社交互動對於動物的心理健康至關重要。幼年的社交經驗對於終身的腦部功能發展及社交行為具有深遠的影響。社交隔離 (social isolation) 不僅對於動物的行為產生及時影響，還可能帶來長期的神經功能及行為的改變。儘管急性社交隔離會增加對社交接觸的動機，但其背後的神經機制尚未完全明瞭。本研究結果發現，雄性及雌性的C57BL/6J小鼠在青春期經過為期七天的社交隔離後，會顯著增加對社交互動 (free interaction)和物品探索 (object exploration) 的渴望，同時導致短期社交適應 (short-tern habituation)、社交新奇偏好 (social novelty) 及社交辨識記憶 (social recognition memory) 受損。這些現象即使在重新群居 (regrouping) 三週後仍然存在。透過化學遺傳操作 (chemogenetic manipulation) 方法進行細胞特異性標記，我們確認了下視丘旁核 (paraventricular nucleus) 催產素神經元在調節社交隔離引發的社交行為改變中扮演著重要角色。當我們在群居小鼠中活化下視丘旁核催產素神經元時，模擬了社交隔離小鼠的社交行為改變。相反，當我們抑制這些神經元時，則能逆轉社交隔離所致的行為改變。此外，我們還發現中腦腹側蓋區 (ventral tegmental area) 的多巴胺神經元通過投射至內側前額葉 (medial prefrontal cortex)，而非伏隔核 (nucleus accumbens) 的路徑來調控社交隔離誘導的社交渴望。我們透過在中腦腹側蓋區注射催產素受體拮抗劑 (L368,899)，以及透過在內側前額葉局部注射6-羥基多巴胺 (6-hydroxydopamine) 以化學性損壞多巴胺神經元軸突末端，都能緩解社交隔離引起的社交行為改變。這些實驗結果說明，催產素訊號在中腦腹側蓋區投射至內側前額葉多巴胺神經迴路的活性中的關鍵調節作用。總結，此等發現不僅揭開了青春期社交隔離對雄性及雌性小鼠的社交行為具有長期影響，還說明了催產素在調控這項行為中的重要性。

Social interactions are essential for mental health across animal species. Early-life social experiences strongly influence brain function and social behavior later in life. Although acute social isolation (SI) increases the motivation to engage in social interactions, the underlying neural mechanisms remain largely unknown. Here, we demonstrate that in both male and female C57BL/6 mice, one week of SI during adolescence leads to an increased craving for social interactions and object exploration. This increase is accompanied by impaired social habituation, social novelty preference, and social recognition memory (SRM). Notably, the SI-induced social craving and SRM deficits persisted even after the mice were regrouped. Using cell-type-specific manipulations with designer receptors exclusively activated by designer drugs (DREADD), we identified a key role for oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) in mediating SI-induced changes in social behavior. Chemogenetic inhibition of PVN oxytocin neurons rescued the social behavior deficits caused by SI, while chemogenetic activation of these neurons mimicked the social behavior alterations observed in socially isolated mice. Furthermore, we discovered that dopaminergic neurons in the ventral tegmental area (VTA) play a crucial role in mediating SI-induced social craving through their projections to the medial prefrontal cortex (mPFC), but not the nucleus accumbens. Injection of the oxytocin receptor antagonist L368,899 into the VTA, or using 6-hydroxydopamine to chemical lesions of dopaminergic axon terminals in the mPFC, mitigated the social behavior changes induced by SI. In summary, our findings suggest that SI during adolescence has long-lasting effects on social behaviors in both sexes via oxytocinergic modulation of the VTA-to-mPFC dopaminergic circuit activity.

Arakawa H (2018) Ethological approach to social isolation effects in behavioral studies of laboratory rodents. Behav Brain Res 341:98-108.
Almeida-Santos AF, Carvalho VR, Jaimes LF, de Castro CM, Pinto HP, Oliveira TPD, Vieira LB, Moraes MFD, Pereira GS (2019) Social isolation impairs the persistence of social recognition memory by disturbing the glutamatergic tonus and the olfactory bulb-dorsal hippocampus coupling. Sci Rep 9:473.
Baik, J. H. (2013). Dopamine signaling in reward-related behaviors. Front. Neural Circuits 7: 152.
Baumeister RF, Leary MR (1995) The need to belong: desire for interpersonal attachments as a fundamental human motivation. Psychol Bull 117:497-529.
Borland JM, Grantham KN, Aiani LM, Frantz KJ, Albers HE (2018) Role of oxytocin in the ventral tegmental area in social reinforcement. Psychoneuroendocrinology 95:128-137.
Brandt, L., Liu, S., Heim, C., & Heinz, A. (2022). The effects of social isolation stress and discrimination on mental health. Transl. Psychiatry 12: 398.
Cacioppo JT, Hawkley LC, Norman GJ, Berntson GG (2011) Social isolation. Ann N Y Acad Sci 1231:17-22.
Chen P, Hong W (2018) Neural circuit mechanisms of social behavior. Neuron 98:16-30.
Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrand M, Domingos A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532-536.
Dale, H. H. (1906). On some physiological actions of ergot. J Physiol 34: 163.
Du Vigneaud, V., Ressler, C., & Trippett, S. (1953). The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J. Biol. Chem. 205: 949-957.
Du Vigneaud, V., Ressler, C., Swan, J. M., Roberts, C. W., & Katsoyannis, P. G. (1954). The synthesis of oxytocin1. J. Am. Chem. Soc. 76: 3115-3121.
Elovainio M, Hakulinen C, Pulkki-Råback L, Virtanen M, Josefsson K, Jokela M, Vahtera J, Kivimäki M (2017). Contribution of risk factors to excess mortality in isolated and lonely individuals: an analysis of data from the UK Biobank cohort study. Lancet Public Health 2:e260-e266.
Fegert, J. M., Vitiello, B., Plener, P. L., & Clemens, V. (2020). Challenges and burden of the Coronavirus 2019 (COVID-19) pandemic for child and adolescent mental health: a narrative review to highlight clinical and research needs in the acute phase and the long return to normality. Child Adolesc Psychiatry Ment Health 14: 1-11.
Grippo AJ, Trahanas DM, Zimmerman RR 2nd, Porges SW, Carter CS (2009) Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation. Psychoneuroendocrinology 34:1542-1553.
Gunaydin LA, Grosenick L, Finkelstein JC, Kauvar IV, Fenno LE, Adhikari A, Lammel S, Mirzabekov JJ, Airan RD, Zalocusky KA, Tye KM, Anikeeva P, Malenka RC, Deisseroth K (2014) Natural neural projection dynamics underlying social behavior. Cell 157:1535-1551.
Hawes MT, Szenczy AK, Olino TM, Nelson BD, Klein DN (2021) Trajectories of depression, anxiety and pandemic experiences; A longitudinal study of youth in New York during the Spring-Summer of 2020. Psychiatry Res 298:113778.
Holt-Lunstad J, Smith TB, Baker M, Harris T, Stephenson D (2015) Loneliness and social isolation as risk factors for mortality: a meta-analytic review. Perspect Psychol Sci 10:227-237.
Hung LW, Neuner S, Polepalli JS, Beier KT, Wright M, Walsh JJ, Lewis EM, Luo L, Deisseroth K, Dölen G, Malenka RC (2017) Gating of social reward by oxytocin in the ventral tegmental area. Science 357:1406-1411.
Jurek B, Neumann ID (2018) The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev 98:1805-1908.
Karelina, K., & DeVries, A. C. (2011). Modeling social influences on human health. Psychosom. Med. 73: 67-74.
Kemp, A. H., & Quintana, D. S. (2013). The relationship between mental and physical health: insights from the study of heart rate variability. Int. J. Psychophysiol. 89: 288-296.
Kim CK, Ye L, Jennings JH, Pichamoorthy N, Tang DD, Yoo AW, Ramakrishnan C, Deisseroth K (2017) Molecular and circuit-dynamical identification of top-down neural mechanisms for restraint of reward seeking. Cell 170:1013-1027.
Krimberg JS, Lumertz FS, Orso R, Viola TW, de Almeida RMM (2022) Impact of social isolation on the oxytocinergic system: A systematic review and meta-analysis of rodent data. Neurosci Biobehav Rev 134:104549.
Lee CR, Chen A, Tye KM (2021). The neural circuitry of social homeostasis: consequences of acute versus chronic social isolation. Cell 184:1500-1516.
Lin YT, Hsu KS (2018) Oxytocin receptor signaling in the hippocampus: Role in regulating neuronal excitability, network oscillatory activity, synaptic plasticity and social memory. Prog Neurobiol 171:1-14.
Lin YT, Hsieh TY, Tsai TC, Chen CC, Huang CC, Hsu KS (2018) Conditional deletion of hippocampal CA2/CA3a oxytocin receptors impairs the persistence of long-term social recognition memory in mice. J Neurosci 38:1218-1231.
Liu D, Tang QQ, Yin C, Song Y, Liu Y, Yang JX, Liu H, Zhang YM, Wu SY, Song Y, Juarez B, Ding HL, Han MH, Zhang H, Cao JL (2018) Brain-derived neurotrophic factor-mediated projection-specific regulation of depressive-like and nociceptive behaviors in the mesolimbic reward circuitry. Pain 159:175.
Love, TM. (2014). Oxytocin, motivation and the role of dopamine. Pharmacol Biochem Behav 119: 49-60.
Ma XC, Jiang D, Jiang WH, Wang F, Jia M, Wu J, Hashimoto K, Dang YH, Gao CG (2011) Social isolation-induced aggression potentiates anxiety and depressive-like behavior in male mice subjected to unpredictable chronic mild stress. PLoS One 6:e20955.
Marlin BJ, Mitre M, D'amour JA, Chao MV, Froemke RC (2015) Oxytocin enables maternal behavior by balancing cortical inhibition. Nature 520:499-504.
Matthews GA, Nieh EH, Vander Weele CM, Halbert SA, Pradhan RV, Yosafat AS, Glober GF, Izadmehr EM, Thomas RE, Lacy GD, Wildes CP, Ungless MA, Tye KM (2016) Dorsal raphe dopamine neurons represent the experience of social isolation. Cell 164:617-631.
Matthews GA, Tye KM (2019) Neural mechanisms of social homeostasis. Ann N Y Acad Sci 1457:5-25.
Menegas W, Akiti K, Amo R, Uchida N, Watabe-Uchida M (2018) Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli. Nat Neurosci 21:1421-1430.
Menon R, Neumann ID (2023) Detection, processing and reinforcement of social cues: regulation by the oxytocin system. Nat Rev Neurosci 24:761-777.
Msherghi A, Alsuyihili A, Alsoufi A, Ashini A, Alkshik Z, Alshareea E, Idheiraj H, Nagib T, Abusriwel M, Mustafa N, Mohammed F, Eshbeel A, Elbarouni A, Elhadi M (2021) Mental health consequences of lockdown during the COVID-19 pandemic: a cross-sectional study. Front Psychol 12:605279.
Musardo S, Contestabile A, Knoop M, Baud O, Bellone C (2022) Oxytocin neurons mediate the effect of social isolation via the VTA circuits. Elife 11:e73421.
Oettl LL, Ravi N, Schneider M, Scheller MF, Schneider P, Mitre M, da Silva Gouveia M, Froemke RC, Chao MV, Young WS, Meyer-Lindenberg A, Grinevich V, Shusterman R, Kelsch W (2016) Oxytocin enhances social recognition by modulating cortical control of early olfactory processing. Neuron 90:609-621.
Orben A, Tomova L, Blakemore SJ (2020) The effects of social deprivation on adolescent development and mental health. Lancet Child Adolesc Health 4:634-640.
Ott, I., & Scott, J. C. (1910). The action of infundibulin upon the mammary secretion. Proc. Soc. Exp. Biol. Med. 8: 48-49.
Padilla-Coreano N, Tye KM, Zelikowsky M (2022) Dynamic influences on the neural encoding of social valence. Nat Rev Neurosci 23:535-550.
Pancani L, Marinucci M, Aureli N, Riva P (2021) Forced social isolation and mental health: a study on 1,006 Italians under COVID-19 lockdown. Front Psychol 12:663799.
Park G, Ryu C, Kim S, Jeong SJ, Koo JW, Lee YS, Kim SJ (2021) Social isolation impairs the prefrontal-nucleus accumbens circuit subserving social recognition in mice. Cell Rep 35:109104.
Rivera-Irizarry JK, Skelly MJ, Pleil KE (2020) Social isolation stress in adolescence, but not adulthood, produces hypersocial behavior in adult male and female C57BL/6J mice. Front Behav Neurosci 14:129.
Santini ZI, Jose PE, York Cornwell E, Koyanagi A, Nielsen L, Hinrichsen C, Meilstrup C, Madsen KR, Koushede V (2020) Social disconnectedness, perceived isolation, and symptoms of depression and anxiety among older Americans (NSHAP): a longitudinal mediation analysis. Lancet Public Health 5:e62-e70.
Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593-1599.
Shamay-Tsoory SG, Abu-Akel A (2016) The social salience hypothesis of oxytocin. Biol Psychiatry 79:194-202.
Solié C, Girard B, Righetti B, Tapparel M, Bellone C (2022) VTA dopamine neuron activity encodes social interaction and promotes reinforcement learning through social prediction error. Nat Neurosci 25:86-97.
Speranza, L., Di Porzio, U., Viggiano, D., de Donato, A., & Volpicelli, F. (2021). Dopamine: The neuromodulator of long-term synaptic plasticity, reward and movement control. Cells 10: 735.
Stuber GD (2023) Neurocircuits for motivation. Science 382:394-398.
Teo AR, Choi H, Valenstein M (2013) Social relationships and depression: ten-year follow-up from a nationally representative study. PLoS One 8:e62396.
Tomova L, Wang KL, Thompson T, Matthews GA, Takahashi A, Tye KM, Saxe R (2020) Acute social isolation evokes midbrain craving responses similar to hunger. Nat Neurosci 23:1597-1605.
Toyoshima M, Yamada K (2023) Enhanced social motivation in briefly isolated male rats. IBRO Neurosci Rep 15:203-208.
Traniello IM, Robinson GE (2021) Neural and molecular mechanisms of biological embedding of social interactions. Annu Rev Neurosci 44:109-128.
Trezza V, Campolongo P, Vanderschuren LJ (2011) Evaluating the rewarding nature of social interactions in laboratory animals. Dev Cogn Neurosci 1:444-458.
Tsai TC, Huang CC, Hsu KS (2019) Infantile amnesia is related to developmental immaturity of the maintenance mechanisms for long-term potentiation. Mol Neurobiol 56:907-919.
Tsai TC, Yu TH, Hung YC, Fong LI, Hsu KS (2022) Distinct contribution of granular and agranular subdivisions of the retrosplenial cortex to remote contextual fear memory retrieval. J Neurosci 42:877-893.
Veening JG, de Jong TR, Waldinger MD, Korte SM, Olivier B (2015) The role of oxytocin in male and female reproductive behavior. Eur J Pharmacol 753:209-228.
Vitale EM, Smith AS (2022) Neurobiology of loneliness, isolation, and loss: integrating human and animal perspectives. Front Behav Neurosci 16:846315.
Wu Z, Xu Y, Zhu Y, Sutton AK, Zhao R, Lowell BB, Olson DP, Tong Q (2012) An obligate role of oxytocin neurons in diet induced energy expenditure. PLoS One 7:e45167.
Xiao L, Priest MF, Kozorovitskiy Y (2018) Oxytocin functions as a spatiotemporal filter for excitatory synaptic inputs to VTA dopamine neurons. Elife 7:e33892.
Xiong Y, Hong H, Liu C, Zhang YQ (2023) Social isolation and the brain: effects and mechanisms. Mol Psychiatry 28:191-201.
Yamamuro K, Bicks LK, Leventhal MB, Kato D, Im S, Flanigan ME, Garkun Y, Norman KJ, Caro K, Sadahiro M, Kullander K, Akbarian S, Russo SJ, Morishita H (2020) A prefrontal-paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice. Nat Neurosci 23:1240-1252.
Zelikowsky M, Hui M, Karigo T, Choe A, Yang B, Blanco MR, Beadle K, Gradinaru V, Deverman BE, Anderson DJ (2018) The neuropeptide Tac2 controls a distributed brain state induced by chronic social isolation stress. Cell 173:1265-1279.