Korean J Physiol Pharmacol.  2023 Jan;27(1):113-125. 10.4196/kjpp.2023.27.1.113.

Maternal separation in mice leads to anxiety-like/aggressive behavior and increases immunoreactivity for glutamic acid decarboxylase and parvalbumin in the adolescence ventral hippocampus

• Kim EG
• Chang W
• Shin S
• Adhikari AS
• Seol GH
• Song DY
• Min SS

• KMID: 2537509
• DOI: http://doi.org/10.4196/kjpp.2023.27.1.113

Abstract

It has been reported that stressful events in early life influence behavior in adulthood and are associated with different psychiatric disorders, such as major depression, post-traumatic stress disorder, bipolar disorder, and anxiety disorder. Maternal separation (MS) is a representative animal model for reproducing childhood stress. It is used as an animal model for depression, and has well-known effects, such as increasing anxiety behavior and causing abnormalities in the hypothalamicpituitary-adrenal (HPA) axis. This study investigated the effect of MS on anxiety or aggression-like behavior and the number of GABAergic neurons in the hippocampus. Mice were separated from their dams for four hours per day for 19 d from postnatal day two. Elevated plus maze (EPM) test, resident-intruder (RI) test, and counted glutamic acid decarboxylase 67 (GAD67) or parvalbumin (PV) positive cells in the hippocampus were executed using immunohistochemistry. The maternal segregation group exhibited increased anxiety and aggression in the EPM test and the RI test. GAD67-positive neurons were increased in the hippocampal regions we observed: dentate gyrus (DG), CA3, CA1, subiculum, presubiculum, and parasubiculum. PVpositive neurons were increased in the DG, CA3, presubiculum, and parasubiculum.Consistent with behavioral changes, corticosterone was increased in the MS group, suggesting that the behavioral changes induced by MS were expressed through the effect on the HPA axis. Altogether, MS alters anxiety and aggression levels, possibly through alteration of cytoarchitecture and output of the ventral hippocampus that induces the dysfunction of the HPA axis.

Keyword

Aggression; Anxiety; Gamma-aminobutyric acid; Hippocampus; Parvalbumins

Figure

• 

  Fig. 1 Experimental design. To characterize the effect of MS, pups were weaned at PND 21 and regrouped by gender at PND 22. The behavior changes by MS in the adolescence period were analyzed using an EPM test and RI test. EPM test was conducted between PND 42 and PND 46. RI test was conducted at PND 49 following single-housing of animals for two weeks from PND 35. CORT assay and IHC for GAD67 and PV experiments were conducted between PND 42 and 49. MS, maternal separation; PND, postnatal day; EPM, elevated plus maze; RI, resident-intruder; CORT, corticosterone; IHC, immunohistochemistry; GAD, glutamic acid decarboxylase; PV, parvalbumin.

• 

  Fig. 2 Assessment of anxiety and aggressive behavior caused by neonatal maternal separation (MS). EPM: (A, B) times spent in the open arms (A) and closed arms (B): times to open arms or closed arms/total time spent. (C, D) the ratio of entries into the open and the closed arms of total entries: the ratio of entries into the open arms (C) or the closed arms (D). RI test. (E) Latency to attack: time between the introduction of the intruder and the first attack of the resident. (F) Duration of attack: total time spent in clinch attack, lateral threat, and keep down. (G) The total number of attacks by the resident. (H) Corticosterone levels in HD and MS mice. Plasma corticosterone levels in mice (EPM: n = 9; RI test: n = 10; CORT: n = 10). EPM, elevated plus maze; RI, resident-intruder; HD, handling; CORT, corticosterone. Values are expressed as the mean ± SEM. Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001.

• 

  Fig. 3 Glutamic acid decarboxylase 67 (GAD67). Hippocampal distribution of GAD67-ir interneurons in the various experimental mice. Representative micrographs of GAD67-stained whole hippocampal transverse sections from the hippocampal region (A, E), DG (B, F), CA3 (C, G), CA1 (D, H) of HD (A–D), MS (E–H) treated mice. The number of GAD67-ir interneurons in the entire hippocampal region (A, E), DG (B, F), CA3 (C, G), and CA1 (D, H) was higher in the MS group than in the HD group. Scale bar = 100-μm (A, E), Scale bar = 200-μm (B–D, F–H). ir, immunoreactive; DG, dentate gyrus; MS, maternal separation; HD, handling; gl, granular layer; ml, molecular layer; so, stratum oriens; sp, stratum pyramidale; sl, stratum lacunosum; sr, stratum radiatum; slm, stratum lacunosum-moleculare. Values are expressed as the means ± SEM. Student’s t-test (n = 13). **p < 0.01, ***p < 0.001.

• 

  Fig. 4 Glutamic acid decarboxylase 67 (GAD67). Distribution in areas near the Sub of GAD67-immunoreactive interneurons in the different experimental mice. Representative micrographs of GAD67-stained whole hippocampal transverse sections from the total region near Sub (A, E), Sub (B, F), PrS (C, G), PaS (D, H) of HD (A–D), MS (E–H) treated mice. The number of GAD67-ir interneurons in the Sub (B, F), PrS (C, G) PaS (D, H) was higher in the MS group than in the HD group. Scale bar = 400-μm, x40 (A–H). MS, maternal separation; HD, handling; pyr, pyramidal; slm, stratum lacunosum-moleculare; Sub, subiculum; PrS, presubiculum; PaS, parasubiculum. Values are expressed as the means ± SEM. Student’s t-test (n = 13). *p < 0.05, **p < 0.01, ***p < 0.001.

• 

  Fig. 5 Parvalbumin (PV). Hippocampal distribution of PV-immunoreactive interneurons in the different experimental mice. Representative micrographs of PV-stained whole hippocampal transverse sections from the hippocampal region (A, E), DG (B, F), CA3 (C, G), CA1 (D, H) of HD (A–D), MS (E–H) treated mice. The number of PV interneurons in the whole hippocampal region DG (B, F), CA3 (C, G), and CA1 (D, H) was higher in the MS group than in the HD group. Scale bar = 100-μm (A, E). Scale bar = 200-μm (B–D, F–H). DG, dentate gyrus; MS, maternal separation; HD, handling; gl, granular layer; ml, molecular layer; so, stratum oriens; sp, stratum pyramidale; sl, stratum lacunosum; sr, stratum radiatum; slm, stratum lacunosum-moleculare. Values are expressed as the means ± SEM. Student’s t-test (n = 13). *p < 0.05, **p < 0.01, ***p < 0.001.

• 

  Fig. 6 Parvalbumin (PV). Hippocampal distribution of PV-immunoreactive interneurons in the different experimental mice. Representative micrographs of PV-stained whole hippocampal transverse sections from the total region near Sub (A, E), Sub (B, F), PrS (C, G), PaS (D, H) of HD (A–D), MS (E–H) treated mice. The number of PV interneurons in the PrS (C, G) PaS (D, H) was higher in the MS group than in the HD group. There was no significant difference in the number of PV interneurons in the Sub (B, F) between the MS and the HD groups. Scale bar = 400-μm (A–H). Sub, subiculum; PrS, presubiculum; PaS, parasubiculum; MS, maternal separation; HD, handling; pyr, pyramidal; slm, stratum lacunosum-moleculare. Values are expressed as the means ± SEM. Student’s t-test (n = 13). **p < 0.01, ***p < 0.001.

Reference

1. Cirulli F, Francia N, Berry A, Aloe L, Alleva E, Suomi SJ. 2009; Early life stress as a risk factor for mental health: role of neurotrophins from rodents to non-human primates. Neurosci Biobehav Rev. 33:573–585. DOI: 10.1016/j.neubiorev.2008.09.001. PMID: 18817811. PMCID: PMC2692357. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=61849179516&origin=inward.

2. Kikusui T, Takeuchi Y, Mori Y. 2004; Early weaning induces anxiety and aggression in adult mice. Physiol Behav. 81:37–42. DOI: 10.1016/j.physbeh.2003.12.016. PMID: 15059682. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=1842418490&origin=inward.

3. Stone LL, Otten R, Soenens B, Engels RC, Janssens JM. 2015; Relations between parental and child separation anxiety: the role of dependency-oriented psychological control. J Child Fam Stud. 24:3192–3199. DOI: 10.1007/s10826-015-0122-x. PMID: 26472930. PMCID: PMC4598341. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84943349722&origin=inward.

4. Veenema AH, Neumann ID. 2009; Maternal separation enhances offensive play-fighting, basal corticosterone and hypothalamic vasopressin mRNA expression in juvenile male rats. Psychoneuroendocrinology. 34:463–467. DOI: 10.1016/j.psyneuen.2008.10.017. PMID: 19056182. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=59249096603&origin=inward.

5. Ellenbroek BA, van den Kroonenberg PT, Cools AR. 1998; The effects of an early stressful life event on sensorimotor gating in adult rats. Schizophr Res. 30:251–260. DOI: 10.1016/S0920-9964(97)00149-7. PMID: 9589519. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0032502849&origin=inward.

6. Walker EF, Diforio D. 1997; Schizophrenia: a neural diathesis-stress model. Psychol Rev. 104:667–685. DOI: 10.1037/0033-295X.104.4.667. PMID: 9337628. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0031255540&origin=inward.

7. Llorente R, O'Shea E, Gutierrez-Lopez MD, Llorente-Berzal A, Colado MI, Viveros MP. 2010; Sex-dependent maternal deprivation effects on brain monoamine content in adolescent rats. Neurosci Lett. 479:112–117. DOI: 10.1016/j.neulet.2010.05.039. PMID: 20493239. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=77953913552&origin=inward.

8. Llorente R, Villa P, Marco EM, Viveros MP. 2012; Analyzing the effects of a single episode of neonatal maternal deprivation on metabolite profiles in rat brain: a proton nuclear magnetic resonance spectroscopy study. Neuroscience. 201:12–19. DOI: 10.1016/j.neuroscience.2011.11.033. PMID: 22120435. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84855520370&origin=inward.

9. Tóth M, Halász J, Mikics E, Barsy B, Haller J. 2008; Early social deprivation induces disturbed social communication and violent aggression in adulthood. Behav Neurosci. 122:849–854. DOI: 10.1037/0735-7044.122.4.849. PMID: 18729638. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=50849107709&origin=inward.

10. Fanselow MS, Dong HW. 2010; Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 65:7–19. DOI: 10.1016/j.neuron.2009.11.031. PMID: 20152109. PMCID: PMC2822727. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=73549123839&origin=inward.

11. Fabricius K, Wörtwein G, Pakkenberg B. 2008; The impact of maternal separation on adult mouse behaviour and on the total neuron number in the mouse hippocampus. Brain Struct Funct. 212:403–416. DOI: 10.1007/s00429-007-0169-6. PMID: 18200448. PMCID: PMC2226080. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=38549090692&origin=inward.

12. Hock E, McBride S, Gnezda MT. 1989; Maternal separation anxiety: mother-infant separation from the maternal perspective. Child Dev. 60:793–802. https://psycnet.apa.org/record/1989-38627-001. DOI: 10.2307/1131019.

13. Nuss P. 2015; Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr Dis Treat. 11:165–175. DOI: 10.2147/NDT.S58841. PMID: 25653526. PMCID: PMC4303399. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84921513295&origin=inward.

14. Lye TC, Piguet O, Grayson DA, Creasey H, Ridley LJ, Bennett HP, Broe GA. 2004; Hippocampal size and memory function in the ninth and tenth decades of life: the Sydney Older Persons Study. J Neurol Neurosurg Psychiatry. 75:548–554. DOI: 10.1136/jnnp.2003.010223. PMID: 15026494. PMCID: PMC1739036. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=1642523794&origin=inward.

15. Heun R, Mazanek M, Atzor KR, Tintera J, Gawehn J, Burkart M, Gänsicke M, Falkai P, Stoeter P. 1997; Amygdala-hippocampal atrophy and memory performance in dementia of Alzheimer type. Dement Geriatr Cogn Disord. 8:329–336. DOI: 10.1159/000106651. PMID: 9370084. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0030698742&origin=inward.

16. Lee AC, Buckley MJ, Gaffan D, Emery T, Hodges JR, Graham KS. 2006; Differentiating the roles of the hippocampus and perirhinal cortex in processes beyond long-term declarative memory: a double dissociation in dementia. J Neurosci. 26:5198–5203. DOI: 10.1523/JNEUROSCI.3157-05.2006. PMID: 16687511. PMCID: PMC6674247. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=33646926960&origin=inward.

17. Graham KS, Hodges JR. 1997; Differentiating the roles of the hippocampal complex and the neocortex in long-term memory storage: evidence from the study of semantic dementia and Alzheimer's disease. Neuropsychology. 11:77–89. DOI: 10.1037/0894-4105.11.1.77. PMID: 9055272. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0031027495&origin=inward.

18. O'Leary OF, Cryan JF. 2014; A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis. Trends Pharmacol Sci. 35:675–687. DOI: 10.1016/j.tips.2014.09.011. PMID: 25455365. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84912531587&origin=inward.

19. Goodman AM, Wheelock MD, Harnett NG, Mrug S, Granger DA, Knight DC. 2016; The hippocampal response to psychosocial stress varies with salivary uric acid level. Neuroscience. 339:396–401. DOI: 10.1016/j.neuroscience.2016.10.002. PMID: 27725214. PMCID: PMC5118067. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84994037287&origin=inward.

20. Kim EJ, Pellman B, Kim JJ. 2015; Stress effects on the hippocampus: a critical review. Learn Mem. 22:411–416. DOI: 10.1101/lm.037291.114. PMID: 26286651. PMCID: PMC4561403. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84942100658&origin=inward.

21. Aust S, Stasch J, Jentschke S, Alkan Härtwig E, Koelsch S, Heuser I, Bajbouj M. 2014; Differential effects of early life stress on hippocampus and amygdala volume as a function of emotional abilities. Hippocampus. 24:1094–1101. DOI: 10.1002/hipo.22293. PMID: 24753197. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84906789700&origin=inward.

22. Mohlenhoff BS, Chao LL, Buckley ST, Weiner MW, Neylan TC. 2014; Are hippocampal size differences in posttraumatic stress disorder mediated by sleep pathology? Alzheimers Dement. 10(3 Suppl):S146–S154. DOI: 10.1016/j.jalz.2014.04.016. PMID: 24924666. PMCID: PMC4111235. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84902457708&origin=inward.

23. Syed SA, Nemeroff CB. 2017; Early life stress, mood, and anxiety disorders. Chronic Stress (Thousand Oaks). 1:2470547017694461. DOI: 10.1177/2470547017694461. PMID: 28649671. PMCID: PMC5482282. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85096216020&origin=inward.

24. Xie H, Claycomb Erwin M, Elhai JD, Wall JT, Tamburrino MB, Brickman KR, Kaminski B, McLean SA, Liberzon I, Wang X. 2018; Relationship of hippocampal volumes and posttraumatic stress disorder symptoms over early posttrauma periods. Biol Psychiatry Cogn Neurosci Neuroimaging. 3:968–975. DOI: 10.1016/j.bpsc.2017.11.010. PMID: 30409391. PMCID: PMC6233727. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85040252331&origin=inward.

25. Shin LM, Shin PS, Heckers S, Krangel TS, Macklin ML, Orr SP, Lasko N, Segal E, Makris N, Richert K, Levering J, Schacter DL, Alpert NM, Fischman AJ, Pitman RK, Rauch SL. 2004; Hippocampal function in posttraumatic stress disorder. Hippocampus. 14:292–300. DOI: 10.1002/hipo.10183. PMID: 15132428. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=2342576835&origin=inward.

26. Averill CL, Satodiya RM, Scott JC, Wrocklage KM, Schweinsburg B, Averill LA, Akiki TJ, Amoroso T, Southwick SM, Krystal JH, Abdallah CG. 2017; Posttraumatic stress disorder and depression symptom severities are differentially associated with hippocampal subfield volume loss in combat veterans. Chronic Stress (Thousand Oaks). 1:2470547017744538. DOI: 10.1177/2470547017744538. PMID: 29520395. PMCID: PMC5839647. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068793685&origin=inward.

27. Jung MW, Wiener SI, McNaughton BL. 1994; Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J Neurosci. 14:7347–7356. DOI: 10.1523/JNEUROSCI.14-12-07347.1994. PMID: 7996180. PMCID: PMC6576902. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0027973505&origin=inward.

28. Hock BJ Jr, Bunsey MD. 1998; Differential effects of dorsal and ventral hippocampal lesions. J Neurosci. 18:7027–7032. DOI: 10.1523/JNEUROSCI.18-17-07027.1998. PMID: 9712671. PMCID: PMC6792982. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=17344371189&origin=inward.

29. Royer S, Sirota A, Patel J, Buzsáki G. 2010; Distinct representations and theta dynamics in dorsal and ventral hippocampus. J Neurosci. 30:1777–1787. DOI: 10.1523/JNEUROSCI.4681-09.2010. PMID: 20130187. PMCID: PMC2825159. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=76149123572&origin=inward.

30. Lee AR, Kim JH, Cho E, Kim M, Park M. 2017; Dorsal and ventral hippocampus differentiate in functional pathways and differentially associate with neurological disease-related genes during postnatal development. Front Mol Neurosci. 10:331. DOI: 10.3389/fnmol.2017.00331. PMID: 29085281. PMCID: PMC5650623. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85032305631&origin=inward.

31. Veenema AH, Blume A, Niederle D, Buwalda B, Neumann ID. 2006; Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin. Eur J Neurosci. 24:1711–1720. DOI: 10.1111/j.1460-9568.2006.05045.x. PMID: 17004935. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=33748892141&origin=inward.

32. Veenema AH, Bredewold R, Neumann ID. 2007; Opposite effects of maternal separation on intermale and maternal aggression in C57BL/6 mice: link to hypothalamic vasopressin and oxytocin immunoreactivity. Psychoneuroendocrinology. 32:437–450. DOI: 10.1016/j.psyneuen.2007.02.008. PMID: 17433558. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=34248577678&origin=inward.

33. Shiah IS, Yatham LN. 1998; GABA function in mood disorders: an update and critical review. Life Sci. 63:1289–1303. DOI: 10.1016/S0024-3205(98)00241-0. PMID: 9768867. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0032483234&origin=inward.

34. Kelsom C, Lu W. 2013; Development and specification of GABAergic cortical interneurons. Cell Biosci. 3:19. DOI: 10.1186/2045-3701-3-19. PMID: 23618463. PMCID: PMC3668182. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84878470649&origin=inward.

35. Herman JP, Ostrander MM, Mueller NK, Figueiredo H. 2005; Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry. 29:1201–1213. DOI: 10.1016/j.pnpbp.2005.08.006. PMID: 16271821. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=27944442385&origin=inward.

36. Donato F, Rompani SB, Caroni P. 2013; Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature. 504:272–276. DOI: 10.1038/nature12866. PMID: 24336286. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84890343407&origin=inward.

37. Courtin J, Chaudun F, Rozeske RR, Karalis N, Gonzalez-Campo C, Wurtz H, Abdi A, Baufreton J, Bienvenu TC, Herry C. 2014; Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature. 505:92–96. DOI: 10.1038/nature12755. PMID: 24256726. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84892372575&origin=inward.

38. Klausberger T, Marton LF, O'Neill J, Huck JH, Dalezios Y, Fuentealba P, Suen WY, Papp E, Kaneko T, Watanabe M, Csicsvari J, Somogyi P. 2005; Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J Neurosci. 25:9782–9793. DOI: 10.1523/JNEUROSCI.3269-05.2005. PMID: 16237182. PMCID: PMC6725722. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=27144440359&origin=inward.

39. Wu C, Sun D. 2015; GABA receptors in brain development, function, and injury. Metab Brain Dis. 30:367–379. DOI: 10.1007/s11011-014-9560-1. PMID: 24820774. PMCID: PMC4231020. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84939873845&origin=inward.

40. Cenquizca LA, Swanson LW. 2007; Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex. Brain Res Rev. 56:1–26. DOI: 10.1016/j.brainresrev.2007.05.002. PMID: 17559940. PMCID: PMC2171036. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=36049036839&origin=inward.

41. Loureiro M, Kramar C, Renard J, Rosen LG, Laviolette SR. 2016; Cannabinoid transmission in the hippocampus activates nucleus accumbens neurons and modulates reward and aversion-related emotional salience. Biol Psychiatry. 80:216–225. DOI: 10.1016/j.biopsych.2015.10.016. PMID: 26681496. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84949659520&origin=inward.

42. Swanson LW. 1981; A direct projection from Ammon's horn to prefrontal cortex in the rat. Brain Res. 217:150–154. DOI: 10.1016/0006-8993(81)90192-X. PMID: 7260612. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0019407810&origin=inward.

43. Tannenholz L, Jimenez JC, Kheirbek MA. 2014; Local and regional heterogeneity underlying hippocampal modulation of cognition and mood. Front Behav Neurosci. 8:147. DOI: 10.3389/fnbeh.2014.00147. PMID: 24834033. PMCID: PMC4018538. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84899815131&origin=inward.

44. Chang CH, Gean PW. 2019; The ventral hippocampus controls stress-provoked impulsive aggression through the ventromedial hypothalamus in post-weaning social isolation mice. Cell Rep. 28:1195–1205.e3. DOI: 10.1016/j.celrep.2019.07.005. PMID: 31365864. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85069592810&origin=inward.

45. Herman JP, Mueller NK, Figueiredo H. 2004; Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci. 1018:35–45. DOI: 10.1196/annals.1296.004. PMID: 15240350. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=3242703975&origin=inward.

46. Jacobson L, Sapolsky R. 1991; The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. . Endocr Rev. 12:118–134. DOI: 10.1210/edrv-12-2-118. PMID: 2070776. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0025804787&origin=inward.

47. Shin SY, Han SH, Woo RS, Jang SH, Min SS. 2016; Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation. Neuroscience. 316:221–231. DOI: 10.1016/j.neuroscience.2015.12.041. PMID: 26733385. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84953231951&origin=inward.

48. Shin SY, Baek NJ, Han SH, Min SS. 2019; Chronic administration of ketamine ameliorates the anxiety- and aggressive-like behavior in adolescent mice induced by neonatal maternal separation. Korean J Physiol Pharmacol. 23:81–87. DOI: 10.4196/kjpp.2019.23.1.81. PMID: 30627013. PMCID: PMC6315094. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85060146333&origin=inward.

49. Liu D, Caldji C, Sharma S, Plotsky PM, Meaney MJ. 2000; Influence of neonatal rearing conditions on stress-induced adrenocorticotropin responses and norepinepherine release in the hypothalamic paraventricular nucleus. J Neuroendocrinol. 12:5–12. DOI: 10.1046/j.1365-2826.2000.00422.x. PMID: 10692138. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0033952402&origin=inward.

50. Andersen SL, Teicher MH. 2004; Delayed effects of early stress on hippocampal development. Neuropsychopharmacology. 29:1988–1993. DOI: 10.1038/sj.npp.1300528. PMID: 15316569. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=4544304901&origin=inward.

51. Borel C, Welti DH, Fernandez I, Colmenares M. 1993; Dicranin, an antimicrobial and 15-lipoxygenase inhibitor from the moss Dicranum scoparium. J Nat Prod. 56:1071–1077. DOI: 10.1021/np50097a010. PMID: 8377015. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0027185686&origin=inward.

52. Li A, Zhang RX, Wang Y, Zhang H, Ren K, Berman BM, Tan M, Lao L. 2007; Corticosterone mediates electroacupuncture-produced anti-edema in a rat model of inflammation. BMC Complement Altern Med. 7:27. DOI: 10.1186/1472-6882-7-27. PMID: 17697336. PMCID: PMC1976320. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=34548723303&origin=inward.

53. Goymann W, Möstl E, Gwinner E. 2002; Corticosterone metabolites can be measured noninvasively in excreta of European Stonechats (Saxicola torquata rubicola). The Auk. 119:1167–1173. https://academic.oup.com/auk/article/119/4/1167/5561800. DOI: 10.1642/0004-8038(2002)119[1167:CMCBMN]2.0.CO;2.

54. Millspaugh JJ, Washburn BE, Milanick MA, Slotow R, van Dyk G. 2003; Effects of heat and chemical treatments on fecal glucocorticoid measurements: implications for sample transport. Wildlife Soc Bull. 31:399–406. https://www.jstor.org/stable/3784319.

55. Vázquez-Palacios G, Retana-Márquez S, Bonilla-Jaime H, Velázquez-Moctezuma J. 2001; Further definition of the effect of corticosterone on the sleep-wake pattern in the male rat. Pharmacol Biochem Behav. 70:305–310. DOI: 10.1016/S0091-3057(01)00620-7. PMID: 11701201. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0035169314&origin=inward.

56. Paxinos G, Watson C. 2013. The rat brain in stereotaxic coordinates. Elsevier Science;Amsterdam: https://www.elsevier.com/books/the-rat-brain-in-stereotaxic-coordinates/paxinos/978-0-12-391949-6.

57. Witter MP, Amaral DG. Paxinos G, editor. 2004. Hippocampal formation. The rat nervous system. Elsevier Inc.;Amsterdam: p. 635–704. https://doi.org/10.1016/B978-012547638-6/50022-5. DOI: 10.1016/B978-012547638-6/50022-5. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84942605875&origin=inward.

58. Lajud N, Torner L. 2015; Early life stress and hippocampal neurogenesis in the neonate: sexual dimorphism, long term consequences and possible mediators. Front Mol Neurosci. 8:3. DOI: 10.3389/fnmol.2015.00003. PMID: 25741234. PMCID: PMC4327304. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84923309306&origin=inward.

59. Litvin Y, Tovote P, Pentkowski NS, Zeyda T, King LB, Vasconcellos AJ, Dunlap C, Spiess J, Blanchard DC, Blanchard RJ. 2010; Maternal separation modulates short-term behavioral and physiological indices of the stress response. Horm Behav. 58:241–249. DOI: 10.1016/j.yhbeh.2010.03.010. PMID: 20298695. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=77953360240&origin=inward.

60. He T, Guo C, Wang C, Hu C, Chen H. 2020; Effect of early life stress on anxiety and depressive behaviors in adolescent mice. Brain Behav. 10:e01526. DOI: 10.1002/brb3.1526. PMID: 31961515. PMCID: PMC7066350. PMID: 1d97728c73c84648a64b209073c8af64. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85078719618&origin=inward.

61. Ennaceur A. 2012; Open space anxiety test in rodents: the elevated platform with steep slopes. Methods Mol Biol. 829:177–191. DOI: 10.1007/978-1-61779-458-2_11. PMID: 22231814. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84856329943&origin=inward.

62. Koolhaas JM, Coppens CM, de Boer SF, Buwalda B, Meerlo P, Timmermans PJ. 2013; The resident-intruder paradigm: a standardized test for aggression, violence and social stress. J Vis Exp. (77):e4367. DOI: 10.3791/4367. PMID: 23852258. PMCID: PMC3731199. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84894672265&origin=inward.

63. Kikusui T, Mori Y. 2009; Behavioural and neurochemical consequences of early weaning in rodents. J Neuroendocrinol. 21:427–431. DOI: 10.1111/j.1365-2826.2009.01837.x. PMID: 19207810. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=63549145538&origin=inward.

64. Ito A, Kikusui T, Takeuchi Y, Mori Y. 2006; Effects of early weaning on anxiety and autonomic responses to stress in rats. Behav Brain Res. 171:87–93. DOI: 10.1016/j.bbr.2006.03.023. PMID: 16677722. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=33646540405&origin=inward.

65. Millstein RA, Holmes A. 2007; Effects of repeated maternal separation on anxiety- and depression-related phenotypes in different mouse strains. Neurosci Biobehav Rev. 31:3–17. DOI: 10.1016/j.neubiorev.2006.05.003. PMID: 16950513. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=33845342923&origin=inward.

66. Vetulani J. 2013; Early maternal separation: a rodent model of depression and a prevailing human condition. Pharmacol Rep. 65:1451–1461. DOI: 10.1016/S1734-1140(13)71505-6. PMID: 24552992. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84886668177&origin=inward.

67. Bian Y, Yang L, Wang Z, Wang Q, Zeng L, Xu G. 2015; Repeated three-hour maternal separation induces depression-like behavior and affects the expression of hippocampal plasticity-related proteins in C57BL/6N mice. Neural Plast. 2015:627837. DOI: 10.1155/2015/627837. PMID: 26798520. PMCID: PMC4700195. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84983094590&origin=inward.

68. Zheng Y, He J, Guo L, Yao L, Zheng X, Yang Z, Xia Y, Wu X, Su Y, Xu N, Chen Y. 2019; Transcriptome analysis on maternal separation rats with depression-related manifestations ameliorated by electroacupuncture. Front Neurosci. 13:314. DOI: 10.3389/fnins.2019.00314. PMID: 31024237. PMCID: PMC6460510. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068475069&origin=inward.

69. Žiburkus J, Cressman JR, Schiff SJ. 2013; Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events. J Neurophysiol. 109:1296–1306. DOI: 10.1152/jn.00232.2012. PMID: 23221405. PMCID: PMC3602838. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84874619418&origin=inward.

70. Gao R, Penzes P. 2015; Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med. 15:146–167. DOI: 10.2174/1566524015666150303003028. PMID: 25732149. PMCID: PMC4721588. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84930196553&origin=inward.

71. Bi D, Wen L, Wu Z, Shen Y. 2020; GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease. Alzheimers Dement. 16:1312–1329. DOI: 10.1002/alz.12088. PMID: 32543726. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85091958888&origin=inward.

72. Nelson SB, Valakh V. 2015; Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron. 87:684–698. DOI: 10.1016/j.neuron.2015.07.033. PMID: 26291155. PMCID: PMC4567857. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84939540039&origin=inward.

73. Ruden JB, Dugan LL, Konradi C. 2021; Parvalbumin interneuron vulnerability and brain disorders. Neuropsychopharmacology. 46:279–287. DOI: 10.1038/s41386-020-0778-9. PMID: 32722660. PMCID: PMC7852528. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85088704526&origin=inward.

74. Orsini CA, Kim JH, Knapska E, Maren S. 2011; Hippocampal and prefrontal projections to the basal amygdala mediate contextual regulation of fear after extinction. J Neurosci. 31:17269–17277. DOI: 10.1523/JNEUROSCI.4095-11.2011. PMID: 22114293. PMCID: PMC3241946. PMID: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=81855184631&origin=inward.

75. Santos M, D'Amico D, Spadoni O, Amador-Arjona A, Stork O, Dierssen M. 2013; Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model. J Neurosci. 33:15259–15271. DOI: 10.1523/JNEUROSCI.2161-13.2013. PMID: 24048855. PMCID: PMC6618414.

76. Mahmoodkhani M, Ghasemi M, Derafshpour L, Amini M, Mehranfard N. 2020; Long-term decreases in the expression of calcineurin and GABAA receptors induced by early maternal separation are associated with increased anxiety-like behavior in adult male rats. Dev Neurosci. 42:135–144. DOI: 10.1159/000512221. PMID: 33341802.

77. Herman JP, Mueller NK. 2006; Role of the ventral subiculum in stress integration. Behav Brain Res. 174:215–224. DOI: 10.1016/j.bbr.2006.05.035. PMID: 16876265.

78. Dedovic K, Duchesne A, Andrews J, Engert V, Pruessner JC. 2009; The brain and the stress axis: the neural correlates of cortisol regulation in response to stress. Neuroimage. 47:864–871. DOI: 10.1016/j.neuroimage.2009.05.074. PMID: 19500680.

79. Parfitt GM, Nguyen R, Bang JY, Aqrabawi AJ, Tran MM, Seo DK, Richards BA, Kim JC. 2017; Bidirectional control of anxiety-related behaviors in mice: role of inputs arising from the ventral hippocampus to the lateral septum and medial prefrontal cortex. Neuropsychopharmacology. 42:1715–1728. DOI: 10.1038/npp.2017.56. PMID: 28294135. PMCID: PMC5518909.

80. Jimenez JC, Su K, Goldberg AR, Luna VM, Biane JS, Ordek G, Zhou P, Ong SK, Wright MA, Zweifel L, Paninski L, Hen R, Kheirbek MA. 2018; Anxiety cells in a hippocampal-hypothalamic circuit. Neuron. 97:670–683.e6. DOI: 10.1016/j.neuron.2018.01.016. PMID: 29397273. PMCID: PMC5877404.

81. Bernier BE, Lacagnina AF, Ayoub A, Shue F, Zemelman BV, Krasne FB, Drew MR. 2017; Dentate gyrus contributes to retrieval as well as encoding: evidence from context fear conditioning, recall, and extinction. J Neurosci. 37:6359–6371. DOI: 10.1523/JNEUROSCI.3029-16.2017. PMID: 28546308. PMCID: PMC5490069.

82. Karolewicz B, Maciag D, O'Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G. 2010; Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol. 13:411–420. DOI: 10.1017/S1461145709990587. PMID: 20236554. PMCID: PMC2857696.

83. Wang J, Tang J, Liang X, Luo Y, Zhu P, Li Y, Xiao K, Jiang L, Yang H, Xie Y, Zhang L, Deng Y, Li J, Tang Y. 2021; Hippocampal PGC-1α-mediated positive effects on parvalbumin interneurons are required for the antidepressant effects of running exercise. Transl Psychiatry. 11:222. DOI: 10.1038/s41398-021-01339-1. PMID: 33859158. PMCID: PMC8050070. PMID: 94fef0a417fc4695a7aba104a91ccfd8.

84. Czéh B, Varga ZK, Henningsen K, Kovács GL, Miseta A, Wiborg O. 2015; Chronic stress reduces the number of GABAergic interneurons in the adult rat hippocampus, dorsal-ventral and region-specific differences. Hippocampus. 25:393–405. DOI: 10.1002/hipo.22382. PMID: 25331166.

85. Csabai D, Seress L, Varga Z, Ábrahám H, Miseta A, Wiborg O, Czéh B. 2017; Electron microscopic analysis of hippocampal axo-somatic synapses in a chronic stress model for depression. Hippocampus. 27:17–27. DOI: 10.1002/hipo.22650. PMID: 27571571. PMCID: PMC5215622.

86. Joëls M, Karst H, Krugers HJ, Lucassen PJ. 2007; Chronic stress: implications for neuronal morphology, function and neurogenesis. Front Neuroendocrinol. 28:72–96. DOI: 10.1016/j.yfrne.2007.04.001. PMID: 17544065.

87. Travis S, Coupland NJ, Silversone PH, Huang Y, Fujiwara E, Carter R, Seres P, Malykhin NV. 2015; Dentate gyrus volume and memory performance in major depressive disorder. J Affect Disord. 172:159–164. DOI: 10.1016/j.jad.2014.09.048. PMID: 25451411.

88. Deller T, Haas CA, Deissenrieder K, Del Turco D, Coulin C, Gebhardt C, Drakew A, Schwarz K, Mundel P, Frotscher M. 2002; Laminar distribution of synaptopodin in normal and reeler mouse brain depends on the position of spine-bearing neurons. J Comp Neurol. 453:33–44. DOI: 10.1002/cne.10362. PMID: 12357430.

89. Ulrich-Lai YM, Herman JP. 2009; Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 10:397–409. DOI: 10.1038/nrn2647. PMID: 19469025. PMCID: PMC4240627.

90. Smith SM, Vale WW. 2006; The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 8:383–395. DOI: 10.31887/DCNS.2006.8.4/ssmith. PMID: 17290797. PMCID: PMC3181830.

91. Stephens MA, Wand G. 2012; Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res. 34:468–483. PMID: 23584113. PMCID: PMC3860380.

92. Sapolsky RM. 2000; Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry. 57:925–935. DOI: 10.1001/archpsyc.57.10.925. PMID: 11015810.

93. Weeden CS, Roberts JM, Kamm AM, Kesner RP. 2015; The role of the ventral dentate gyrus in anxiety-based behaviors. Neurobiol Learn Mem. 118:143–149. DOI: 10.1016/j.nlm.2014.12.002. PMID: 25498221.

94. Lesuis SL, Brosens N, Immerzeel N, van der Loo RJ, Mitrić M, Bielefeld P, Fitzsimons CP, Lucassen PJ, Kushner SA, van den Oever MC, Krugers HJ. 2021; Glucocorticoids promote fear generalization by increasing the size of a dentate gyrus engram cell population. Biol Psychiatry. 90:494–504. DOI: 10.1016/j.biopsych.2021.04.010. PMID: 34503674.

95. Zetzsche T, Preuss UW, Frodl T, Schmitt G, Seifert D, Münchhausen E, Tabrizi S, Leinsinger G, Born C, Reiser M, Möller HJ, Meisenzahl EM. 2007; Hippocampal volume reduction and history of aggressive behaviour in patients with borderline personality disorder. Psychiatry Res. 154:157–170. DOI: 10.1016/j.pscychresns.2006.05.010. PMID: 17306512.

96. Davies CH, Starkey SJ, Pozza MF, Collingridge GL. 1991; GABA autoreceptors regulate the induction of LTP. Nature. 349:609–611. DOI: 10.1038/349609a0. PMID: 1847993.

97. Lussier SJ, Stevens HE. 2016; Delays in GABAergic interneuron development and behavioral inhibition after prenatal stress. Dev Neurobiol. 76:1078–1091. DOI: 10.1002/dneu.22376. PMID: 26724783. PMCID: PMC6355144.