Background: Depression is often associated with an increase in hypothalamic-pituitary-adrenal (HPA) axis reactivity and immune response. To investigate this relationship, we examined the consequences of environmental manipulation on the neural correlates of the HPA axis and immune response in an animal model of depression, the Wistar-Kyoto (WKY) rat. Additionally, female animals are often overlooked in preclinical research because of the hormone fluctuations inherent in the estrous cycle. Methods: Female rats were randomly assigned to 1 of 3 environments for 30 days: (1) environmental enrichment (EE), (2) standard housing (SH), and (3) isolated housing (IH). Immunoreactivity of astrocytes (glial fibrillary acidic protein [GFAP]), glucocorticoid receptors (GRs), and microglia (Iba1) in the hippocampus and amygdala were measured using immunohistochemistry. Results: WKY animals had significantly more GR staining area and Iba1 staining intensity and area in the CA1 of the hippocampus. In enriched Wistar rats, GFAP staining intensity and area were greater in the CA1. A trend towards a greater percent of area stained with GR was found in WKY animals as compared to that of the Wistar animals. This was due to WKY females in EE having significantly higher GR staining intensity and area in the amygdala as compared to that of animals in SH. Discussion: These strain differences lend support to the use of WKY animals as an animal model of depression. Furthermore, due to the effects of EE on GFAP and GR staining in WKY females, we suggest that EE can be used as an intervention to potentially alleviate the negative effects of depression.

1.
Piccinelli M, Wilkinson G: Gender differences in depression. Critical review. Br J Psychiatry 2000;177:486-492.
2.
Zucker I, Beery AK: Males still dominate animal studies. Nature 2010;465:690-690.
3.
Beery AK, Zucker I: Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 2011;35:565-572.
4.
Mileva G, Bielajew C, Konkle ATM: Sex Differences in Physiology and Behaviour: The Importance of Hormones and Rearing Environment. Hauppauge, Nova Science Publishers, 2013, pp 1-44.
5.
Chryssikopoulos A: The relationship between the immune and endocrine systems. Ann NY Acad Sci 1997;816:83-93.
6.
Kiess W, Belohradsky BH: Endocrine regulation of the immune system. Klin Wochenschr 1986;64:1-7.
7.
Procaccini C, Pucino V, De Rosa V, Marone G, Matarese G: Neuro-endocrine networks controlling immune system in health and disease. Front Immunol 2014;5:143.
8.
Varghese FP, Brown ES: The hypothalamic-pituitary-adrenal axis in major depressive disorder: a brief primer for primary care physicians. Prim Care Companion J Clin Psychiatry 2001;3:151-155.
9.
Vreeburg SA, Hoogendijk WJG, van Pelt J, Derijk RH, Verhagen JCM, van Dyck R, Smit JH, Zitman FG, Penninx BWJH: Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry 2009;66:617-626.
10.
Hyman SE: How adversity gets under the skin. Nat Neurosci 2009:12:241-243.
11.
Carvalho LA, Bergink V, Sumaski L, Wijkhuijs J, Hoogendijk WJ, Birkenhager TK, Drexhage HA: Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder. Transl Psychiatry 2014;4:e344.
12.
Hellstrom IC, Dhir SK, Diorio JC, Meaney MJ: Maternal licking regulates hippocampal glucocorticoid receptor transcription through a thyroid hormone-serotonin-NGFI-A signalling cascade. Philos Trans R Soc Lond B Biol Sci 2012;367:2495-2510.
13.
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ: Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997;277:1659-1662.
14.
Juruena MF, Cleare AJ, Papadopoulos AS, Poon L, Lightman S, Pariante CM: Different responses to dexamethasone and prednisolone in the same depressed patients. Psychopharmacology (Berl) 2006;189:225-235.
15.
Anacker C, Zunszain PA, Carvalho LA, Pariante CM: The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 2011;36:415-425.
16.
Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, Price J, Pariante CM: Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry 2011;16:738-750.
17.
Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, Turner RB: Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci USA 2012;109:5995-5999.
18.
Stark JL, Avitsur R, Padgett DA, Campbell KA, Beck FM, Sheridan JF: Social stress induces glucocorticoid resistance in macrophages. Am J Physiol Regul Integr Comp Physiol 2001;280:R1799-R1805.
19.
Miller AH, Raison CL: The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2015;16:22-34.
20.
Miller AH, Maletic V, Raison CL: Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732-741.
21.
Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N: Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun 2014;42:50-59.
22.
Jinno S, Kosaka T: Reduction of Iba1-expressing microglial process density in the hippocampus following electroconvulsive shock. Exp Neurol 2008;212:440-447.
23.
Benarroch EE: Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin Proc 2005;80:1326-1338.
24.
Song H, Stevens CF, Gage FH: Astroglia induce neurogenesis from adult neural stem cells. Nature 2002;417:39-44.
25.
Rajkowska G, Stockmeier CA: Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 2013;14:1225-1236.
26.
Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, Hellemann G, Vinters HV: Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord 2010;12:541-549.
27.
Peng L, Verkhratsky A, Gu L, Li B: Expert review of neurotherapeutics targeting astrocytes in major depression targeting astrocytes in major depression. Expert Rev Neurother 2015;15:1299-1306.
28.
Simpson J, Kelly JP: The impact of environmental enrichment in laboratory rats-Behavioural and neurochemical aspects. Behav Brain Res 2011;222:246-264.
29.
During MJ, Young D, Lawlor PA, Leone P, Dragunow M: Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 1999;5:448-453.
30.
Ickes BR, Pham TM, Sanders LA, Albeck DS, Mohammed AH, Granholm A-C: Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol 2000;164:45-52.
31.
Olson AK, Eadie BD, Ernst C, Christie BR: Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 2006;16:250-260.
32.
Segovia G, Yagüe AG, García-Verdugo JM, Mora F: Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats. Brain Res Bull 2006;70:8-14.
33.
Francis DD, Diorio J, Plotsky PM, Meaney MJ: Environmental enrichment reverses the effects of maternal separation on stress reactivity. J Neurosci 2002;22:7840-7843.
34.
Mileva GR, Bielajew C: Environmental manipulation affects depressive-like behaviours in female Wistar-Kyoto rats. Behav Brain Res 2015;293:208-216.
35.
Overstreet DH: Modeling depression in animal models. Methods Mol Biol 2012;829:125-144.
36.
Pariante CM, Miller AH: Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry 2001;49:391-404.
37.
Leuner B, Gould E: Structural plasticity and hippocampal function. Annu Rev Psychol 2010;61:111-140, C1-C3.
38.
Ji J, Maren S: Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear. Learn Mem 2008;15:244-251.
39.
Farovik A, Dupont LM, Eichenbaum H: Distinct roles for dorsal CA3 and CA1 in memory for sequential nonspatial events. Learn Mem 2010;17:12-17.
40.
Collingridge GL, Kehl SJ, McLennan H: Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol 1983;334:33-46.
41.
Harris EW, Cotman CW: Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists. Neurosci Lett 1986;70:132-137.
42.
Madeira MD, Lieberman AR: Sexual dimorphism in the mammalian limbic system. Prog Neurobiol 1995;45:275-333.
43.
Viola GG, Rodrigues L, Américo JC, Hansel G, Vargas RS, Biasibetti R, Swarowsky A, Gonçalves CA, Xavier LL, Achaval M, Souza DO, Amaral OB: Morphological changes in hippocampal astrocytes induced by environmental enrichment in mice. Brain Res 2009;1274:47-54.
44.
Ehninger D, Kempermann G: Regional effects of wheel running and environmental enrichment on cell genesis and microglia proliferation in the adult murine neocortex. Cereb Cortex 2003;13:845-851.
45.
Salmaso N, Silbereis J, Komitova M, Mitchell P, Chapman K, Ment LR, Schwartz ML, Vaccarino FM: Environmental enrichment increases the GFAP+ stem cell pool and reverses hypoxia-induced cognitive deficits in juvenile mice. J Neurosci 2012;32:8930-8939.
46.
Servatius RJ, Jiao X, Beck KD, Pang KCH, Minor TR: Rapid avoidance acquisition in Wistar-Kyoto rats. Behav Brain Res 2008;192:191-197.
47.
Mileva GR, Rooke J, Ismail N, Bielajew C: Corticosterone and immune cytokine characterization following environmental manipulation in female WKY rats. Behav Brain Res 2017;316:197-204.
48.
Pavlides C, Ogawa S, Kimura A, McEwen BS: Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices. Brain Res 1996;738:229-235.
49.
Yoshiya M, Komatsuzaki Y, Hojo Y, Ikeda M, Mukai H, Hatanaka Y, Murakami G, Kawata M, Kimoto T, Kawato S: Corticosterone rapidly increases thorns of CA3 neurons via synaptic/extranuclear glucocorticoid receptor in rat hippocampus. Front Neural Circuits 2013;7:191.
50.
Meaney MJ, Aitken DH, Bodnoff SR, Iny LJ, Tatarewicz JE, Sapolsky RM: Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions. Behav Neurosci 1985;99:765-770.
51.
Wang Q, Verweij EWE, Krugers HJ, Joels M, Swaab DF, Lucassen PJ: Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients. Brain Struct Funct 2014;219:1615-1626.
52.
Arnett MG, Pan MS, Doak W, Cyr PEP, Muglia LM, Muglia LJ: The role of glucocorticoid receptor-dependent activity in the amygdala central nucleus and reversibility of early-life stress programmed behavior. Transl Psychiatry 2015;5:e542.
53.
Han F, Ding J, Shi Y: Expression of amygdala mineralocorticoid receptor and glucocorticoid receptor in the single-prolonged stress rats. BMC Neurosci 2014;15:77.
54.
Pérez-Ortiz JM, García-Gutiérrez MS, Navarrete F, Giner S, Manzanares J: Gene and protein alterations of FKBP5 and glucocorticoid receptor in the amygdala of suicide victims. Psychoneuroendocrinology 2013;38:1251-1258.
55.
Sherwin E, Gormley S, McGuinness B, Harkin A: Enhanced glucocorticoid sensitivity coupled with reduced microglial activation in a genetically predisposed animal model of depression. Brain Behav Immun 2014;40.
56.
Kapoor K, Bhandare AM, Mohammed S, Farnham MMJ, Pilowsky PM: Microglial number is related to the number of tyrosine hydroxylase neurons in SHR and normotensive rats. Auton Neurosci 2016;198:10-18.
57.
Meaney MJ, Aitken DH, Bodnoff SR, Iny LJ, Tatarewicz JE, Sapolsky RM: Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions. Behav Neurosci 1985;99:765-770.
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