The Neurons that Keep You Up at Night

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A recent study by Stanford University and Cold Spring Harbor Laboratory found that a distinct circuit in the brain is responsible for all those sleepless nights in times of stress. Insomnia is one of the most prevalent stress-related complaints and the link between stress and insomnia has long been recognized. However, the underlying mechanisms that cause this phenomenon remain to be clarified, which poses a therapeutic challenge.

The study, done in adult mice, is the first to find that insomnia induced by stress is associated with the activation of specific neurons in the hypothalamus, a region that is located at the base of the brain. Within the hypothalamus there are distinct aggregations of neurons, called the hypothalamic nuclei.

The hypothalamus (circled), is a region at the base of the brain where the CRH neurons are found in the paraventricular hypothalamic nucleus.

The study found that the paraventricular nucleus, which is one of the hypothalamic nuclei, is the specific region where the neurons that stimulate hyperarousal (or wakefulness) due to stress, are located. These neurons are called the corticotropin-releasing neurons (CRH) and they are responsible for the production of cortisol. The CRH neurons, when activated, also communicate with nearby neurons, namely the hypocretin-secreting neurons of the hypothalamus, which further promote waking state. 

In simple terms, the study found that while you have been tossing and turning and losing sleep, these CRH neurons, which are sensitive to stress, have been working hard to produce cortisol hormone and communicate with other regions of the hypothalamus. In turn, the cortisol as well as the activation of nearby hypothalamic regions lead to hyperarousal, thereby causing insomnia. 

This was discovered through the use of adult mice that were put in a moderately stressful environment and subsequently scanned using electroencephalogram (EEG) and electromyography (EGM). They found that when the mice were exposed to stress, their CRH neurons were activated and they signalled for the nearby hypocretin-secreting neurons, which were then activated and promoted wakefulness. 

This cycle of stress, cortisol production and inter-hypothalamic communications was also examined by the use of genetic engineering. When the mices’ DNA was manipulated to artificially overexpress CRH neurons, the mice suffered long episodes of insomnia under stressed conditions. Conversely, when the researchers deactivated CRH neurons, thereby interfering the communications between the CRH neurons and the hypocretin-secreting neurons, the mice could sleep peacefully, despite still experiencing stressful conditions. This suggests that the CRH neurons, which are found in the hypothalamus of the brain, play a vital role in orchestrating stress-induced insomnia. 

These results provide new, exciting potential for therapeutics in the area of stress and insomnia, as this study may open the door to a deeper understanding of stress-induced insomnia and its mechanisms.

Study: Li, S. et al. (2020). Hypothalamic Circuitry underlying stress-induced insomnia and peripheral immunosuppression. Science Advances, Vol. 6, no. 37. https://advances.sciencemag.org/content/6/37/eabc2590

Illustration by David Wyffels



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