neurons in the hypothalamus, a brain region located roughly behind the eyes and between the ears. Hypocretins are neurotransmitters, chemicals that transmit signals from a neuron to a target neuron. Recent research has revealed that narcolepsy with cataplexy is caused by a lack of hypocretins, key brain chemicals that help sustain alertness and prevent REM sleep from occurring at the wrong times.
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