Messing with the ‘Flip-Flop’ Switch: Why Getting Sick Makes You Sleepy

We all know how it feels to be sick.  The fatigue, increased sleep, and general malaise that accompany a cold are the primary reasons people stay bedridden when ill.  Even in ~350 BC, Aristotle wrote On Sleep and Waking and documented that the basic human experience of fever was accompanied by feelings of lethargy and fatigue.  But why?

To understand, we need to learn a bit about sleep circuitry.  There are two primary brain areas governing sleep: the hypothalamus and brainstem.  Each contains specific wake- and sleep-promoting neuronal populations, which mutually inhibit each other.  In this way, the neuronal assemblies that keep you awake inhibit those that put you to sleep, and vice-versa.  This creates what is known by engineers as a flip-flop switch, a circuit with two stable states acting independently but not simultaneously.

When sick, your immune system responds by sending messages through your body with cytokines.  These signals enhance immune system function by allowing the body to properly defend against foreign invaders, resulting in inflammation.  Neurons in the hypothalamus respond by shifting the balance towards sleep rather than wakefulness.  This is an important step in fighting off and recovering from infection.  However, this neuronal response also results in sickness behavior, a suite of adaptive behaviors during infection.  These include reduced appetite and sex drive, increased lethargy, social isolation, and, in some cases depression.

Of the many sleep-related neuronal populations in the brain, a few deserve special attention.  Hypothalamic orexin neurons stabilize the flip-flop switch so you don’t transition between sleep and wakefulness too quickly.  Cytokines activate neurotensin-expressing interneurons, which inhibit orexin neurons.  Consequently, activation of these inhibitory neurons by inflammatory signals decreases orexin neuron activity, making you sleepy.  Interestingly, individuals with specific mutations in orexin or orexin receptors rapidly transition between sleep states, a condition known as narcolepsy.

Another well-defined population of neurons affected during sickness is serotonin-releasing (i.e., serotonergic) neurons in the raphe nucleus of the brainstem.  These neurons are highly active during waking and much less so during sleep.  Serotonergic neurons maintain wakefulness by inhibiting neurons in the hypothalamus that promote sleep and excite other wake-promoting neurons.  In response to cytokines, serotonergic neurons in the raphe become inhibited, resulting in drowsiness.  Interestingly, histamine-producing (i.e., histaminergic) neurons in the hypothalamus also promote wakefulness.  Inhibition of their activity by anti-histamines that cross the blood-brain-barrier (e.g., Benadryl) causes marked drowsiness, whereas those that don’t make it into the brain (e.g., Allegra) don’t have this side-effect.

As sleep is an ancient and widespread trait throughout the animal kingdom, many more redundant and overlapping neuron populations exist to provide fine-tune regulation.  So next time you get sick and can’t crawl out of bed, blame your immune system.  In an interesting dichotomy, the immune system is both a savior from death and bringer of discomfort during sickness.

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Written by Jeremy Borniger.

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References:

Grossberg, A. J., Zhu, X., Leinninger, G. M., Levasseur, P. R., Braun, T. P., Myers, M. G., & Marks, D. L. (2011). Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. The Journal of Neuroscience, 31(31), 11376-11386.

Imeri, L., & Opp, M. R. (2009). How (and why) the immune system makes us sleep. Nature Reviews Neuroscience, 10(3), 199-210.

Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., & Mignot, E. (2000). Hypocretin (orexin) deficiency in human narcolepsy. The Lancet,355(9197), 39-40.

Saper, C. B., Fuller, P. M., Pedersen, N. P., Lu, J., & Scammell, T. E. (2010). Sleep state switching.Neuron, 68(6), 1023-1042.

Saper, C. B., Chou, T. C., & Scammell, T. E. (2001). The sleep switch: hypothalamic control of sleep and wakefulness. Trends in neurosciences, 24(12), 726-731.

Images from adapted from Saper, C. B., Chou, T. C., & Scammell, T. E. (2001). The sleep switch: hypothalamic control of sleep and wakefulness. Trends in neurosciences, 24(12), 726-731.

and made by Jooyeun Lee.