Nat Neurosci︱睡眠具有社会性：青少年睡眠与社会互动行为之间的发展联系
Author︱Wen-Jie Bian
Editor-in-Chief︱Sizhen Wang
Associate Editor︱Yi Lu
Editor︱Jiaxue Zha, Tiantian Yang
Sleep is an essential process for almost all animals and in humans, takes nearly one third of our lives. Sleep allows our body and mind to rest and recharge, and regain balance from previous waking activities, and also carries out specific cognitive functions such as memory consolidation and synaptic plasticity. While most of these sleep functions were identified in adult individuals, the role of sleep in development remains a mystery. In a study recently published in Nature Neuroscience, Prof Luis de Lecea’s group at Stanford University found that sleep during adolescence helps to shape the behavioral pattern during social interactions later in adulthood. Whether an adult person enjoys social occasions or finds them not so appealing or even aversive may have been predetermined many years ago when he/she was still a teenager and having sleep problems at night.
How much sleep does a person need every day? That highly depends on what developmental stage you are at, that is, how old you are. Newborn babies spend most of their time sleeping (14 - 17 hours per day). Then, the daily sleep amount gradually decreases as the individual grows from childhood, through adolescence, and to adulthood when the daily requirement for sleep is kept at a range of 7 - 8 hours. According to the National Sleep Foundation, older adolescents (14 - 17 years) should get at least 8-10 hours of sleep per day while younger adolescents (school-age) should get even more. In addition, brain activity during adolescent sleep, revealed by electroencephalogram (EEG), contains more featured components, such as so-called slow waves and sleep spindles, compared to adult sleep. So, why is adolescent sleep different from adult sleep? Does the former carry a special function in development?
To answer this question, researchers in the de Lecea group sought to disrupt the sleep in adolescent mice (35 - 42 days after birth) for 4 hours per day and 5 consecutive days (referred to as SD mice below). As a result,they found that these SD mice exhibited different social interaction behavior than the control animals without prior sleep disruption. Mice are social animals and likes to explore and investigate novel conspecifics upon encounter, and when a novel stranger and a familiar mouse both are present, they prefer to interact more with the novel stranger. This is calledthe social novelty preferencein mice. When examined at a young adult stage using a test called the three-chamber social interaction test, SD mice did not show this social novelty preference. They basically spent equal amount of time interacting with both the stranger and the familiar mouse. Interestingly, when the same sleep disruption was performed in adult mice, it did not lead to any defect in social interaction behavior, suggesting that this is a sleep effect specific to the adolescent stage.
Fig. 1. Adolescent SD impairs social novelty preference in adulthood
(Bian WJ, et al., Nat Neurosci, 2022)
What is changed at the neural circuit level that underlies this sleep effect on social interaction behavior? The dopaminergic neurons in a brain region called the ventral tegmental area (VTA) in midbrain as well as their projections to the nucleus accumbens (NAc) and prefrontal cortex (PFC) constitute the mesocorticolimbic pathway, which is a key player in motivation, addiction and reward seeking behavior. The VTA dopaminergic signaling also regulates social interaction behavior because social stimuli are perceived as reward signals in social animals like mice and humans. Combining the cutting-edge fiber photometry technique with the neuronal activity indicator (GCaMP6f) or with the dopamine biosensor (GRABDA), scientists found that in control mice, both the neuronal response in VTA dopaminergic neurons and the dopamine release at their terminals in NAc exhibited a social novelty-dependent pattern; great responses occurred when the test mouse first encountered the novel stranger and declined rapidly as the stranger got familiar, and when a second stranger mouse was encountered, this rise-and-decline pattern reappeared. However, this pattern was not seen in SD mice. Neither the neuronal response in VTA nor the dopamine release in NAc showed this novelty-dependent, rise-and-decline pattern to the first social stimulus, and neither of them responded to the second stranger mouse. In addition to this functional change, scientists also found that the VTA axonal projections to the NAc were aberrantly enhanced in SD mice, suggesting that adolescent SD may have impaired the circuit wiring/refinement process which led to excessive connections between the two regions incapable of properly signaling social novelty. Furthermore, using chemogenetic tools, they found that a balanced level of VTA dopaminergic activity during adolescence is critical for this developmental sleep function. Adolescent overexcitation of VTA neurons mimicked the social impairment caused by SD, whereas inhibition of these neurons concurrent with SD prevented the social novelty defect.
Fig. 2. Adolescent VTA activity is critical for social novelty preference
(Bian WJ, et al., Nat Neurosci, 2022)
In the last part of the study, researchers in the de Lecea group explored the possibility of using adolescent sleep intervention as a means to ameliorate social deficits. In a mouse model bearing autism-associated Shank3 mutation, they used pharmacological, optogenetic or chemogenetic methods during adolescence to increase either the non-rapid-eye-movement (NREM) sleep, or a particular NREM component called the slow wave activity, or to directly inhibit VTA activity. All of these manipulations resulted to an significantly improved social novelty preference later in adulthood inShank3 InsG3680 knock-in (InsG3680) mice.
Fig. 3. Adolescent sleep restoration rescues social deficits in InsG3680 mice
(Bian WJ, et al., Nat Neurosci, 2022)
“The connection we found between adolescent sleep and adult social interaction behavior via the dopaminergic signaling is in mice, while in humans, the situation is a bit more complicated, because we humans not only have an interest in novel social stimuli but also have strong social bonding that keeps us close with our old friends and family. ” says Dr. Wen-Jie Bian, the leading author and co-corresponding author of the study, “However, a lack of interest in new social encounter, or even being frightened by that, might cause problems in life, because one would not be able to make new friends, to build up his connections, to handle everyday social challenges from school or work. Even the people you call family, some of them were, once, new in your life.”
The study deepens our understanding of sleep and social behavior by connecting them in the context of adolescent development. Dr. Bian further pointed out, “For generally well people, good sleep during adolescence may have a greater impact on the quality of social life later on than we used to realize; and for adolescents unfortunately diagnosed with autism, schizophrenia, or other neurodevelopmental disorders, early sleep interventions might be a promising way to ameliorate or prevent their social symptoms from progression in the future.”
Article: Bian WJ, Brewer CL, Kauer JA, de Lecea L. Adolescent sleep shapes social novelty preference in mice. Nat Neurosci. 2022 May 26. doi: 10.1038/s41593-022-01076-8. PMID: 35618950.
本研究获得Human Frontiers Science Program, Brain & Behavior Research Foundation及NIH基金支持。
第一作者并共同通讯作者：边文杰 （前排右二）；通讯作者：Luis de Lecea （后排左三）。
（照片提供自：Luis de Lecea 实验室）
边文杰
（照片提供自：Luis de Lecea 实验室）
作者介绍：边文杰，博士，本科毕业于浙江工业大学，2016年于中国科学院神经科学研究所取得博士学位，博士期间研究方向为发育中树突棘修剪的分子机制。之后在斯坦福大学Luis de Lecea实验室从事博士后研究，主要工作为睡眠在发育中的功能及其对社交行为的持续影响。
【1】人才招聘︱“ 逻辑神经科学 ”诚聘文章解读/撰写岗位 ( 网络兼职, 在线办公)【2】“ 逻辑神经科学 ”诚聘副主编/编辑/运营岗位（在线办公）
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