社會互動的缺乏可能導致生活品質差以及精神病理狀態的出現，而社會支持被認為可以促進和維持個人的身心健康。在過去的研究中，我們已證實串聯壓力可以造成動物的皮質酮分泌，且降低背側齒狀回中新增殖的細胞及新增生的神經母細胞數量。雖然同種同伴陪伴和催產素的處理不會影響壓力造成的皮質酮分泌，卻可以避免壓力造成背側齒狀回中新增殖細胞數量下降的情形。首先，小鼠的感官接收路徑將被用來探討究竟是何種接收方式以產生這些緩衝壓力的效果，我們的結果表明嗅徑切除不會影響背側齒狀回的細胞增生和神經新生，卻會影響同伴陪伴和催產素的接收。接著，我們試圖強調是何種類型的神經元參與此嗅覺訊息的傳遞，催產素受體基因剔除小鼠首先被使用，並證實此小鼠無法接收空氣暴露催產素的壓力緩衝效果。除此之外，利用腺病毒感染的方式抑制主嗅球中膽鹼性的神經元，也證明了其無法產生壓力緩衝效果, 結果說明從主嗅覺皮層到主嗅球的膽鹼性神經元扮演嗅覺訊息傳遞的角色。有趣的是，利用腺病毒感染的方式探討更下游的路徑，我們發現主嗅球到主要接收嗅覺訊號的梨狀皮質為可能的傳遞路徑，再接著往鄰近背側齒狀回的C A3 傳遞。接著，為了探討附近的轉錄因子是否也參與壓力及緩解效果並影響齒狀回的細胞增生和神經新生，因此評估背側齒狀回中皮質酮轉錄因子以及它的共同調節者，包含STAT5, STAT3, c Jun, 和NF κ B p65p65，重要的是，我們發現受壓力後的小鼠比起沒壓力的控制組， STAT5 的蛋白表現較低，若受壓力時給予緩解效果可以避免STAT5 的蛋白表現下降。總結以上結果，首先證明嗅覺皮層到主嗅球在嗅覺路徑中扮演訊息傳遞的關鍵，特別是其中的膽鹼神經元參與了壓力緩衝效果的機制中，並影響齒狀回的細胞增生以及神經新生，而STAT5 在壓力緩衝機制中的重要性以及其未來值得更深入的探討。

Impairment of social interaction may cause the poor quality of life and the presence of psychopathological states. Social support is well-known for boosting and maintaining individual’s physical and psychological well-beings. In previous studies, we have demonstrated that tandem robust stressors may stimulate animals’ corticosterone (CORT) secretion and decrease the number of newly proliferated cells and proliferative neuroblasts in dorsal hippocampal dentate gyrus (DG). While the presence of conspecifics and treatment with oxytocin (OXT) do not affect the stress-induced CORT secretion, such treatment may prevent the stress-caused decreases in dorsal DG. First, mice’ visual, auditory, and olfactory pathways were assessed to study what reception roles in these stress-buffering effects in this regard. Our data showed that olfactory tract transection (OTX) did not affect dorsal DG cell proliferation and early neurogenesis, while such surgery prevented conspecifics and oxytocin’s buffering effects. Second, we attempted to study which type of neuron in nasal epithelium may be involved in these olfactory encoding processes. Oxytocin receptor (OXTR) knockout (KO) mice were first used here, and we showed that it failed to exhibit OXT buffering effect. Moreover, using AAV infection method to inhibit cholinergic neurons from nasal epithelium to main olfactory bulb (MOB) also failed to exhibit either conspecifics or airborne OXT-associated buffering effects. Interestingly, using AAV infection method to find the underlying circuit, we also found a possible role in MOB to piriform cortex (PIR), a primary region receiving odor information, and further to dorsal CA3, a region near dorsal DG. Next, to study what local transcription factors may be involved in these stress-buffering effects on DG’s cell proliferation and neurogenesis. We assessed CORT transcription factor (p-GR) and its co-activators (or co-repressors), including, STAT5, STAT3, c-Jun, and NFκB-p65 in dorsal DG. It is important to note that we found stressed mice had lower STAT5 protein expressions, while such buffering might prevent them. Taken together, these results prompt us to conclude that MOE-MOB appears to be a mandatory olfactory pathway to relay conspecifics- and airborne OXT-associated stress-buffering effects on neurogenesis in dorsal DG. STAT5 warrants further study for serving as a candidate for switching hub between stress and buffering effects on dorsal DG neurogenesis.

1. Schneiderman, N., Ironson, G. & Siegel, S. D. Stress and health: psychological, behavioral, and biological determinants. Annu Rev Clin Psychol 1, 607–28 (2005).
2. Zhang, L. et al. Relationship Between Acute Stress Responses and Quality of Life in Chinese Health Care Workers During the COVID-19 Outbreak. Front Psychol 12, (2021).
3. Smith, S. M. & Vale, W. W. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8, 383–395 (2006).
4. Stephens, M. A. C. & Wand, G. Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res 34, 468–83 (2012).
5. Joëls, M. Role of corticosteroid hormones in the dentate gyrus. Progress in Brain Research vol. 163 355–370 Preprint at https://doi.org/10.1016/S0079-6123(07)63021-0 (2007).
6. Herman, J. P. & Spencer, R. Regulation of Hippocampal Glucocorticoid Receptor Gene Transcription and Protein Expression In Vivo. The Journal of Neuroscience 18, 7462–7473 (1998).
7. Polman, J. A. E., de Kloet, E. R. & Datson, N. A. Two Populations of Glucocorticoid Receptor-Binding Sites in the Male Rat Hippocampal Genome. Endocrinology 154, 1832–1844 (2013).
8. Schlossmacher, G., Stevens, A. & White, A. Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. Journal of Endocrinology 211, 17–25 (2011).
9. Vyas, S. et al. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration. Neural Plast 2016, 1–15 (2016).
10. Odaka, H., Adachi, N. & Numakawa, T. Impact of glucocorticoid on neurogenesis. Neural Regen Res 12, 1028 (2017).
11. Toda, T., Parylak, S. L., Linker, S. B. & Gage, F. H. The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry 24, 67–87 (2019).
12. Leschik, J., Lutz, B. & Gentile, A. Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience? Int J Mol Sci 22, 7339 (2021).
13. Anacker, C. & Hen, R. Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood. Nat Rev Neurosci 18, 335–346 (2017).
14. Yang-Yen, H.-F. et al. Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction. Cell 62, 1205–1215 (1990).
15. Nissen, R. M. & Yamamoto, K. R. The glucocorticoid receptor inhibits NFκB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 14, 2314–2329 (2000).
16. Shaulian, E. & Karin, M. AP-1 in cell proliferation and survival. Oncogene 20, 2390–2400 (2001).
17. Verzella, D. et al. Life, death, and autophagy in cancer: NF-κB turns up everywhere. Cell Death Dis 11, 210 (2020).
18. Rogatsky, I. & Ivashkiv, L. B. Glucocorticoid modulation of cytokine signaling. Tissue Antigens 68, 1–12 (2006).
19. Halim, C. E., Deng, S., Ong, M. S. & Yap, C. T. Involvement of STAT5 in Oncogenesis. Biomedicines 8, 316 (2020).
20. Niklison-Chirou, M. V., Agostini, M., Amelio, I. & Melino, G. Regulation of Adult Neurogenesis in Mammalian Brain. Int J Mol Sci 21, 4869 (2020).
21. Su, Y. et al. STAT3 Regulates Mouse Neural Progenitor Proliferation and Differentiation by Promoting Mitochondrial Metabolism. Front Cell Dev Biol 8, (2020).
22. Ozbay, F. et al. Social support and resilience to stress: from neurobiology to clinical practice. Psychiatry (Edgmont) 4, 35–40 (2007).
23. Bøen, H., Dalgard, O. S. & Bjertness, E. The importance of social support in the associations between psychological distress and somatic health problems and socio-economic factors among older adults living at home: a cross sectional study. BMC Geriatr 12, 27 (2012).
24. Wang, X., Cai, L., Qian, J. & Peng, J. Social support moderates stress effects on depression. Int J Ment Health Syst 8, 41 (2014).
25. Krach, S. The rewarding nature of social interactions. Front Behav Neurosci (2010) doi:10.3389/fnbeh.2010.00022.
26. Kawamichi, H. et al. Increased frequency of social interaction is associated with enjoyment enhancement and reward system activation. Sci Rep 6, 24561 (2016).
27. Lemos, C. et al. Social interaction reward in rats has anti‐stress effects. Addiction Biology 26, (2021).
28. Tzeng, W.-Y., Cherng, C.-F. G., Wang, S.-W. & Yu, L. Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens. Behavioural Brain Research 306, 146–153 (2016).
29. Cherng, C. G. et al. Presence of conspecifics and their odor-impregnated objects reverse stress-decreased neurogenesis in mouse dentate gyrus. J Neurochem 112, 1138–1146 (2010).
30. Cherng, C.-F. G. et al. Odors from proximal species reverse the stress-decreased neurogenesis via main olfactory processing. Behavioural Brain Research 229, 106–112 (2012).
31. Tzeng, W.-Y. et al. Sex Differences in Stress and Group Housing Effects on the Number of Newly Proliferated Cells and Neuroblasts in Middle-Aged Dentate Gyrus. Front Behav Neurosci 10, (2017).
32. Scatliffe, N., Casavant, S., Vittner, D. & Cong, X. Oxytocin and early parent-infant interactions: A systematic review. Int J Nurs Sci 6, 445–453 (2019).
33. Smith, A. S. & Wang, Z. Hypothalamic Oxytocin Mediates Social Buffering of the Stress Response. Biol Psychiatry 76, 281–288 (2014).
34. Liu, J. C. J., Guastella, A. J. & Dadds, M. R. Effects of oxytocin on human social approach measured using intimacy equilibriums. Horm Behav 62, 585–591 (2012).
35. Choe, H. K. et al. Oxytocin Mediates Entrainment of Sensory Stimuli to Social Cues of Opposing Valence. Neuron 87, 152–163 (2015).
36. Sun, C. et al. Oxytocin modulates neural processing of mitral/tufted cells in the olfactory bulb. Acta Physiologica 231, (2021).
37. Sakano, H. Developmental regulation of olfactory circuit formation in mice. Dev Growth Differ 62, 199–213 (2020).
38. Davison, I. G. & Katz, L. C. Sparse and Selective Odor Coding by Mitral/Tufted Neurons in the Main Olfactory Bulb. The Journal of Neuroscience 27, 2091–2101 (2007).
39. Tan, J., Savigner, A., Ma, M. & Luo, M. Odor Information Processing by the Olfactory Bulb Analyzed in Gene-Targeted Mice. Neuron 65, 912–926 (2010).
40. de Olmos, J., Hardy, H. & Heimer, L. The afferent connections of the main and the accessory olfactory bulb formations in the rat: An experimental HRP-study. J Comp Neurol 181, 213–244 (1978).
41. Haberly, L. B. & Price, J. L. Association and commissural fiber systems of the olfactory cortex of the rat II. Systems originating in the olfactory peduncle. J Comp Neurol 181, 781–807 (1978).
42. Balu, R., Pressler, R. T. & Strowbridge, B. W. Multiple Modes of Synaptic Excitation of Olfactory Bulb Granule Cells. The Journal of Neuroscience 27, 5621–5632 (2007).
43. Su, C.-Y., Menuz, K. & Carlson, J. R. Olfactory Perception: Receptors, Cells, and Circuits. Cell 139, 45–59 (2009).
44. Vaccari, C., Lolait, S. J. & Ostrowski, N. L. Comparative Distribution of Vasopressin V1b and Oxytocin Receptor Messenger Ribonucleic Acids in Brain 1. Endocrinology 139, 5015–5033 (1998).
45. Knobloch, H. S. et al. Evoked Axonal Oxytocin Release in the Central Amygdala Attenuates Fear Response. Neuron 73, 553–566 (2012).
46. Oettl, L.-L. et al. Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing. Neuron 90, 609–621 (2016).
47. Sun, L.-H. et al. Relevance of number and physiological status of conspecifics in preventing stress-induced decreases in newly proliferated cells and neuroblasts. Psychopharmacology (Berl) 236, 3329–3339 (2019).
48. Lai, Y.-T. et al. Activation of amygdaloid PKC pathway is necessary for conditioned cues-provoked cocaine memory performance. Neurobiol Learn Mem 90, 164–170 (2008).
49. Ho, M.-C. et al. Chronic treatment with monoamine oxidase-B inhibitors decreases cocaine reward in mice. Psychopharmacology (Berl) 205, 141–149 (2009).
50. Inui-Yamamoto, C. et al. Neural Isolation of the Olfactory Bulbs Severely Impairs Taste-Guided Behavior to Normally Preferred, But Not Avoided, Stimuli. eNeuro 7, ENEURO.0026-20.2020 (2020).
51. Ju, H. M., Lee, S. H., Choi, J. S. & Seo, Y. J. A Simple Model for Inducing Optimal Increase of SDF-1 with Aminoglycoside Ototoxicity. Biomed Res Int 2017, 1–9 (2017).
52. Liao, Y.-H., Sun, L.-H., Su, Y.-C., Yao, W.-J. & Yu, L. Medial and dorsal lateral septum involving social disruption stress-primed escalation in acid-induced writhes. Front Mol Neurosci 16, (2023).
53. Vivar, C. et al. Monosynaptic inputs to new neurons in the dentate gyrus. Nat Commun 3, 1107 (2012).
54. Neumann, I. D. Brain Oxytocin: A Key Regulator of Emotional and Social Behaviours in Both Females and Males. J Neuroendocrinol 20, 858–865 (2008).
55. Ebstein, R. P. et al. Arginine Vasopressin and Oxytocin Modulate Human Social Behavior. Ann N Y Acad Sci 1167, 87–102 (2009).
56. Zhang, R., Zhang, H.-F., Han, J.-S. & Han, S.-P. Genes Related to Oxytocin and Arginine-Vasopressin Pathways: Associations with Autism Spectrum Disorders. Neurosci Bull 33, 238–246 (2017).
57. Kosfeld, M., Heinrichs, M., Zak, P. J., Fischbacher, U. & Fehr, E. Oxytocin increases trust in humans. Nature 435, 673–676 (2005).
58. Ditzen, B. et al. Intranasal Oxytocin Increases Positive Communication and Reduces Cortisol Levels During Couple Conflict. Biol Psychiatry 65, 728–731 (2009).
59. Bielsky, I. F., Hu, S.-B., Ren, X., Terwilliger, E. F. & Young, L. J. The V1a Vasopressin Receptor Is Necessary and Sufficient for Normal Social Recognition: A Gene Replacement Study. Neuron 47, 503–513 (2005).
60. Lim, M. M., Bielsky, I. F. & Young, L. J. Neuropeptides and the social brain: potential rodent models of autism. International Journal of Developmental Neuroscience 23, 235–243 (2005).
61. Veenema, A. H., Beiderbeck, D. I., Lukas, M. & Neumann, I. D. Distinct correlations of vasopressin release within the lateral septum and the bed nucleus of the stria terminalis with the display of intermale aggression. Horm Behav 58, 273–281 (2010).
62. Gibbs, D. M. Vasopressin and oxytocin: hypothalamic modulators of the stress response: a review. Psychoneuroendocrinology 11, 131–9 (1986).
63. Sippel, L. M. et al. Oxytocin and Stress-related Disorders: Neurobiological Mechanisms and Treatment Opportunities. Chronic Stress 1, 247054701668799 (2017).
64. Rash, J. A. et al. Evaluating the efficacy of intranasal oxytocin on pain and function among individuals who experience chronic pain: a protocol for a multisite, placebo-controlled, blinded, sequential, within-subjects crossover trial. BMJ Open 11, e055039 (2021).
65. Sikich, L. et al. Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder. New England Journal of Medicine 385, 1462–1473 (2021).
66. Shimshek, D. R. et al. Enhanced Odor Discrimination and Impaired Olfactory Memory by Spatially Controlled Switch of AMPA Receptors. PLoS Biol 3, e354 (2005).
67. Sakamoto, M., Kageyama, R. & Imayoshi, I. The functional significance of newly born neurons integrated into olfactory bulb circuits. Front Neurosci 8, (2014).
68. Case, D. T. et al. Layer- and cell type-selective co-transmission by a basal forebrain cholinergic projection to the olfactory bulb. Nat Commun 8, 652 (2017).
69. Dâ€TMSouza, R. D. & Vijayaraghavan, S. Paying attention to smell: cholinergic signaling in the olfactory bulb. Front Synaptic Neurosci 6, (2014).
70. Soudry, Y., Lemogne, C., Malinvaud, D., Consoli, S.-M. & Bonfils, P. Olfactory system and emotion: Common substrates. Eur Ann Otorhinolaryngol Head Neck Dis 128, 18–23 (2011).
71. van Groen, T., Miettinen, P. & Kadish, I. The entorhinal cortex of the mouse: Organization of the projection to the hippocampal formation. Hippocampus 13, 133–149 (2003).
72. Strauch, C. & Manahan-Vaughan, D. Orchestration of Hippocampal Information Encoding by the Piriform Cortex. Cerebral Cortex 30, 135–147 (2020).
73. Marciante, A. B., Wang, L. A., Little, J. T. & Cunningham, J. T. Caspase lesions of PVN-projecting MnPO neurons block the sustained component of CIH-induced hypertension in adult male rats. American Journal of Physiology-Heart and Circulatory Physiology 318, H34–H48 (2020).
74. Yang, C. F. et al. Sexually Dimorphic Neurons in the Ventromedial Hypothalamus Govern Mating in Both Sexes and Aggression in Males. Cell 153, 896–909 (2013).
75. Pfisterer, U. & Khodosevich, K. Neuronal survival in the brain: neuron type-specific mechanisms. Cell Death Dis 8, e2643–e2643 (2017).
76. Engblom, D. et al. Direct glucocorticoid receptor–Stat5 interaction in hepatocytes controls body size and maturation-related gene expression. Genes Dev 21, 1157–1162 (2007).
77. Nieto-Estévez, V., Defterali, Ç. & Vicario-Abejón, C. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain. Front Neurosci 10, (2016).
78. Morel, G. R., León, M. L., Uriarte, M., Reggiani, P. C. & Goya, R. G. Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging. Neurogenesis 4, e1259709 (2017).
79. Urbán, N., Blomfield, I. M. & Guillemot, F. Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest. Neuron 104, 834–848 (2019).
80. Denoth-Lippuner, A. & Jessberger, S. Formation and integration of new neurons in the adult hippocampus. Nature Reviews Neuroscience vol. 22 223–236 Preprint at https://doi.org/10.1038/s41583-021-00433-z (2021).
81. Otsuki, L. & Brand, A. H. Quiescent Neural Stem Cells for Brain Repair and Regeneration: Lessons from Model Systems. Trends in Neurosciences vol. 43 213–226 Preprint at https://doi.org/10.1016/j.tins.2020.02.002 (2020).