Ameliorative effect of vitamin D3 on prenatal-postpartum stress-induced neurological alterations in primiparous rats
Keywords:
Amygdala, Heat stress, Hypothalamus, Recurrent stress, Refugee camp, Vitamin D.Abstract
Introduction
Recurrent heat waves and internally displaced persons (IDP) camp conditions and their associated impacts are prevalent and increasing worldwide. These conditions can confer physical and neuropsychological stress, especially among first-time mothers. This study elucidated the role of Vitamin D3 (Calcitriol) on the hypothalamic-amygdala pathway following recurrent prenatal and postpartum stress in primiparous rats.
Methodology
Eighteen pregnant Long-Evans rats at gestational day 5 were randomly assigned into three groups (n=6): Control, Recurrent Stress, and Recurrent Stress plus vitamin D (RSVD). Recurrent stress and RSVD groups were subjected to heat waves alternating with simulated IDP Camp-like conditions prenatally for one week, followed by postpartum exposure to these stressors for two weeks (postnatal days 21 – 35). The RSVD group was given oral vitamin D at 2000 IU/kg/day (1.5 mg/kg) concurrently with stress exposure. The rats were exposed to cognition and depressive-like behavioural tests a day after postpartum exposure. Rats were later euthanized; their brains and blood were collected and processed for biochemical and immunohistochemical assays.
Results
Results revealed induction of anxiety- and depressive-like behaviours with a corresponding alteration in blood and tissue levels of vitamin D3 and corticosterone. Histoarchitectural distortions in the amygdala and hypothalamus were also observed in the stressed rats. Furthermore, immunofluorescence assessment revealed microglia activation and downregulation of vascular endothelial growth factor-1 expression in the amygdala and hypothalamus. However, compared to control rats, these aberrations were ameliorated following vitamin D3 administration.
Conclusion
The findings from this study demonstrate that vitamin D3 improved these behavioural deficits by modulating stress responses, microgliosis and vasculogenesis.
References
Talge NM, Neal C, Glover V, Early Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health. Antenatal maternal stress and long‐term effects on child neurodevelopment: how and why?. Journal of Child Psychology and Psychiatry. 2007 Mar;48(3‐4):245-61.
DiPietro JA. Maternal stress in pregnancy: considerations for fetal development. Journal of Adolescent Health. 2012 Aug 1;51(2):S3-8.
Fernando M, Ellery SJ, Marquina C, Lim S, Naderpoor N, Mousa A. Vitamin D-binding protein in pregnancy and reproductive health. Nutrients. 2020 May 20;12(5):1489.
Roth DE, Abrams SA, Aloia J, Bergeron G, Bourassa MW, Brown KH, Calvo MS, Cashman KD, Combs G, De‐Regil LM, Jefferds ME. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low‐and middle‐income countries. 2018 Oct.
Kočovská E, Andorsdóttir G, Weihe P, Halling J, Fernell E, Stóra T, Biskupstø R, Gillberg IC, Shea R, Billstedt E, Bourgeron T. Vitamin D in the general population of young adults with autism in the Faroe Islands. Journal of autism and developmental disorders. 2014 Dec;44:2996-3005.
Kassotaki I, Valsamakis G, Mastorakos G, Grammatopoulos DK. Placental CRH as a signal of pregnancy adversity and impact on fetal neurodevelopment. Frontiers in Endocrinology. 2021 Aug 2;12:714214.
Bao AM, Swaab DF. The human hypothalamus in mood disorders: The HPA axis in the center. IBRO reports. 2019 Jun 1;6:45-53.
Sheng JA, Bales NJ, Myers SA, Bautista AI, Roueinfar M, Hale TM, Handa RJ. The hypothalamic-pituitary-adrenal axis: development, programming actions of hormones, and maternal-fetal interactions. Frontiers in behavioral neuroscience. 2021 Jan 13;14:601939.
Wang X, Ge S, Zhang C. Bed nuclei of the stria terminalis: A key hub in the modulation of anxiety. European Journal of Neuroscience. 2023 Mar;57(6):900-17.
Annweiler C, Cao Z, Sabatier JM. Point of view: Should COVID-19 patients be supplemented with vitamin D?. Maturitas. 2020 Oct 1;140:24-6.
Bakhtiari-Dovvombaygi, Hossein, Saeed Izadi, Mostafa Zare Moghaddam, Milad Hashemzehi, Mahmoud Hosseini, Hassan Azhdari-Zarmehri, Hossein Dinpanah, and Farimah Beheshti. "Beneficial effects of vitamin D on anxiety and depression-like behaviors induced by unpredictable chronic mild stress by suppression of brain oxidative stress and neuroinflammation in rats." Naunyn-Schmiedeberg's Archives of Pharmacology 394, no. 4 (2021): 655-667.
Komada M, Takao K, Miyakawa T. Elevated plus maze for mice. Journal of visualized experiments: JoVE. 2008 Dec 22(22):1088.
Edem EE, Ihaza BE, Fafure AA, Ishola AO, Nebo KE, Enye LA, Akinluyi ET. Virgin coconut oil abrogates depression-associated cognitive deficits by modulating hippocampal antioxidant balance, GABAergic and glutamatergic receptors in mice. Drug Metabolism and Personalized Therapy. 2022 Jun 23;37(2):177-90.
Zou J, Wang W, Pan YW, Abel GM, Storm DR, Xia Z. Conditional inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 MAP kinase is not associated with anxiety/depression-like behaviors. eneuro. 2015 Mar 1;2(2).
Lefter R, Ciobica A, Timofte D, Ababei D, Dobrin R, Luca A, Trifan A, Stanciu C, Sfarti C. A new biological approach in generating an irritable bowel syndrome rat model-focusing on depression in sucrose splash test and body weight change. Romanian Biotehnological Letters. 2018;2:2018.
Várkonyi D, Török B, Sipos E, Fazekas CL, Bánrévi K, Correia P, Chaves T, Farkas S, Szabó A, Martínez-Bellver S, Hangya B. Investigation of anxiety-and depressive-like symptoms in 4-and 8-month-old male triple transgenic mouse models of Alzheimer’s disease. International Journal of Molecular Sciences. 2022 Sep 16;23(18):10816.
Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. Journal of visualized experiments: JoVE. 2017 Aug 30(126):55718.
Wallace KJ, Hofmann HA. Equal performance but distinct behaviors: sex differences in a novel object recognition task and spatial maze in a highly social cichlid fish. Animal Cognition. 2021 Sep;24(5):1057-73.
Leenaars CH, van der Mierden S, Durst M, Goerlich-Jansson VC, Ripoli FL, Keubler LM, Talbot SR, Boyle E, Habedank A, Jirkof P, Lewejohann L. Measurement of corticosterone in mice: a protocol for a mapping review. Laboratory animals. 2020 Feb;54(1):26-32.
Ankle MR, Joshi PS. A study to evaluate the efficacy of xylene-free hematoxylin and eosin staining procedure as compared to the conventional hematoxylin and eosin staining: An experimental study. Journal of oral and maxillofacial pathology. 2011 May 1;15(2):161-7.
Ibanez FG, Picard K, Bordeleau M, Sharma K, Bisht K, Tremblay MÈ. Immunofluorescence staining using IBA1 and TMEM119 for microglial density, morphology and peripheral myeloid cell infiltration analysis in mouse brain. Journal of Visualized Experiments (JoVE). 2019 Oct 27(152):e60510.
Vital TM, Stein AM, de Melo Coelho FG, Arantes FJ, Teodorov E, Santos-Galduroz RF. Physical exercise and vascular endothelial growth factor (VEGF) in elderly: A systematic review. Archives of gerontology and geriatrics. 2014 Sep 1;59(2):234-9.
Lupien SJ, Juster RP, Raymond C, Marin MF. The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity. Frontiers in neuroendocrinology. 2018 Apr 1;49:91-105.
Biedermann SV, Biedermann DG, Wenzlaff F, Kurjak T, Nouri S, Auer MK, Wiedemann K, Briken P, Haaker J, Lonsdorf TB, Fuss J. An elevated plus-maze in mixed reality for studying human anxiety-related behavior. BMC biology. 2017 Dec;15:1-3.
Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety-and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2012 Oct 1;39(1):112-9.
Kouba BR, Camargo A, Gil-Mohapel J, Rodrigues AL. Molecular basis underlying the therapeutic potential of vitamin D for the treatment of depression and anxiety. International journal of molecular sciences. 2022 Jan;23(13):7077.
Okeowo OM, Oke OO, David GO, Ijomone OM. Caffeine administration mitigates chronic stress-induced behavioral deficits, neurochemical alterations, and glial disruptions in rats. Brain Sciences. 2023 Nov 30;13(12):1663.
Hu C, Luo Y, Wang H, Kuang S, Liang G, Yang Y, Mai S, Yang J. Re-evaluation of the interrelationships among the behavioral tests in rats exposed to chronic unpredictable mild stress. PloS one. 2017 Sep 20;12(9):e0185129.
Reis‐Silva TM, Sandini TM, Calefi AS, Orlando BC, Moreira N, Lima AP, Florio JC, Queiroz‐Hazarbassanov NG, Bernardi MM. Stress resilience evidenced by grooming behaviour and dopamine levels in male mice selected for high and low immobility using the tail suspension test. European Journal of Neuroscience. 2019 Sep;50(6):2942-54.
Luo C, Xu X, Wei X, Feng W, Huang H, Liu H, Xu R, Lin J, Han L, Zhang D. Natural medicines for the treatment of fatigue: Bioactive components, pharmacology, and mechanisms. Pharmacological Research. 2019 Oct 1;148:104409.
Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019 Apr 3;102(1):75-90.
Prager EM, Bergstrom HC, Wynn GH, Braga MF. The basolateral amygdala γ‐aminobutyric acidergic system in health and disease. Journal of neuroscience research. 2016 Jun;94(6):548-67.
Huang J, Xu F, Yang L, Tuolihong L, Wang X, Du Z, Zhang Y, Yin X, Li Y, Lu K, Wang W. Involvement of the GABAergic system in PTSD and its therapeutic significance. Frontiers in molecular neuroscience. 2023 Feb 1;16:1052288.
Blas J. Stress in birds. In Sturkie's avian physiology 2015 Jan 1 (pp. 769-810). Academic Press.
Donner NC. Glucocorticoid actions on brain serotonergic systems (Doctoral dissertation, University of Colorado at Boulder).
Mironova V, Fedotova J. Modulation of depression-like behavior by a combination with vitamin D3 and 17β-estradiol in middle-aged Ovariectomized rats subjected to chronic mild stress. Opera Medica et Physiologica. 2020;7(2):30-53.
Wang H, Xing X, Liang J, Bai Y, Lui Z, Zheng X. High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response. Pharmacology Biochemistry and Behavior. 2014 Sep 1;124:188-95.
Hegde Nagarajan A. Early life rearing of stressed animals in complex housing environment drives stress resilience in physiology, behavior and brain plasticity during adulthood (Doctoral dissertation).
Gaetano A. Stress in critical period of early life influences glutamate excitatory neurotransmission: implication for neuropsychiatric disorders.
Liu J, Zhao L, Xue Y, Shi J, Suo L, Luo Y, Chai B, Yang C, Fang Q, Zhang Y, Bao Y. An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory. Biological psychiatry. 2014 Dec 1;76(11):895-901.
Bastin C, Harrison BJ, Davey CG, Moll J, Whittle S. Feelings of shame, embarrassment and guilt and their neural correlates: A systematic review. Neuroscience & Biobehavioral Reviews. 2016 Dec 1;71:455-71.
Korte SM. Corticosteroids in relation to fear, anxiety and psychopathology. Neuroscience & Biobehavioral Reviews. 2001 Mar 1;25(2):117-42.
Nasereddin L, Alnajjar O, Bashar H, Abuarab SF, Al-Adwan R, Chellappan DK, Barakat M. Corticosteroid-Induced Psychiatric Disorders: Mechanisms, Outcomes, and Clinical Implications. Diseases. 2024 Nov 23;12(12):300.
Leistner C, Menke A. Hypothalamic–pituitary–adrenal axis and stress. Handbook of clinical neurology. 2020 Jan 1;175:55-64.
Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, Scheimann J, Myers B. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Comprehensive physiology. 2016 Mar 15;6(2):603.
Gaffey AE, Bergeman CS, Clark LA, Wirth MM. Aging and the HPA axis: Stress and resilience in older adults. Neuroscience & Biobehavioral Reviews. 2016 Sep 1;68:928-45.
Allen J. The antidepressant-like effects of intravenous reelin in the repeated-corticosterone paradigm of chronic stress (Doctoral dissertation).
Schiavone S, Jaquet V, Trabace L, Krause KH. Severe life stress and oxidative stress in the brain: from animal models to human pathology. Antioxidants & redox signaling. 2013 Apr 20;18(12):1475-90.
Yulyaningsih E. Neuropeptide Y6 receptors are critical regulators of energy metabolism (Doctoral dissertation, UNSW Sydney).
Christensen SM, Varney C, Gupta V, Wenz L, Bays HE. Stress, psychiatric disease, and obesity: an obesity medicine association (OMA) clinical practice statement (CPS) 2022. Obesity Pillars. 2022 Nov 4;4:100041.
Chen TB, Yang CC, Tsai IJ, Yang HW, Hsu YC, Chang CM, Yang CP. Neuroimmunological effects of omega-3 fatty acids on migraine: A review. Frontiers in Neurology. 2024 May 6;15:1366372.
Robinson OJ, Pike AC, Cornwell B, Grillon C. The translational neural circuitry of anxiety. Journal of Neurology, Neurosurgery & Psychiatry. 2019 Dec 1;90(12):1353-60.
Hassamal S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Frontiers in psychiatry. 2023 May 11;14:1130989.
Mahfoz AM, Shahzad N. Neuroinflammation impact in epileptogenesis and new treatment strategy. Behavioural Pharmacology. 2019 Dec 1;30(8):660-74.
Sedaghat K, Yousefian Z, Vafaei AA, Rashidy-Pour A, Parsaei H, Khaleghian A, Choobdar S. Mesolimbic dopamine system and its modulation by vitamin D in a chronic mild stress model of depression in the rat. Behavioural Brain Research. 2019 Jan 1;356:156-69.
Ray A, Gulati K, Rai N. Stress, anxiety, and immunomodulation: a pharmacological analysis. Vitamins and hormones. 2017 Jan 1;103:1-25.
Ahmad A, Nawaz MI. Molecular mechanism of VEGF and its role in pathological angiogenesis. Journal of cellular biochemistry. 2022 Dec;123(12):1938-65.
Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology. 2005 Nov 1;69(Suppl. 3):4-10.
D'Andrea LD, De Rosa L, Vigliotti C, Cataldi M. VEGF mimic peptides: Potential applications in central nervous system therapeutics. New Horizons in Translational Medicine. 2017 Jan 1;3(5):233-51.
Wang Q, Jie W, Liu JH, Yang JM, Gao TM. An astroglial basis of major depressive disorder? An overview. Glia. 2017 Aug;65(8):1227-50.
Bambico FR, Belzung C. Novel insights into depression and antidepressants: a synergy between synaptogenesis and neurogenesis?. Neurogenesis and neural plasticity. 2012 Dec 28:243-91.
Miyata S. Advances in understanding of structural reorganization in the hypothalamic neurosecretory system. Frontiers in endocrinology. 2017 Oct 17;8:275.
Mayegowda SB, Thomas C. Glial pathology in neuropsychiatric disorders: a brief review. Journal of basic and clinical physiology and pharmacology. 2019 Jul 26;30(4):20180120.
G. Argandona E, Bengoetxea H, Ortuzar N, Bulnes S, Rico-Barrio I, Vicente Lafuente J. Vascular endothelial growth factor: adaptive changes in the neuroglialvascular unit. Current neurovascular research. 2012 Feb 1;9(1):72-81.
Lopes R, Soares R, Coelho R, Figueiredo-Braga M. Angiogenesis in the pathophysiology of schizophrenia—a comprehensive review and a conceptual hypothesis. Life sciences. 2015 May 1;128:79-93.
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