The Effect of Nucleus Accumbens Medium Spiny Neuron Subtypes on Stress-Induced Sleep Changes

Post by Lincoln Tracy

What's the science?

Stress is a key contributor to both major depressive disorder and post-traumatic stress disorder. These two conditions have common symptoms, including diminished motivation and sleep dysregulation. Chronic social defeat stress (CSDS) is commonly used to study altered motivation in rodents. Medium spiny neurons within the nucleus accumbens (NAc) release dopamine and contribute to altered motivation in CSDS. Although CSDS can disrupt sleep in mice, the NAc cells’ role in sleep disruption is unknown. This week in Biological Psychiatry, McCullough and colleagues used chemogenetics (the use of chemicals to activate or deactivate certain cells) to selectively manipulate the function of the two dopamine-expressing, medium spiny neuron populations in the NAc to explore the neural mechanisms responsible for the effects of stress on sleep in mice.

How did they do it?

The authors infused viral vectors into the NAc, which would later be activated through clozapine administration in drinking water. Electroencephalography (used to measure brain activity) and electromyography (used to measure muscle activity) wires were attached to the skull and sutured into the trapezius muscle (respectively), while transmitters were implanted into the abdomen of mice to quantify sleep, locomotion, and body temperature. After recovery, mice underwent 10 days of CSDS. Two cohorts of mice were used: one to assess sleep, and the other to assess stress susceptibility. The effects of activating or inhibiting two NAc medium spiny neuron subtypes, D1 and D2 receptor-expressing neurons, were examined over a 10-day period in the former cohort. The latter cohort underwent a battery of behavioral tests: social interaction tests, open field tests, and elevated plus maze tests.   

What did they find?

First, the authors found that chronic inhibition or excitation of medium spiny neurons expressing D1 or D2 receptors in the NAc had unique effects on sleep. Inhibition of medium spiny neurons expressing D1 receptors mimicked the effects of CSDS on rapid eye movement (REM) sleep (i.e., it disrupted sleep) without affecting slow-wave sleep. Activation of the D1-medium spiny neurons had the opposite effect. Conversely, activation of D2-medium spiny neurons increased the time spent in slow-wave sleep. There was no effect of D2-medium spiny neuron activation or inhibition on any of the REM sleep metrics. Taken together, the combined effects of inhibiting D1-medium spiny neurons and activating D2-medium spiny neurons on sleep mirror that of CSDS. They also found that, while activating or inhibiting D1-medium spiny neurons did not reliably alter the daily rhythms in body temperature, activating D2-medium spiny neurons decreased average body temperature. Finally, behavioral testing revealed that D1-medium spiny neuron inhibition increased susceptibility to stress, while D1-medium spiny neuron activation promoted stress resilience, suggesting that they have opposing behavioral effects. 

What's the impact?

McCullough et al. have identified novel information about how stress changes neuronal circuits and leads to numerous diagnostic features of psychiatric illnesses. These findings have translational relevance, as sleep can be defined and measured consistently in both mice and humans. An enhanced understanding of the neural mechanisms underlying the common symptoms of major depressive and post-traumatic stress disorders may improve diagnoses and assist in developing novel treatments that target specific NAc neuronal populations to relieve stress-related illnesses.

McCullough et al. Nucleus accumbens medium spiny neuron subtypes differentially regulate stress-associated alterations in sleep architecture. Biological Psychiatry (2021). Access the original scientific publication here.