Dosing Dopamine to Regulate Rest

Sleep is great.  We all do it (sort of), and the fortunate among us can look forward to getting some sweet slumber every night.  But sometimes, something better comes along.  A new video game, Netflix series, or Tinder date might be so captivating that even late into the night, our body’s need for sleep seems to disappear completely.  On the other hand, there are times when staying awake—during a lecture, for example—can seem impossible even after a full-night’s sleep.  How does our brain decide when to stay awake or take a snooze?  Could disruption to this system underlie insomnia or other sleeping disorders?

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What time is it again?  [Image: Patrick Brosset, CC BY-NC 2.0]

We need to be awake to perform essential behaviors, like eating, mating, and running from predators.  But once we’re satisfied and safe, we should save up our energy and, if appropriate, go to sleep.  Clearly, there is a connection between sleep and the motivation to engage in rewarding or life-saving activities, but where in the brain does this connection exist?  Dr. Ada Eban-Rothschild and colleagues in the de Lecea lab at Stanford University decided to investigate.

Based on previous research, they suspected that the neurotransmitter dopamine might be involved.  Neurotransmitters are released by neurons to communicate specific messages to other neurons.  Dopamine, for instance, is crucial for processing reward and motivation [1–3].  Importantly, dopamine is also involved in promoting wakefulness [4,5], and stimulants like caffeine and cocaine are thought to keep people awake by increasing the dopamine available in their brains [6,7].

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Bill Murray dosing his dopamine in my favorite movie, Coffee & Cigarettes.

But there are several hubs in the brain that rely on dopamine to communicate.  Which specific population of neurons might be particularly important for regulating sleep and motivation?  Eban-Rothschild and colleagues decided to investigate the ventral tegmental area (VTA), which is an important regulator of motivational processes in the brain [1,3,8].  Although the role of the VTA in sleep/wake has been debated, recent research suggests that it might be a good candidate [9–11].

For their experiments, Eban-Rothschild and colleagues utilized genetic tools in mice to observe and manipulate the activity of dopamine neurons specifically in the VTA.  Using calcium imaging, which allows scientists to visualize which neurons are active, the authors found that VTA dopamine neurons were most active during rapid-eye movement (REM) sleep (when dreams usually occur), less active during wake, and least active during non-REM (deep) sleep.  So, this experiment showed that VTA dopamine neuron activity correlated with sleep-wake state.

In another set of experiments, the authors manipulated the activity of VTA dopamine neurons to see if they could cause changes in sleep-wake state.  Indeed, they found that stimulating the activity of VTA dopamine neurons during the mice’s usual sleeping period could keep them awake for up to 6 hours!   The authors also found that suppressing the activity of the VTA dopamine neurons could put the mice to sleep.  Even when they presented the mice with food, a mate, and the threat of a potential predator (fox pee)—things that very effectively prevent normal mice from sleeping—the mice could not stay awake!  Adorably, however, the authors discovered a new behavior, nest building, that the mice could stay awake for.  If they didn’t have a bed ready before their VTA dopamine activity was suppressed, they would take the time before their slumber to make one.  And during this time, although the mice were engaged in a purposeful waking activity, VTA dopamine activity was reduced.

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Who doesn’t love a nice nest to nap in?

So, it seems that particularly motivating activities may increase VTA dopamine neuron activity enough to effectively prevent us from falling asleep.  de Lecea hopes this information will contribute to the treatment of insomnia.  “Insomnia,” he said in a statement, “has traditionally been treated with drugs such as benzodiazepines that nonspecifically shut down the entire brain.  Now we see the possibility of developing therapies that, by narrowly targeting this newly identified circuit, could induce much higher-quality sleep.”  These findings are also exciting in the context of ADHD, as well as psychiatric disorders, in which motivation, sleep, and the relationships between them seem to be disrupted [12–16].  This research also provides hope for those without sleep disorders.  Just activate your VTA dopamine neurons and never sleep again*!!!

*not advised

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Goodnight!

References:

[1]      E.S. Bromberg-Martin, M. Matsumoto, O. Hikosaka, Dopamine in Motivational Control: Rewarding, Aversive, and Alerting, Neuron. 68 (2010) 815–834. doi:10.1016/j.neuron.2010.11.022.

[2]      K. Morita, M. Morishima, K. Sakai, Y. Kawaguchi, Dopaminergic Control of Motivation and Reinforcement Learning: A Closed-Circuit Account for Reward-Oriented Behavior., J. Neurosci. 33 (2013) 8866–8890. doi:10.1523/JNEUROSCI.4614-12.2013.

[3]      K.C. Berridge, T.E. Robinson, What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?, Brain Res. Brain Res. Rev. 28 (1998) 309–69. http://www.ncbi.nlm.nih.gov/pubmed/9858756.

[4]      R.A. España, T.E. Scammell, Sleep neurobiology from a clinical perspective., Sleep. 34 (2011) 845–58. doi:10.5665/SLEEP.1112.

[5]      J.P. Wisor, S. Nishino, I. Sora, G.H. Uhl, E. Mignot, D.M. Edgar, Dopaminergic role in stimulant-induced wakefulness., J. Neurosci. 21 (2001) 1787–1794. doi:21/5/1787 [pii].

[6]      A.H. Nall, I. Shakhmantsir, K. Cichewicz, S. Birman, J. Hirsh, A. Sehgal, Caffeine promotes wakefulness via dopamine signaling in Drosophila., Sci. Rep. 6 (2016) 20938. doi:10.1038/srep20938.

[7]      B. Boutrel, G.F. Koob, What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications., Sleep. 27 (2004) 1181–1194.

[8]      J.D. Salamone, M. Correa, The Mysterious Motivational Functions of Mesolimbic Dopamine, Neuron. 76 (2012) 470–485. doi:10.1016/j.neuron.2012.10.021.

[9]      J.D. Miller, J. Farber, P. Gatz, H. Roffwarg, D.C. German, Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and waking in the rat, Brain Res. 273 (1983) 133–141. doi:10.1016/0006-8993(83)91101-0.

[10]    M.E. Trulson, D.W. Preussler, Dopamine-Containing Ventral Tegmental Area Neurons Freely Moving Cats : Activity during the Sleep-Waking Cycle and Effects of Stress, Exp. Neurol. 83 (1984) 367–377.

[11]    L. Dahan, B. Astier, N. Vautrelle, N. Urbain, B. Kocsis, G. Chouvet, Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep., Neuropsychopharmacology. 32 (2007) 1232–1241. doi:10.1038/sj.npp.1301251.

[12]    M. Happ, M.M. Halassa, Too bored to stay awake, Nat. Neurosci. 19 (2016) 1274–1276. doi:10.1038/nn.4383.

[13]    K. Wulff, S. Gatti, J.G. Wettstein, R.G. Foster, Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease., Nat. Rev. Neurosci. 11 (2010) 589–99. doi:10.1038/nrn2868.

[14]    A. Jagannath, S.N. Peirson, R.G. Foster, Sleep and circadian rhythm disruption in neuropsychiatric illness., Curr. Opin. Neurobiol. 23 (2013) 888–94. doi:10.1016/j.conb.2013.03.008.

[15]    V. Bromundt, M. Köster, A. Georgiev-Kill, K. Opwis, A. Wirz-Justice, G. Stoppe, C. Cajochen, Sleep-wake cycles and cognitive functioning in schizophrenia., Br. J. Psychiatry. 198 (2011) 269–76. doi:10.1192/bjp.bp.110.078022.

[16]    A. Der-Avakian, A. Markou, The neurobiology of anhedonia and other reward-related deficits., Trends Neurosci. 35 (2012) 68–77. doi:10.1016/j.tins.2011.11.005.

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