目前已知壓力會增加生理或心理疾病的罹患風險，影響免疫及中樞神經系統等。當受到壓力的時候，壓力會使人體血液中的皮質醇濃度或老鼠血液內的腎上腺皮質酮濃度升高，而壓力與皮質醇、腎上腺皮質酮都有不少研究指出會降低中樞神經系統海馬齒狀迴的神經新生以及損害與海馬迴有關的空間學習記憶。而神經新生在近來的研究中指出除了與空間學習記憶有關，也與藥物環境線索的記憶有關，神經新生在哺乳動物扮演了重要的角色，然而當壓力造成生物體神經新生降低時，醫學上並沒有藥物或有效的治療方法來改善。在人類已有不少研究指出社會行為對於個體是有利的，例如當有夥伴的陪伴下能夠緩解壓力對於人們的影響。而過去的研究發現，當有同伴陪伴的情況下受到壓力，壓力所造成的神經新生下降則能夠回復，而這樣的現象並不是透過降低皮質酮所造成的，那麼陪伴作用是透過什麼樣的機制來回復神經新生的呢？目前已知壓力也會造成神經滋養因子在體內的表達量下降，神經滋養因子包括BDNF、NGF以及NT-3，他們在中樞神經系統扮演了重要角色，包括神經細胞增生、生長以及存活都需要神經滋養因子的調控，而且這些神經滋養因子在海馬迴的表達量也很高，因此我們假設壓力降低神經新生可以被陪伴作用所回復的作用是透過影響神經滋養因子的表達量所達成。我們利用小鼠的模式，給予老鼠無規則時距的電擊刺激三十次接著馬上給予禁錮並浸泡在水中三十分鐘作為此實驗的主要壓力程序，實驗分為經歷壓力時有同伴陪伴，或者單獨接受壓力，接著在不同的時間點0，30，60，120，240以及360分鐘將老鼠斷頭犧牲並取下腦組織海馬齒狀迴來進行分析。我們發現單獨接受壓力的老鼠其神經滋養因子NGF在壓力程序後30分鐘便有顯著的下降，且在60分鐘降至最低，接著在120分鐘後開始回復原本表達量，顯示壓力的確會造成神經滋養因子下降。而在經歷壓力時有同伴陪伴的老鼠則發現其神經滋養因子NGF的表達量是被回復的，顯示經歷壓力時的陪伴作用，能抑制NGF表達量下降。而在BDNF以及NT-3兩個神經滋養因子則沒有此現象。因此我們的研究顯示，陪伴作用可以回復壓力所造成的神經新生下降是透過神經滋養因子NGF來調控的。另外我們也發現血液中的NGF在壓力程序後60分鐘會升高。我們也利用了莫式水迷宮以及古柯鹼場地制約偏好兩種行為測驗來檢視陪伴作用的效果。在莫式水迷宮的實驗中，陪伴作用並沒有影響空間學習記憶。在古柯鹼場地制約偏好行為測驗中，壓力會降低動物對古柯鹼配對環境的偏好，但是陪伴作用則會回復動物對於古柯鹼配對環境的偏好。

Stress and health are closely linked. Stress is known to impair physiological functions of the central nervous system. Likewise, stress releases stress hormones such as glucocorticoids. A primary brain target for glucocorticoids is the hippocampus, a brain region concerning learning and memory. Numerous studies report that stress decreases neurogenesis in dentate gyrus, which plays a role in mediating spatial learning and the formation of drug–context conditioning. To date, there is no therapy available for treating stress-reduced neurogenesis. Many lines of evidence suggest that a friend acting in a supportive manner during the stress can attenuate the stress-increased cardiovascular response. Moreover, in a previous study, we find that the stress-decreased neurogenesis in the dentate gyrus can be reversed when mice undergo stress with companions of familiar mice. And the data show that familiar mice’ company reverses the stress-decreased neurogenesis in dentate gyrus independent of down regulation of glucocorticoids. Therefore, the underlying mechanism of companion’s protective effect remains unknown. Neurotrophic factors, NGF, BDNF and NT-3, have critical roles in the proliferation, maintenance and survival of neurons in the adult brain. Therefore, we hypothesize that neurotrophic factors are involved in the companion’s protective effect against stress-decreased neurogenesis. We used a tandem stress procedure, including electrical foot shock followed by restraint stress immersed in water. Mice received the stress procedure with or without companions and were decapitated at different time points: 0, 30, 60, 120, 240 and 360 min after the conclusion of the stress procedure. The brain tissues of hippocampal dentate gyrus were analyzed for the above-mentioned neurotrophic factors. We found that mice exposed to stress without companions exhibited decreased expression of NGF protein in 30 and 60 min. Moreover, mice exposed to stress with companions showed an unaltered expression of NGF. This data indicate that neurotrophic factor, NGF, was implicated in the companion’s protective effect. Morris water maze and cocaine-induced conditioned place preference (coc-CPP) were performed to analysis the companion’s effect. In Morris water maze, stress procedure did not impair performance of spatial learning and memory, but mice undergoing stress with familiar companions did not influence the spatial learning. In cocaine-induced conditioned place preference, stress procedure decreases preference for the cocaine-paired conditioning, and companion’s effect does influence the drug-context conditioning.

1. Aggarwal, B. A. F., Liao, M. and Mosca, L. Physical activity as a potential mechanism through which social support may reduce cardiovascular disease risk. J. Cardiovasc. Nurs. 23: 90-96 (2008).
2. Alleva, E., Petruzzi, S., Cirulli, F., Aloe, L. NGF regulatory role in stress and coping of rodents and humans. Pharmacol. Biochem. Behav. 54: 65–72 (1996).
3. Aloe, L., Bracci-Laudiero, L., Alleva, E., Lambiase, A., Micera, A. and Tirassa, P. Emotional stress induced by parachute jumping enhances blood nerve growth factor levels and the distribution of nerve growth factor receptors in lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 91: 10440–10444 (1994).
4. Aloe, L., Alleva, E. and Fiore, M. Stress and nerve growth factor findings in animal models and humans. Pharmacol. Biochem. Behav. 73: 159–166 (2002).
5. Brown, T. E., Lee, B. R., Ryu, V., Herzog, T., Czaja, K. and Dong, Y. Reducing hippocampal cell proliferation in the adult rat does not prevent the acquisition of cocaine-induced conditioned place preference. Neurosci. Lett. 481: 41–46 (2010).
6. Capodaglio, P., Capodaglio, E. M., Precilios, H., Vismara, L., Tacchini, E., Finozzi, E., Brunani, A. Obesity and work: an emerging problem. G. Ital. Med. Lav. Ergon. 33:47-54 (2011).
7. Cazakoff, B. N., Johnson, K. J. and Howland, J. G. Converging effects of acute stress on spatial and recognition memory in rodents: A review of recent behavioural and pharmacological findings. Progress in Neuro-Psychopharmacology & Biological Psychiatry 34: 733–741 (2010).
8. Cherng, C. G., Lin, P. S., Chuang, J. Y., Chang, W. T., Lee, Y. S., Kao, G. S., Lai, Y. T. and Yu, L. Presence of conspecifics and their odor-impregnated objects reverse stress-decreased neurogenesis in mouse dentate gyrus. J. Neurochem. 112: 1138-1146 (2010).
9. Christenfeld, N., Gerin, W., Linden, W., Sanders, M., Mathur, J., Deich, J. D. and Pickering, T. G. Social support effects on cardiovascular reactivity: is a stranger as effective as a friend? Psychosom. Med. 59: 388-398 (1997).
10. Cobb, S. Social support as a moderator of life stress. Psychosom. Med. 38: 300-314 (1976).
11. Conner, J., Lauterborn, J., Yan, Q., Gall, C., Varon, S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J. Neurosci. 17: 2295–2313 (1997).
12. Conrad, C., Galea, L., Kuroda, Y. and McEwen, B. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav. Neurosci. 110: 1321–1334 (1996).
13. Deng, W., Aimone, J. B. and Gage, F. H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11: 339-350 (2010).
14. Dickerson, S. S., Mycek, P. J. and Zaldivar, F. Negative social evaluation, but not mere social presence, elicits cortisol responses to a laboratory stressor task. Health Psychol. 27: 116–121 (2008).
15. Gould, E., McEwen, B. S., Tanapat, P., Galea, L. A. and Fuchs, E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 17: 2492–2498 (1997).
16. Herna´ndez-Rabaza, V., Hontecillas-Prieto, L., Velazquez-Sanchez, C., Ferragud, A., Perez-Villaba, A., Arcusa, A., Barcia, J. A., Trejo, J. L. and Canales, J. J. The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward. Neurobiol. Learn. Mem. 90: 553–559 (2008).
17. Huang, E. J. and Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24: 677–736 (2001).
18. Huneault, L., Mathieu, M. È., Tremblay, A. Globalization and modernization: an obesogenic combination. Obes. Rev. 12: 64-72 (2011).
19. Jacobs, B.L., van Praag, H. and Gage, F. H. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol. Psychiatry 5: 262–269 (2000).
20. Jaholkowski, P., Kiryk, A., Jedynak, P., Ben Abdallah, N. M., Knapska, E., Kowalczyk, A., Piechal, A., Blecharz-Klin, K., Figiel, I., Lioudyno, V., Widy-Tyszkiewicz, E., Wilczynski, G., M., Lipp, H. P., Kaczmarek, L., and Filipkowski, R. K. New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning. Learning & Memory 16: 439–451 (2009).
21. Karlin, W. A., Brondolo, E. and Schwartz, J. Workplace social support and ambulatory cardiovascular activity in New York City traffic agents. Psychosom. Med. 65: 167-176 (2003).
22. Kee, N., Teixeira, C. M., Wang, A. H. and Frankland, P. W. Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat. Neurosci. 10: 355-362 (2007).
23. Kempermann, G., Wiskott, L. and Gage, F. H. Functional significance of adult neurogenesis. Current Opinion in Neurobiology 14:186–191 (2004).
24. Lu, B., Pang, P. T. and Woo, N. H. The yin and yang of neurotrophin action. Nat. Rev. Neurosci. 6: 603-614 (2005).
25. McAllister, A. K., Katz, L. C. and Lo, D. C. Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22: 295–318 (1999).
26. Magarinos, A. and McEwen, B. Stress-induced atrophy of apical dendrites of hippocampal CA3 neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neurosci. 69: 89–98 (1995).
27. McEwen, B.S. Plasticity of the hippocampus: adaptation to chronic stress and allostatic load. Ann. N. Y. Acad. Sci. 933: 265–277 (2001).
28. Meshi, D., Drew, M. R., Saxe, M., Ansorge, M. S., David, D., Santarelli, L., Malapani, C., Moore, H. and Hen, R. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat. Neurosci. 9: 729–731 (2006).
29. Miller, C. A. and Marshall, J. F. Altered prelimbic cortex output during cue-elicited drug seeking. J. Neurosci. 24: 6889-6897 (2004).
30. Ming, G. L. and Song, H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 28: 223–250 (2005).
31. Mirescu, C. and Gould, E. Stress and Adult Neurogenesis. Hippocampus 16:233–238 (2006).
32. Noonan, M.A., Bulin, S.E., Fuller, D.C. and Eisch, A.J. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J. Neurosci. 30: 304–315 (2010).
33. Pizarro, J. M., Lumley, L. A., Medina, W., Robison, C. L., Chang, W. E., Alagappan, A., Bah, M. J., Dawood, M. Y., Shah, J. D., Mark, B., Kendall, N., Smith, M. A., Saviolakis, G. A. and Meyerhoff, J. L. Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice. Brain Research 1025: 10–20 (2004).
34. Scaccianoce, S., Lombardo, K., Nicolai, R., Affricano, D. and Angelucci, L. Studies on the involvement of histamine in the hypothalamic–pituitary–adrenal axis activation induced by nerve growth factor. Life Sci. 67: 3143–3152 (2000).
35. Schmidt, H. D. and Duman, R. S. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav. Pharmacol. 18: 391-418 (2007).
36. Shen, F., Meredith, G. E. and Napier, T. C. Amphetamine-induced place preference and conditioned motor sensitization require activation of tyrosine kinase receptors in the hippocampus. J. Neurosci. 26: 11041–11051 (2006).
37. Smith, M. A. Hippocampal vulnerability to stress and aging: possible role of neurotrophic factors. Behav. Brain Res. 78: 25-36 (1996).
38. Steckler, T. The molecular neurobiology of stress—evidence from genetic and epigenetic models. Behav. Pharmacol. 12: 381–427 (2001).
39. Thomas, R. M., Hotsenpiller, G. and Peterson, D. A. Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J. Neurosci. 27: 2734-2743 (2007).
40. Ulrich‑Lai Y. M. and Herman, J. P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10: 397-409 (2009).
41. Vanitallie, T. B. Stress: a risk factor for serious illness. Metabolism. Review 51:40-45. (2002).
42. Wellen, K. E. and Hotamisligil, G. S. Inflammation, stress, and diabetes. J Clin. Invest. 115:1111-1119 (2005).
43. Whitman, T.L., Borkowski, J.G., Schellenbach, C.J., and Nath, P.S. Predicting and understanding delay of children of adolescent mothers: A multidisciplinary approach. American Journal of Mental Deficiencies 90: 40-56 (1987).
44. Zhao, C., Deng, W. and Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132: 645-660 (2008).