Abstract
Human immunodeficiency virus type 1 (HIV-1) affects the central nervous system (CNS) that may lead to the development of HIV-associated neuropathologies. Tat protein is one of the viral proteins that have been linked to the neurotoxic effects of HIV. Since many individuals living with HIV often experience significant adverse circumstances, the present study investigated whether exposure to stressful conditions would exacerbate harmful effects of tat protein on brain function. Tat protein (10 μg/10 μl) was injected bilaterally into the dorsal hippocampus of the animal using stereotaxic techniques. The control group received an injection of saline (10 μl). Some control and tat protein-treated animals were subjected to restrain stress for 6 h per day for 28 days and compared to a non-stress group. All animals underwent two behavioural tests, the open field test (OFT) and the novel object recognition test (NORT) to assess their mood state and cognitive function respectively. The release of pro-inflammatory cytokines (TNF-α and IL-1β) and the expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were also measured to see whether the impact of the repetitive stress on Tat protein-induced behavioural effects was mediated by elements of the immune system and the HPA axis. Rats treated with tat protein showed the following behavioural changes when compared to control animals: there was a significant decrease in time spent in the center of the open field during the OFT, a significant reduction in time spent with the novel object during the NORT, but no change in locomotor activity. Real-time PCR data showed that the expression levels of GR and MR mRNA were significantly reduced, while Western blot analysis showed that the protein expression levels of TNF-α and IL-1β were significantly increased. The present findings indicated that injection of tat protein into the hippocampus of rats not subjected to stress may lead to anxiety-like behaviour and deficits in learning and memory. Tat-treated animals subjected to stress evoked only a modest effect on their behaviour and neurochemistry, while stress alone led to behavioural and neurochemical changes similar to tat protein.
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References
Agrawal L, Louboutin JP, Reyes BA, Van Bockstaele EJ, Strayer DS (2012) HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis 45:657–670
Aleisa AM, Alzoubi KH, Gerges NZ, Alkadhi KA (2006) Chronic psychosocial stress-induced impairment of hippocampal LTP: Possible role of BDNF. Neurobiol Dis 22:453–462
Ali I, Hogberg J, Hsieh JH, Auerbach S, Korhonen A et al (2016) Gender differences in cancer susceptibility: role of oxidative stress. Carcinogenesis 37:985–992
Amin SN, El-Aidi AA, Ali MM, Attia YM, Rashed LA (2015) Modification of hippocampal markers of synaptic plasticity by memantine in animal models of acute and repeated restraint stress: implications for memory and behavior. Neuromol Med 17:121–136
Ashraf T, Jiang W, Hoque MT, Henderson J, Wu C, Bendayan R (2014) Role of anti-inflammatory compounds in human immunodeficiency virus-1 glycoprotein120-mediated brain inflammation. J Neuroinflammation 11:91
Banerjee A, Zhang X, Manda KR, Banks WA, Ercal N (2010) HIV proteins (gp120 and Tat) and methamphetamine in oxidative stress-induced damage in the brain: potential role of the thiol antioxidant N-acetylcysteine amide. Free Radic Biol Med 48:1388–1398
Bansal AK, Mactutus CF, Nath A, Maragos W, Hauser KF, Booze RM (2000) Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum. Brain Res 879:42–49
Brabers NACH, Nottet HSLM (2006) Role of the pro-inflammatory cytokines TNF-α and IL-1β in HIV-associated dementia. Eur J Clin Investig 36:447–458
Caudal D, Jay TM, Godsil BP (2014) Behavioral stress induces regionally-distinct shifts of brain mineralocorticoid and glucocorticoid receptor levels. Front Behav Neurosci 8:19
Chao HM, McEwen BS (1994) Glucocorticoids and the expression of mRNAs for neurotrophins, their receptors and GAP-43 in the rat hippocampus. Brain Res Mol Brain Res 26:271–276
Cheng B, Mattson MP (1991) NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron 7:1031–1041
Cheng B, Christakos S, Mattson MP (1994) Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12:139–153
Chittiprol S, Shetty KT, Kumar AM, Bhimasenarao RS, Satishchandra P et al (2007) HPA axis activity and neuropathogenesis in HIV-1 clade C infection. Front Biosci 12:1271–1277
Cole SW (2008) Psychosocial influences on HIV-1 disease progression: neural, endocrine, and virologic mechanisms. Psychosom Med 70:562–568
Daniels WM, Jaffer A, Engelbrecht AH, Russell VA, Taljaard JJ (1990) The effect of intrahippocampal injection of kainic acid on corticosterone release in rats. Neurochem Res 15:495–499
Daniels WM, Pietersen CY, Carstens ME, Stein DJ (2004a) Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 19:3–14
Daniels WM, Richter L, Stein DJ (2004b) The effects of repeated intra-amygdala CRF injections on rat behavior and HPA axis function after stress. Metab Brain Dis 19:15–23
de Rezende MG, Garcia-Leal C, de Figueiredo FP, Cavalli RC, Spanghero MS et al (2016) Altered functioning of the HPA axis in depressed postpartum women. J Affect Disord 193:249–256
Dean RL 3rd, Scozzafava J, Goas JA, Regan B, Beer B, Bartus RT (1981) Age-related differences in behavior across the life span of the C57BL/6J mouse. Exp Aging Res 7:427–451
Ennaceur A (2010) One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res 215:244–254
Faure A, Naldi A, Chaouiya C, Thieffry D (2006) Dynamical analysis of a generic Boolean model for the control of the mammalian cell cycle. BMC (Oxford, England) 22:e124–e131
Fumaz CR, Gonzalez-Garcia M, Borras X, Muñoz-Moreno JA, Perez-Alvarez N et al (2012) Psychological stress is associated with high levels of IL-6 in HIV-1 infected individuals on effective combined antiretroviral treatment. Brain Behav Immun 26:568–572
Gądek-Michalska A, Bugajski J (2010) Interleukin-1 (IL-1) in stress-induced activation of limbic-hypothalamic-pituitary adrenal axis. Pharmacol Rep 62(6):969–982
Grant I (2008) Neurocognitive disturbances in HIV. Int Rev Psychiatry (Abingdon, England) 20:33–47
Guedia J, Brun P, Bhave S, Fitting S, Kang M et al (2016) HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system. Sci Rep 6:31203
Harricharan R, Thaver V, Russell VA, Daniels WM (2015) Tat-induced histopathological alterations mediate hippocampus-associated behavioural impairments in rats. Behav Brain Funct: BBF 11:3
Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087–2096
Howland LC, Gortmaker SL, Mofenson LM, Spino C, Gardner JD et al (2000) Effects of negative life events on immune suppression in children and youth infected with human immunodeficiency virus type 1. Pediatrics 106:540–546
Jurgens HA, Johnson RW (2012) Environmental enrichment attenuates hippocampal neuroinflammation and improves cognitive function during influenza infection. Brain Behav Immun 26:1006–1016
Kasahara E, Inoue M (2015) Cross-talk between HPA-axis-increased glucocorticoids and mitochondrial stress determines immune responses and clinical manifestations of patients with sepsis. Redox Report: Free Radic Res 20:1–10
Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG (2010) Animal research: Reporting in vivo experiments: The ARRIVE guidelines. Br J Pharmacol 160:1577–1579
Kirby ED, Muroy SE, Sun WG, Covarrubias D, Leong MJ et al (2013) Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2. eLife 2:e00362
Kruman II, Nath A, Mattson MP (1998) HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol 154:276–288
Kumar M, Kumar AM, Waldrop D, Antoni MH, Eisdorfer C (2003) HIV-1 infection and its impact on the HPA axis, cytokines, and cognition. Stress (Amsterdam, Netherlands) 6:167–172
Lawson MA, Kelley KW, Dantzer R (2011) Intracerebroventricular administration of HIV-1 Tat induces brain cytokine and indoleamine 2,3-dioxygenase expression: a possible mechanism for AIDS comorbid depression. Brain Behav Immun 25:1569–1575
Leserman J (2003) HIV disease progression: depression, stress, and possible mechanisms. Biol Psychiatry 54:295–306
Leserman J (2008) Role of depression, stress, and trauma in HIV disease progression. Psychosom Med 70:539–545
Lewis CF (2005) Post-traumatic stress disorder in HIV-positive incarcerated women. J Am Acad Psychiatry Law 33:455–464
Lindberg C, Selenica ML, Westlind-Danielsson A, Schultzberg M (2005) Beta-amyloid protein structure determines the nature of cytokine release from rat microglia. J Mol Neurosci: MN 27:1–12
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434
Makhathini KB, Abboussi O, Stein DJ, Mabandla MV, Daniels WMU (2017) Repetitive stress leads to impaired cognitive function that is associated with DNA hypomethylation, reduced BDNF and a dysregulated HPA axis. Int J Dev Neurosci 60:63–69
McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87:873–904
Membreno L, Irony I, Dere W, Klein R, Biglieri EG, Cobb E (1987) Adrenocortical function in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 65:482–487
Nicoli F, Finessi V, Sicurella M, Rizzotto L, Gallerani E et al (2013) The HIV-1 Tat protein induces the activation of CD8+ T cells and affects in vivo the magnitude and kinetics of antiviral responses. PLoS One 8:e77746
Ogłodek E, Szota A, Just M, Moś D, Araszkiewicz A (2014) The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol Rep 66(5):776–781
Paul D, Madan V, Bartenschlager R (2014) Hepatitis C virus RNA replication and assembly: living on the fat of the land. Cell Host Microbe 16:569–579
Paxinos G, Watson C, Pennisi M, Topple A (1985) Bregma, lambda and the interaural midpoint in stereotaxic surgery with rats of different sex, strain and weight. J Neurosci Methods 13(2):139–143
Planes R, Ben Haij N, Leghmari K, Serrero M, BenMohamed L, Bahraoui E (2016) HIV-1 Tat Protein Activates both the MyD88 and TRIF Pathways To Induce Tumor Necrosis Factor Alpha and Interleukin-10 in Human Monocytes. J Virol 90:5886–5898
Puccini JM, Marker DF, Fitzgerald T, Barbieri J, Kim CS et al (2015) Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders. J Neurosci 35:5271–5283
Ramautar A, Mabandla M, Blackburn J, Daniels WMU (2012) Inhibition of HIV-1 tat-induced transactivation and apoptosis by the divalent metal chelators, fusaric acid and picolinic acid—Implications for HIV-1 dementia. Neurosci Res 74:59–63
Roth KA, Katz RJ (1979) Stress, behavioral arousal, and open field activity--a reexamination of emotionality in the rat. Neurosci Biobehav Rev 3:247–263
Royal W, Cherner M, Carr J, Habib AG, Akomolafe A et al (2012) Clinical Features and Virological Correlates of Neurocognitive Impairment among HIV-Infected Individuals in Nigeria. J Neurovirol 18:191–199
Rubinstein PG, Aboulafia DM, Zloza A (2014) Malignancies in HIV/AIDS: From Epidemiology to Therapeutic Challenges. AIDS (London, England) 28:453–465
Saadat M, Behboodi ZM, Saadat E (2015) Comparison of depression, anxiety, stress, and related factors among women and men with human immunodeficiency virus infection. J Hum Reprod Sci 8:48–51
Shih R-H, Wang C-Y, Yang C-M (2015) NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci 8:77
Singh D, Joska JA, Goodkin K, Lopez E, Myer L et al (2008) Normative scores for a brief neuropsychological battery for the detection of HIV-associated neurocognitive disorder (HAND) among South Africans. BMC Res Notes 3:28
Sterley TL, Howells FM, Russell VA (2016) Genetically determined differences in noradrenergic function: The spontaneously hypertensive rat model. Brain Res 1641:291–305
Uys JD, Marais L, Faure J, Prevoo D, Swart P et al (2006) Developmental trauma is associated with behavioral hyperarousal, altered HPA axis activity, and decreased hippocampal neurotrophin expression in the adult rat. Ann N Y Acad Sci 1071:542–546
Valdez AN, Rubin LH, Neigh GN (2016) Untangling the Gordian knot of HIV, stress, and cognitive impairment. Neurobiology of Stress 10:1–11
Viel J, McManus D, Smith SS, Brewer G (2001) Age-and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from β-amyloid. J Neurosci Res 64:454–465
Wang P, Barks JD, Silverstein FS (1999) Tat, a human immunodeficiency virus-1-derived protein, augments excitotoxic hippocampal injury in neonatal rats. Neuroscience 88:585–597
Wrona D, Listowska M, Kubera M, Glac W, Grembecka B et al (2014) Effects of chronic desipramine pretreatment on open field-induced suppression of blood natural killer cell activity and cytokine response depend on the rat's behavioral characteristics. J Neuroimmunol 268:13–24
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The authors wish to thank the National Research Foundation of South Africa (NRF grant number 83792) and the University of KwaZulu-Natal for financial support, as well as the staff of the Biomedical Resource Centre of the University of KwaZulu-Natal for technical assistance.
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Makhathini, K.B., Abboussi, O., Mabandla, M.V. et al. The effects of repetitive stress on tat protein-induced pro-inflammatory cytokine release and steroid receptor expression in the hippocampus of rats. Metab Brain Dis 33, 1743–1753 (2018). https://doi.org/10.1007/s11011-018-0283-6
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DOI: https://doi.org/10.1007/s11011-018-0283-6