在群居性動物中，壓力所引起的行為與激素反應，會在個體間進行相互間的傳遞作用，這種現象被稱之為社交轉移 (social transmission) 現象。反之，受壓個體在與同伴進行社交互動後進產生壓力減輕反應的現象則稱為社交中和 (social buffering) 現象。目前對於社交轉移及社交中和現象發生的神經生物機制的了解還是相當有限。再可塑性 (metaplasticity) 係指神經突觸塑性的誘導能力及方向會受到神經元所處的狀態而有所不同，其主要反應調整持續性突觸可塑性 (synaptic plasticity) 發生的一種能力。雖然先前的研究已報導遭受壓力的個體會引發海馬迴CA1區域的再可塑性現象，然而是否透過在社交轉移而感受到壓力的個體是否也具有產生此種現象的能力則仍然未知。
在此研究中，我們利用束縛性壓力及尾巴電擊 (acute restraint-tailshock stress) 所誘發的急性小鼠壓力模式來探討壓力社交轉移及社交中和現象的突觸作用。我們發現在C57BL/6雄性小鼠上不論是自體本身遭受的壓力或透過社交傳遞而感受到的壓力，都具有促進海馬迴 CA1腦區神經突觸誘發長期抑制現象 (long-term depression; LTD) 的作用。因此，我們利用長期抑制現象的表現與否作為壓力轉移與中和現象發生的指標來探討其發生的特性。首先我們發現在熟悉的雄性小鼠經過與同伴社交互動後約有54%的機率會發生壓力的社交轉移與中和現象。在以社交層級試驗 (social dominant tube test) 分別出熟悉公小鼠的社交層級，我們證實階級較低的雄性小鼠遭受壓力後，不容易被同伴進行撫慰及發生壓力減輕的社交中和現象。我們進一步去分析同籠小鼠間三十分鐘的互動行為發現壓力的傳遞與同伴小鼠嗅聞受壓力小鼠的生殖器區域的時間長短有關。反之，壓力個體則可能是透過被同伴理毛而有壓力減輕的社交中和現象。此外，我們利用dichlobenil破壞小鼠嗅覺系統或將兩隻小鼠以隔板隔開避免直接社交互動，結果發現壓力的傳遞與中和現象皆受到阻斷。此等研究結果顯示壓力的傳遞現象發生可能透過嗅覺與社交接觸，而壓力的中和現象則可能是透過社交接觸有關。綜合以上的研究發現顯示同伴傳遞而來的壓力與自體本身遭受的壓力一樣，都會透過皮質酮 (corticosterone) 進而誘導雄性小鼠海馬迴CA1區域發生長期抑制現象。此等研究的生理意義為藉由揭示壓力在個體間的轉移與中和作用誘導雄性小鼠海馬迴CA1區域發生突觸再可塑性的因素，可能為透過同伴的壓力傳遞所造成的精神病 (如焦慮症及憂鬱症等) 的治療提供新的策略。

In social animals, such as rodent, primate, or human, the behavioral and hormonal responses to stress can be transmitted from one individual to another through a social transmission process, and conversely, social support ameliorates stress responses, a phenomenon referred to as social buffering. Metaplasticity represents activity-dependent changes in neural functions that modulate the ability to elicit subsequent synaptic plasticity. Authentic stress can induce hippocampal metaplasticity, but whether transmitted stress has the same ability remains unknown. Here, using an acute restraint-tailshock stress paradigm, we report that both authentic and transmitted stress in adult male mice trigger metaplastic facilitation of long-term depression (LTD) induction at hippocampal CA1 synapses. Using LTD as a readout of persistent synaptic consequences of stress, our findings demonstrate that, in a male-male dyad, stress transmission happens in nearly 54% of naïve partners and stress buffering occurs in approximately 54% of male stressed mice which closely interact with naïve partners. By employing a social-confrontation tube test to assess dominant-subordinate relationship in a male-male dyad, we found that stressed subordinate mice are not buffered by naïve dominant partners and stress transmission exhibits in approximately 60% of dominant naïve partners. Furthermore, the appearance of stress transmission correlates with more time spent in sniffing the anogenital area of stressed mice, and the appearance of stress buffering correlates with more time engaged in allogrooming from naïve partners. Chemical ablation of the olfactory epithelium with dichlobenil or physical separation between social contacts diminishes stress transmission. Together, our data demonstrate that transmitted stress can elicit metaplastic facilitation of LTD induction as authentic stress.

Abelson JL, Khan S, Giardino N (2010) HPA axis, respiration and the airways in stress--a review in search of intersections. Biol Psychol. 84(1):57-65.
Albeanu DF, Provost AC, Agarwal, P et al (2018) Olfactory marker protein (OMP) regulates formation and refinement of the olfactory glomerular map. Nat Commun 9, 5073.
Beery AK, Kaufer D (2015) Stress, social behavior, and resilience: insights from rodents. Neurobiol Stress 1:116-127.
Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path (1973) J Physiol. 232(2):331-356.
Brechbühl J, Moine F, Klaey M, Nenniger-Tosato M, Hurni N, Sporkert F, Giroud C, Broillet MC (2013) Mouse alarm pheromone shares structural similarity with predator scents. Proc Natl Acad Sci USA 110:4762-4767.
Bruchey AK, Jones CE, Monfils MH (2010) Fear conditioning by-proxy: social transmission of fear during memory retrieval. Behav Brain Res 214:80-84.
Brudzynski SM (2013) Ethotransmission: communication of emotional states through ultrasonic vocalization in rats. Curr Opin Neurobiol 23:310-317.
Burkett JP, Andari E, Johnson ZV, Curry DC, de Waal FB, Young LJ (2016) Oxytocin-dependent consolation behavior in rodents. Science 351:375-378.
de Waal FBM, Preston SD (2017) Mammalian empathy: behavioural manifestations and neural basis. Nat Rev Neurosci 18:498-509.
Cao J, Chen N, Xu T, Xu L (2004) Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus. Neurosci Res 49:229-239.
Cannon WB (1935) Stresses and strains of homeostasis. American Journal of the Medical Sciences 189:13-14.
Chen CC, Yang CH, Huang CC, Hsu KS (2010) Acute stress impairs hippocampal mossy fiber-CA3 long-term potentiation by enhancing cAMP-specific phosphodiesterase 4 activity. Neuropsychopharmacology 35:1605-1617.
Citri A, Malenka R (2008) Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms. Neuropsychopharmacol 33, 18–41.
Clark LH, Schein MW (1996) Activities associated with conflict behaviour in mice. Anim Behav 14:44-49.
Crockford C, Deschner T, Wittig RM (2018) The Role of Oxytocin in Social Buffering: What Do Primate Studies Add? Curr Top Behav Neurosci 35:155-173.
Debiec J, Olsson A (2017) Social fear learning: from animal models to human function. Trends Cogn Sci 21:546-555.
Diamond DM, Bennett MC, Fleshner M, Rose GM (1992) Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2:421-430.
Diamond DM, Fleshner M, Ingersoll N, Rose GM (1996) Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function. Behavioral Neuroscience 110(4):661-672.
Dudek SM, Bear MF (1992) Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci 89(10):4363-4367.
Garcia R (2001) Stress, hippocampal plasticity, and spatial learning. Synapse. 40(3):180-183.
Gold PW, Chrousos GP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry.7(3):254-275.
Gunnar MR, Hostinar CE, Sanchez MM, Tottenham N, Sullivan RM (2015) Parental buffering of fear and stress neurobiology: Reviewing parallels across rodent, monkey, and human models. Soc Neurosci 10:474-478.
Gutiérrez-García AG, Contreras CM, Mendoza-López MR, García-Barradas O, Cruz-Sánchez JS (2007) Urine from stressed rats increases immobility in receptor rats forced to swim: role of 2-heptanone. Physiol Behav. 91(1):166-172.
Gray, J.A. (1987) The psychology of fear and stress. Cambridge University Press, Cambridge.
Grant, S. G., O'Dell, T. J., Karl, K. A., Stein, P. L., Soriano, P., & Kandel, E. R. (1992). Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258(5090), 1903–1910.
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC,Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Frontiers in Neuroendocrinology 24, 151–180.
Horii Y, Nagasawa T, Sakakibara H., et al (2017) Hierarchy in the home cage affects behaviour and gene expression in group-housed C57BL/6 male mice. Sci Rep 7, 6991.
Hsiao YM, Tsai TC, Lin YT, Chen CC, Huang CC, Hsu KS (2016) Early life stress dampens stress responsiveness in adolescence: Evaluation of neuroendocrine reactivity and coping behavior. Psychoneuroendocrinology 67:86-99.
Huang CC, Yang CH, Hsu KS (2005) Do stress and long-term potentiation share the same molecular mechanisms? Mol Neurobiol 32:223-235.
Huang CC, Chen JP, Yeh CM, Hsu KS (2012) Sex difference in stress-induced enhancement of hippocampal CA1 long-term depression during puberty. Hippocampus 22:1622-1634.
Hrabetova S, Sacktor TC (1996) Bidirectional regulation of protein kinase M zeta in the maintenance of long-term potentiation and long-term depression. J Neurosci. 16(17):5324-5333.
Inagaki H, Nakamura K, Kiyokawa Y, Kikusui T, Takeuchi Y, Mori Y (2009) The volatility of an alarm pheromone in male rats. Physiol Behav 96:749-752.
Khoo GH, Lin YT, Tsai TC, Hsu KS (2019) Perineuronal nets restrict the induction of long-term depression in the mouse hippocampal CA1 region. Mol Neurobiol 56:6436-6450.
Kim JJ, Foy MR, Thompson RF (1996) Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation. Proc Natl Acad Sci USA 93:4750-4753.
Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3:453-462.
Kingsbury L, Huang S, Wang J, Gu K, Golshani P, Wu YE, Hong W (2019) Correlated neural activity and encoding of behavior across brains of socially interacting animals. Cell 178:429-446.
Kiyokawa Y, Kikusui T, Takeuchi Y, Mori Y (2004) Alarm pheromones with different functions are released from different regions of the body surface of male rats. Chem Senses 29:35-40.
Kiyokawa Y, Kikusui T, Takeuchi Y, Mori Y (2005) Mapping the neural circuit activated by alarm pheromone perception by c-Fos immunohistochemistry. Brain Res 1043:145-154.
Kiyokawa Y, Shimozuru M, Kikusui T, Takeuchi Y, Mori Y (2006) Alarm pheromone increases defensive and risk assessment behaviors in male rats. Physiol Behav 87:383-387.
Kiyokawa Y, Takeuchi Y, Mori Y. Two types of social buffering differentially mitigate conditioned fear responses (2007) Eur J Neurosci 26:3606–13.
Kiyokawa Y, Kodama Y, Kubota T, Takeuchi Y, Mori Y (2013) Alarm pheromone is detected by the vomeronasal organ in male rats. Chem Senses 38:661-668.
Kiyokawa Y, Hiroshima S, Takeuchi Y, Mori Y (2014) Social buffering reduces male rats’ behavioral and corticosterone responses to a conditioned stimulus. Horm Behav 65:114–8.
Kiyokawa Y (2017) Social odors: alarm pheromones and social buffering. Curr Top Behav Neurosci 30:47-65.
Kiyokawa Y, Kawai K, Takeuchi Y (2018) The benefits of social buffering are maintained regardless of the stress level of the subject rat and enhanced by more conspecifics. Physiol Behav 194:177-183.
Knapska E, Mikosz M, Werka T, Maren S (2009) Social modulation of learning in rats. Learn Mem 17:35-42.
Kobayakawa K, Kobayakawa R, Matsumoto H, Oka Y, Imai T, Ikawa M, Okabe M, Ikeda T, Itohara S, Kikusui T, Mori K, Sakano H (2007) Innate versus learned odour processing in the mouse olfactory bulb. Nature 450:503-508.
Kondoh K, Lu Z, Ye X, Olson DP, Lowell BB, Buck LB (2016) A specific area of olfactory cortex involved in stress hormone responses to predator odours. Nature 532:103-106.
Kunkel T, Wang H (2018) Socially dominant mice in C57BL6 background show increased social motivation. Behav Brain Res 336:173-176.
Landfield PW, Eldridge JC (1991) The glucocorticoid hypothesis of brain aging and neurodegeneration: recent modifications. Acta Endocrinol (Copenh). 125 Suppl 1:54-64.
Larrieu T, Cherix A, Duque A, Rodrigues J, Lei H, Gruetter R, Sandi C (2017) Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress. Curr Biol 27:2202-2210.
Lazarini F, Gabellec MM, Torquet N, Lledo PM (2012) Early activation of microglia triggers long-lasting impairment of adult neurogenesis in the olfactory bulb. J Neurosci 32:3652-3664.
Lee W, Hiura LC, Yang E, Broekman KA, Ophir AG, Curley JP (2019) Social status in mouse social hierarchies is associated with variation in oxytocin and vasopressin 1a receptor densities. Horm Behav. 114:104551.
Li Q, Navakkode S, Rothkegel M, Soong TW, Sajikumar S, Korte M (2017) Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer's disease. Proc Natl Acad Sci U S A. 114(21):5527-5532.
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.
Lindzey G, Winston H, Manosevitz M (1961) Social Dominance in Inbred Mouse Strains. Nature 191, 474–476.
Lucion A, Vogel WH (1994) Effects of stress on defensive aggression and dominance in a water competition test. Integrative Physiological and Behavioral Science 29, 415–422.
Manahan-Vaughan D, Braunewell KH. Novelty acquisition is associated with induction of hippocampal long-term depression (1999) Proceedings of the National Academy of Sciences of the United States of America. 96(15):8739-8744.
Martin LJ, Hathaway G, Isbester K, Mirali S, Acland EL, Niederstrasser N, Slepian PM, Trost Z, Bartz JA, Sapolsky RM, Sternberg WF, Levitin DJ, Mogil JS (2015) Reducing social stress elicits emotional contagion of pain in mouse and human strangers. Curr Biol 25:326-332.
McEwen BS. Stress and hippocampal plasticity (1999) Annu Rev Neurosci. 22:105-122.
McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN (2008) Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 7:152-163.
Milner AJ, Cummings DM, Spencer JP, Murphy KP (2004) Bi-directional plasticity and age-dependent long-term depression at mouse CA3-CA1 hippocampal synapses. Neurosci Lett 367:1-5.
Monfils MH, Agee LA (2019) Insights from social transmission of information in rodents. Genes Brain Behav 18:e12534.
Morris RG, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5 (1986) Nature 319(6056):774-776.
Mulkey RM, Malenka RC. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus (1992) Neuron. 9(5):967-975.
Neff, E.P. (2018) The social transmission of stress. Lab Anim 47, 64.
Novotny M, Jemiolo B, Harvey S, Wiesler D, Marchlewska-Koj A (1986) Adrenal-mediated endogenous metabolites inhibit puberty in female mice. Science 231(4739):722-725.
Oliveira RF, Faustino AI (2017) Social information use in threat perception: social buffering, contagion and facilitation of alarm responses. Commun Integr Biol 10:e1325049.
Park M, Seo B.A, Lee B (2018) Stress-induced changes in social dominance are scaled by AMPA-type glutamate receptor phosphorylation in the medial prefrontal cortex. Sci Rep 8, 15008.
Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders (2003) Am J Psychiatry. 160(9):1554-1565.
Schmidt MV, Abraham WC, Maroun M, Stork O, Richter-Levin G (2013) Stress-induced metaplasticity: from synapses to behavior. Neuroscience 250:112-120.
Selye H (1978) The stress of life.(Red ed.) Oxford, Elgland: Mcgraw Hill.
Shors TJ, Gallegos RA, Breindl A (1997) Transient and persistent consequences of acute stress on long-term potentiation (LTP), synaptic efficacy, theta rhythms and bursts in area CA1 of the hippocampus. Synapse 26:209-217.
Smith AS, Wang Z (2014) Hypothalamic oxytocin mediates social buffering of the stress response. Biol Psychiatry 76:281-288.
Sotocinal SG, Sorge RE, Zaloum A, Tuttle AH, Martin LJ, Wieskopf JS, Mapplebeck JC, Wei P, Zhan S, Zhang S, McDougall JJ, King OD, Mogil JS (2011) The Rat Grimace Scale: a partially automated method for quantifying pain in the laboratory rat via facial expressions. Mol Pain 7:55.
Sterley TL, Baimoukhametova D, Füzesi T, Zurek AA, Daviu N, Rasiah NP, Rosenegger D, Bains JS (2018) Social transmission and buffering of synaptic changes after stress. Nat Neurosci 21:393-403.
Storace DA, Cohen LB (2017) Measuring the olfactory bulb input-output transformation reveals a contribution to the perception of odorant concentration invariance. Nat Commun 8, 81.
Veldhuis HD, De Kloet ER, Van Zoest I, Bohus B (1982) Adrenalectomy reduces exploratory activity in the rat: a specific role of corticosterone. Horm Behav 16(2):191-198.
Wang F, Zhu J, Zhu H, Zhang Q, Lin Z, Hu H (2011) Bidirectional control of social hierarchy by synaptic efficacy in medial prefrontal cortex. Science 334:693-697.
Wang F, Kessels HW, Hu H (2014) The mouse that roared: neural mechanisms of social hierarchy. Trends Neurosci 37:674-682.
Williamson CM, Romeo RD, Curley JP (2016) Dynamic changes in social dominance and mPOA GnRH expression in male mice following social opportunity. Horm Behav 87:80-88.
Xu L, Anwyl R, Rowan MJ (1997) Behavioural stress facilitates the induction of long-term depression in the hippocampus. Nature 387:497-500.
Yang CH, Huang CC, Hsu KS (2004) Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. J Neurosci 24:11029-11034.
Yang CH, Huang CC, Hsu KS (2005) Behavioral stress enhances hippocampal CA1 long-term depression through the blockade of the glutamate uptake. J Neurosci 25:4288-4293.
Yang CH, Huang CC, Hsu KS (2006) Novelty exploration elicits a reversal of acute stress-induced modulation of hippocampal synaptic plasticity in the rat. J Physiol 577:601-615.
Yoon H, Enquist LW, Dulac C (2005) Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell 123:669-682.
Zalaquett C, Thiessen D (1991) The effects of odors from stressed mice on conspecific behavior. Physiol Behav 50:221-227.