Top

Published in:

01-06-2020 | Obesity | Original Article

Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates

Authors: Georg Gosztonyi, Hanns Ludwig, Liv Bode, Moujahed Kao, Manfred Sell, Peter Petrusz, Béla Halász

Published in: Brain Structure and Function | Issue 5/2020

Abstract

Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity which might help to better understand underlying processes in human obesity. Eighty Wistar rats, between 30 and 60 days of age, were intracerebrally inoculated with Borna disease virus (BDV-1), a neurotropic negative-strand RNA virus infecting an unusually broad host spectrum including humans. Half of the rats developed fatal encephalitis, while the other half, after 3–4 months, continuously gained weight. At tripled weights, rats were sacrificed by trans-cardial fixative perfusion. Neuropathology revealed prevailing inflammatory infiltrates in the median eminence (ME), progressive degeneration of neurons of the paraventricular nucleus, the entorhinal cortex and the amygdala, and a strikingly high-grade involution of the hippocampus with hydrocephalus. Immune histology revealed that major BDV-1 antigens were preferentially present at glutamatergic receptor sites, while GABAergic areas remained free from BDV-1. Virus-induced suppression of the glutamatergic system caused GABAergic predominance. In the hypothalamus, this shifted the energy balance to the anabolic appetite-stimulating side governed by GABA, allowing for excessive fat accumulation in obese rats. Furthermore, inflammatory infiltrates in the ME and ventro-medial arcuate nucleus hindered free access of appetite-suppressing hormones leptin and insulin. The hormone transport system in hypothalamic areas outside the ME became blocked by excessively produced leptin, leading to leptin resistance. The resulting hyperleptinemic milieu combined with suppressed glutamatergic mechanisms was a characteristic feature of the found metabolic pathology. In conclusion, the study provided clear evidence that BDV-1 induced obesity in the rat model is the result of interdependent structural and functional metabolic changes. They can be explained by an immunologically induced hypothalamic microcirculation-defect, combined with a disturbance of neurotransmitter regulatory systems. The proposed mechanism may also have implications for human health. BDV-1 infection has been frequently found in depressive patients. Independently, comorbidity between depression and obesity has been reported, either. Future studies should address the exciting question of whether BDV-1 infection could be a link, whatsoever, between these two conditions.

Amarasinghe GK, Bao Y, Baslern CF et al (2017) Taxonomy of the order Mononegavirales: update. Arch Virol 162:2493–2504PubMedPubMedCentralCrossRef

Ambach G, Palkovits M (1979) The blood supply of the hypothalamus. In: Morgane PJ, Panksepp J (eds) Anatomy of the hypothalamus, vol 1. Marcel Dekker, Inc., New York, pp 267–377

Ambach G, Palkovits M, Szentágothai J (1976) Blood supply of the rat hypothalamus. IV. Retrochiasmatic area, median eminence, arcuate nucleus. Acta Morphol Acad Sci Hung 24:93–119PubMed

Ankarcona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P (1995) Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15:961–973CrossRef

Atkinson RL (2007) Viruses as an etiology of obesity. Mayo Clin Proc 82:1192–1198PubMedCrossRef

Atkinson RL, Dhurandar NV, Allison DB, Bowen RL, Israel BA, Albu JB, Augustus AS (2005) Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (London) 29:281–286CrossRef

Atlantis and Baker (2008) Obesity effects on depression: systematic review of epidemiological studies. Int J Obes (Lond) 32:881–891CrossRef

Banks WA (2001) Anorectic effects of circulating cytokines: role of the vascular blood-brain barrier. Nutrition 17:434–437PubMedCrossRef

Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, Morley JE (2004) Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53:1253–1260PubMedCrossRef

Banks WA, DiPalma CR, Farrell CL (1999) Impaired transport of leptin across the blood-brain barrier in obesity. Peptides 20:1341–1345PubMedCrossRef

Banks WA, Lebel CR (2002) Strategies for the delivery of leptin to the CNS. J Drug Target 10:297–308PubMedCrossRef

Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17:305–311PubMedCrossRef

Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, Maes M (2013) So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 11:200. https://doi.org/10.1186/1741-7015-11-200 CrossRefPubMedPubMedCentral

Bode L (1995) Human infections with Borna disease virus (BDV) and potential pathogenetic implications. Curr Top Microbiol Immunol 190:103–130PubMed

Bode L (2008) Human Bornavirus infection—towards a valid diagnostic system. APMIS suppl 124(116):21–39CrossRef

Bode L, Ludwig H (1997) Bornavirus-Infektion und psychiatrische Erkrankungen. Infektionsepidemiologische Forschung, InFo III(97):15–20

Bode L, Ludwig H (2003) Borna disease virus infection, a human mental-health risk. Clin Microbiol Rev 16:534–545PubMedPubMedCentralCrossRef

Bode L, Dietrich DE, Stoyloff R, Emrich HM, Ludwig H (1997) Amantadine and human Borna disease virus in vitro and in vivo in an infected patient with bipolar depression. Lancet 349:178–179PubMedCrossRef

Bode L, Dürrwald R, Rantam FA, Ferszt R, Ludwig H (1996) First isolates of infectious human Borna disease virus from patients with mood disorders. Mol Psychiatry 1:200–212PubMed

Bode L, Ferszt R, Czech G (1993) Borna disease virus infection and affective disorders in man. Arch Virol Suppl 7:159–167PubMedCrossRef

Bode L, Reckwald P, Severus EW, Stoyloff R, Ferszt R, Dietrich DE, Ludwig H (2001) Borna disease virus-specific circulating immune complexes, antigenemia, and free antibodies—the key marker triplet determining infection and prevailing in severe mood disorders. Mol Psychiatry 6:481–491PubMedCrossRef

Bode L, Riegel S, Lange W, Ludwig H (1992) Human infections with Borna disease virus: seroprevalence in patients with chronic diseases and healthy individuals. J Med Virol 36:309–315PubMedCrossRef

Bode L, Riegel S, Ludwig H, Amsterdam JD, Lange W, Koprowski H (1988) Borna disease virus specific antibodies in patiens with HIV infections and with mental disorders. Lancet I I:689CrossRef

Bode L, Zimmermann W, Ferszt R, Steinbach F, Ludwig H (1995) Borna disease virus genome transcribed and expressed in psychiatric patients. Nat Med 1:232–236PubMedCrossRef

Bode L, Stoyloff R, Ludwig H (2000) Human Borna viruses and laboratory strains. Lancet 355:1462PubMedCrossRef

Booker SA, Vida I (2018) Morphological diversity and connectivity of hippocampal interneurons. Cell Tissue Res 373:619–641PubMedPubMedCentralCrossRef

Bornstein SR, Schuppenies A, Wong ML, Licinio J (2006) Approaching the shared biology of obesity and depression: the stress axis as the focus of gene-environment interactions. Mol Psychiatry 11:892–902PubMedCrossRef

Briese T, de la Torre JC, Lewis A, Ludwig H, Lipkin WI (1992) Borna disease virus, a negative-strand RNA virus, transcribes in the nucleus of infected cells. Proc Natl Acad Sci USA 89:11486–11489PubMedCrossRef

Briese T, Schneemann A, Lewis AJ, Park IS, Kim S, Ludwig H et al (1994) Genomic organization of Borna disease virus. Proc Natl Acad Sci USA 91:4362–4366PubMedCrossRef

Brooks CM (1988) The history of thought concerning the hypothalamus and its functions. Brain Res Bull 20:657–667PubMedCrossRef

Byrne ML, O’Brien-Simpson NM, Mitchell SA, Allen NB (2015) Adolescent-onset depression: are obesity and inflammation developmental mechanisms or outcomes? Child Psychiatry Hum Dev 46:839–850PubMedCrossRef

Capuron L, Lasselin J, Castanon N (2017) Role of adiposity-driven inflammation in depressive morbidity. Neuropsychopharmacology 42:115–128PubMedCrossRef

Ciofi P (2011) The arcuate nucleus as a circumventricular organ in the mouse. Neurosci Lett 487:187–190PubMedCrossRef

Ciofi P, Garret M, Lapirot O, Loyens A, Prévot V, Levine JE (2009) Brain-endocrine interactions: a microvascular route in the medkobasal hypothalamus. Endocrinology 150:5509–5519PubMedPubMedCentralCrossRef

Ciofi P, Leroy D, Tramu G (2006) Sexual dimorphism in the organization of the rat hypothalamic infundibular area. Neuroscience 141:1731–1745PubMedCrossRef

Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578PubMedCrossRef

Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–484PubMedCrossRef

Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL et al (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel circuit regulating energy homeostasis. Neuron 37:649–661PubMedCrossRef

Csáki A, Kocsis K, Halász B, Kiss J (2000) Localization of glutamatergic/aspartatergic neurons projecting to the hypothalamic paraventricular nucleus studied by retrograde transport of [³H]D-aspartate autoradiography. Neuroscience 101:637–655PubMedCrossRef

Daly M (2013) The relationship of C-reactive protein to obesity-related depressive symptoms: a longitudinal study. Obesity (Silver Spring) 21:248–250CrossRef

De La Torre JC, Bode L, Dürrwald R, Cubitt B, Ludwig H (1996) Sequence characterization of human Borna disease virus. Virus Res 44:33–44PubMedCrossRef

De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, Saad MJ, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199PubMedCrossRef

Deuschle M, Bode L, Schnitzler P, Meyding-Lamade U, Plesch A, Ludwig H, Hamann B, Heuser I (2003) Hypothalamic-pituitary-adrenal (HPA) system activity in depression and infection with Borna disease virus and Chlamydiapneumonia. Mol Psychiatry 8(5):469–470PubMedCrossRef

De Wit L, Luppino F, van Straten A, Penninx B, Zitman F, Cuijpers P (2010) Depression and obesity: a meta-analysis of community-based studies. Psychiatry Res 178:230–235PubMedCrossRef

Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA et al (2006) Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49:191–203PubMedCrossRef

Dhurandar NV, Kulkarni P, Ajinkya SM, Sherikar A (1992) Effect of adenovirus infection on adiposity in chicken. Vet Microbiol 31:101–107CrossRef

Dhurandar NV, Israel BA, Kolesar JM, Mayhew GF, Cook ME, Atkinson RL (2000) Increased adiposity in animals due to a human virus. Int J Obes Relat Metab Disord 24:989–996CrossRef

Dietrich DE, Bode L, Spannhuth CW, Lau T, Huber TJ, Brodhun B, Ludwig H, Emrich HM (2000) Amantadine in depressive patients with Borna disease virus (BDV) infection: an open trial. Bipol Disord 2:65–70CrossRef

Dietrich DE, Bode L, Spannhuth CW, Hecker H, Ludwig H (2020) Emrich HM (2020) Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial. BMC Pharmacol Toxicol 21:12. https://doi.org/10.1186/s40360-020-0391-x CrossRefPubMedPubMedCentral

Dietrich MO, Horvath TL (2009) Feeding signals and brain circuitry. Eur J Neurosci 30:1688–1696PubMedCrossRef

Dietrich MO, Horvath TL (2012) Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons. Nat Rev Drug Discov 11:675–691PubMedCrossRef

Dittrich W, Bode L, Ludwig H, Kao M, Schneider K (1989) Learning deficiencies in Borna disease virus-infected but clinically healthy rats. Biol Psychiatry 26:818–828PubMedCrossRef

Engelhardt B (2003) Development of the blood-brain barrier. Cell Tissue Res 314:119–129PubMedCrossRef

Everitt BJ, Meister B, Hökfelt T, Melander T et al (1986) The hypothalamic arcuate nucleus-median eminence complex: immunohistochemistry of transmitters, peptides and DARPP-32 with special reference to coexistence in dopamine neurons. Brain Res Rev 11:97–155CrossRef

Fagiolini A, Frank E, Houck PR, Mallinger AG, Swartz HA, Buysse DJ, Ombao H, Kupfer DJ (2002) Prevalence of obesity and weight change during treatment in patients with bipolar I disorder. J Clin Psychiatry 63:528–533PubMedCrossRef

Faith MS, Butryn M, Wadden TA, Fabricatore A, Nguyen AM, Heymsfield SB (2011) Evidence for prospective associations among depression and obesity in population-based studies. Obes Rev 12:e438–453PubMedCrossRef

Faith MS, Matz PE, Jorge MA (2002) Obesity-depression associations in the population. J Psychosom Res 53:935–942PubMedCrossRef

Ferszt R, Severus E, Bode L, Brehm M, Kühl HP, Berzewski H, Ludwig H (1999a) Activated Borna disease virus in affective disorders. Pharmacopsychiatry 32:93–98PubMedCrossRef

Ferszt R, Kühl KP, Bode L, Severus EW, Winzer B, Berghöfer A, Beelitz G, Brodhun B, Müller-Örlinghausen B, Ludwig H (1999b) Amantadine revisited: an open trial of amantadine sulfate treatment in chronically depressed patients with Borna disease virus infection. Pharmacopsychiatry 32:142–144PubMedCrossRef

Flower R, Ludwig H (2006) Presence of Borna disease virus (BDV)-specific structural components in human blood plasma. J Clin Virol 36:312–313PubMedCrossRef

Freund TF, Buzsáki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470PubMedCrossRef

Gallyas F (1963) Silver impregnation method for microglia. Acta Neuropathol 3:206–209PubMedCrossRef

Ganong WF (2000) Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol 27:422–427PubMedCrossRef

Gosztonyi G (1966) The fine structure of cerebral capillaries in newborn mice (In Hungarian, with English Summary). Ideggyógy Szle 19:307–320

Gosztonyi G (1994) Reproduction of lyssaviruses: ultrastructural composition of lyssavirus and functional aspects of pathogenesis. Curr Top Microbiol Immunol 187:43–68PubMed

Gosztonyi G (2008) Natural and experimental Borna Disease Virus infections—neuropathology and pathogenetic considerations. APMIS Suppl 124(116):53–57CrossRef

Gosztonyi G, Koprowski H (2001) The concept of neurotropism and selective vulnerability (“Pathoclisis”) in virus infections of the nervous system—a historical overview. Curr Top Microbiol Immunol 253:1–13PubMed

Gosztonyi G, Ludwig H (1984) Neurotransmitter receptors and viral neurotropism. Neuropsychiatr Clin 3:107–114

Gosztonyi G, Ludwig H (1995) Borna disease – Neuropathology and pathogenesis. Curr Top Microbiol Immunol 190:39–73PubMed

Gosztonyi G, Ludwig H (2001) Interactions of viral proteins with neurotransmitter receptors may protect or destroy neurons. Curr Top Microbiol Immunol 252:121–144

Gosztonyi G, Sell M (2013) Neuroviral infections. A historical perspective. In: Singh SK, Ruzek D (eds) Neuroviral Infections. CRC, New York, pp 3–19CrossRef

Gosztonyi G, Dietschold B, Kao M, Rupprecht CE, Ludwig H, Koprowski H (1993) Rabies and Borna disease. A comparative pathogenetic study of two neurovirulent agents. Lab Invest 68:285–295PubMed

Gosztonyi G, Kao M, Bode L, Ludwig H (1991) Obesity syndrome in experimental infection of rats with Borna disease virus. Clin Neuropathol 10:33–34

Greenway F (2006) Virus-induced obesity. Am J Physiol 290:R188–R189

Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445PubMedCrossRef

Gross PM (1992) Circumventricular organ capillaries. Prog Brain Res 91:219–233PubMedCrossRef

Guerriero RM, Giza CC, Rotenberg A (2015) Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep 15:27. https://doi.org/10.1007/s11910-015-0545-1 CrossRefPubMedPubMedCentral

Guillemot-Legris O, Muccioli GG (2017) Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci 40:237–253. https://doi.org/10.1016/j.tins.2017.92.005 CrossRefPubMed

Haidar YM, Cosman BC (2011) Obesity epidemiology. Clin Colon Rectal Surg 24:205–210. https://doi.org/10.1055/s-0031-1295684 CrossRefPubMedPubMedCentral

Halász B, Szentágothai J (1960) Control of adrenocorticotrophic function by direct influence of pituitary substance on the hypothalamus. Acta Morph Acad Sci Hung 9:251–261

Halász B, Pupp I, Uhlarik S (1962) Hypophysiotrophic area in the hypothalamus. J Endocrinol 25:147–154PubMedCrossRef

Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR (2012) Energy balance and its components: implications for body weight regulation. Am J Clin Nutr 95:989–994PubMedPubMedCentralCrossRef

Heal DJ, Cheetham SC, Prow MR, Martin KF, Buckett WR (1998) A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents. Br J Pharmacol 125:301–308PubMedPubMedCentralCrossRef

Heisler LK, Cowley MA, Tecott LH, Fan W, Low JL et al (2002) Activation of central melanocortin pathways by Fenfluramine. Science 297:609–611PubMedCrossRef

Herden C, Herzog S, Richt JA, Nesseler A, Christ M, Failing K, Frese K (2000) Distribution of Borna disease virus in the brain of rats infected with an obesity-inducing virus strain. Brain Pathol 10:39–48PubMedCrossRef

Herman JP, Cullinan WE, Ziegler DR, Tasker JG (2002) Role of the paraventricular nucleus microenvironment in stress integration. Eur J Neurosci 16:381–385PubMedCrossRef

Hirano N, Kao M, Ludwig H (1983) Persistent, tolerant or subacute infection in Borna disease virus infected rats. J Gen Virol 64:1521–1530PubMedCrossRef

Holsapple MP, West LJ, Landreth KS (2003) Species comparison of anatomical and functional immune system development. Birth Defects Res B Dev Reprod Toxicol 68:321–334PubMedCrossRef

Hornig M, Briese T, Lipkin WI (2003) Borna disease virus. J Neurovirol 9:259–273PubMedCrossRef

Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141PubMedCrossRef

Imes CC, Burke LE (2014) The obesity epidemic: the USA as a cautionary tale for the rest of the world. Curr Epidemiol Rep 1:82–88. https://doi.org/10.1007/s40471-014-0012-6 CrossRefPubMedPubMedCentral

Jais A, Brüning JC (2017) Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest 127:24–32PubMedPubMedCentralCrossRef

James WPT (2008) WHO recognition of the global obesity epidemic. Int J Obes 32:120–126CrossRef

Jeong JK, Kim JG, Lee BJ (2014) Participation of the central melanocortin system in metabolic regulation and energy homeostasis. Cell Mol Life Sci 71:3799–3809PubMedCrossRef

Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20:68–100PubMed

Kao M, Gosztonyi G, Ludwig H (1983) Obesity syndrome in Borna disease virus infected rats. Zentralbl Bakteriol Mikrobiol Hyg [A] 255:173

Kao M (1985) Die Pathogenese der Borna Krankheit bei der Ratte. Ein Modell für persistierende Infektionen und subakute/akute Krankheiten des Zentralnervensystems und für die Fettsucht (Obesity Syndrome). Vet. med. dissertation, Berlin

Kao M, Bode L, Gosztonyi G, Ludwig H (1990) Escape from lethal disease in rats after Borna disease virus infection: survival with obesity syndrome. In: VIIIth International Congress of Virology, Berlin 1990. Abstracts, p 108

Kao M, Ludwig H, Gosztonyi G (1984) Adaptation of Borna disease virus to the mouse. J Gen Virol 65:1845–1849PubMedCrossRef

Kenis G, Maes M (2002) Effect of antidepressants on the production of cytokines. Int J Neuropsychopharmacol 5:401–412PubMedCrossRef

Khairova RA, Machado-Vieira R, Du J, Manji HK (2009) A potential role for cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 12:561–578PubMedPubMedCentralCrossRef

Kiss J, Léránth C, Halász B (1984) Serotoninergic endings in VIP-neurons in the suprachiasmatic nucleus and on ACTH-neurons in the arcuate nucleus of the rat hypothalamus. A combination of high resolution autoradiography and electron microscopic immunocytochemistry. Neurosci Lett 44:119–124PubMedCrossRef

Kohno D, Yada T (2012) Arcuate NPY neurons sense and integrate peripheral metabolic signals to control feeding. Neuropeptides 46:315–319PubMedCrossRef

Kondo HM, Pressnitzer D, Shimada Y, Kochiyama T, Kashino M (2018) Inhibition-excitation balance in the parietal cortex mediates volitional control for auditory and visual multistability. Sci Rep 8:14548. https://doi.org/10.1038/s41598-018-32892-3 CrossRefPubMedPubMedCentral

Korn K, Coras R, Bobinger T, Herzog SM, Lücking H, Stöhr R et al (2018) Fatal encephalitic Borna disease virus 1 in solid-organ transplant recipients. N Engl J Med 379:1375–1377PubMedCrossRef

Köhler O, Krogh J, Mors O, Benros ME (2016) Inflammation in depression and the potential for anti-inflammatory treatment. Curr Neuropharmacol 14:732–742PubMedPubMedCentralCrossRef

Kunos and Tam (2011) The case for peripheral CB₁ receptor blockade in the treatment of visceral obesity and its cardiometabolic complications. Br J Pharmacol 163:1423–1431PubMedCrossRef

Ladwig KH, Marten-Mittag B, Löwel H, Döring A, Koenig W (2003) Influence of depressive mood on the association of CRP and obesity in 3205 middle aged healthy men. Brain Behav Immun 17:268–275PubMedCrossRef

Lee YS (2009) The role of leptin-melanocortin system and human weight regulation: lessons from experiments of nature. Ann Acad Med Singapore 38:34–44PubMed

Liesche F, Ruf V, Zoubaa S, Kaletka G, Rosati M, Rubbenstroth D et al (2019) The neuropathology of fatal encephalomyelitis in human Borna virus infection. Acta Neuropathol. https://doi.org/10.1007/s00401-019-02047-3 CrossRefPubMedPubMedCentral

Liu S, Bode L, Zhang L, He P, Huang R, Sun L et al (2015a) CG-MS-based metabonomic profiling displayed differing effects of borna disease virus natural strain Hu-H1 and laboratory strain V infection in rat cortical neurons. Int J Mol Sci 16:19347–19368PubMedPubMedCentralCrossRef

Liu X, Bode L, Zhang L, Wang X et al (2015b) Health care professionals at risk of infection with Borna disease virus—evidence from a large hospital in China (Chongqing). Virol J 12:39PubMedPubMedCentralCrossRef

Lucassen EA, Cizza G (2012) The Hypothalamic-Pituitary-Adrenal Axis, obesity, and chronic stress exposure: sleep and the HPA Axis in obesity. Curr Obes Rep 1:208–215PubMedPubMedCentralCrossRef

Ludwig H (2008) The biology of Bornavirus. APMIS Suppl 124 116:14–20CrossRef

Ludwig H, Becht H, Groh L (1973) Borna disease, a slow virus infection. Biological properties of the virus. Mol Microbiol Immunol 158:275–289CrossRef

Ludwig H, Bode L (2012) From latent Herpes viruses to persistent Bornavirus. In: Blaho JA, Baines JD (eds) From the hallowed halls of Herpesvirology. A tribute to Bernhard Roizman. World Scientific Publishing Co., Hackensack, pp 169–186CrossRef

Ludwig H, Bode L, Gosztonyi G (1988) Borna disease: a persistent virus infection of the central nervous system. Prog Med Virol 35:107–151PubMed

Ludwig H, Furuya K, Bode L, Klein N, Dürrwald R, Lee DS (1993) Etiology and neurobiology of Borna disease viruses (BDV) defined by antibodies, neutralizability and their pathogenic potential. Arch Virol Suppl 7:111–133PubMedCrossRef

Ludwig H, Kraft W, Gosztonyi G, Dahme E, Krey H (1985) Borna-Virus-Infektion (Borna Krankheit) bei natürlich und experimentell infizierten Tieren: ihre Bedeutung für Forschung und Praxis. Tierärztl Prax 13:421–453PubMed

Luppino FS, deWit LM, Bouvy PF, Stijnen P, Cuijperts P, Penninx BW, Zitman FG (2010) Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 67:220–229PubMedCrossRef

LuQui IJ, Fox CA (1976) The supraoptic nucleus and the supraopticohypophysial tract in the monkey. J Comp Neurol 168:7–39PubMedCrossRef

Lyons MJ, Faust IM, Hemmes RB, Buskirk DR, Hirsch J, Zabriskie JB (1982) A virally induced obesity syndrome in mice. Science 216:82–85PubMedCrossRef

Lyons MJ, Nagashima K, Zabriskie JB (2002) Animal models of postinfectious obesity: hypothesis and review. J Neurovirol 8:1–5PubMedCrossRef

Maccaferri G (2005) Stratum oriens horizontal interneurone diversity and hippocampal network dynamics. J Physiol 562:73–80PubMedCrossRef

Marazziti D, Rutigliano G, Baroni S, Landi P, Cell Osso L (2014) Metabolic syndrome and major depression. CNS Spectr 19:293–304. https://doi.org/10.1017/S1092852913000667 CrossRefPubMed

Markowitz S, Friedman MA, Arent SM (2008) Understanding the relation between obesity and depression: causal mechanisms and implications for treatment. Clin Psychol 15:1–20

Mazaheri-Tehrani E, Maghsoudi N, Shams J, Soon H, Atashi H, Motamedi F, Bode L, Ludwig H (2014) Borna disease virus (BDV) infection in psychiatric patients and healthy controls in Iran. Virol J 11:161–170PubMedPubMedCentralCrossRef

McElroy SL (2015) The epidemic of depression with obesity. J Clin Psychiatry 76:e1340–1342PubMedCrossRef

McElroy SL, Kotwal R, Malhotra S, Nelson EB, Keck PE, Nemeroff CB (2004) Are mood disorders and obesity related? A review for the mental health professional. J Clin Psychiatry 65:634–651PubMedCrossRef

Meister B (2007) Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiol Behav 92:263–271PubMedCrossRef

Mezey É, Kivovics P, Palkovics M (1979) Pituitary-brain retrograde transport. TINS 3:57–60

Mitra AK, Clarke K (2010) Viral obesity: fact or fiction? Obes Rev 11:289–296. https://doi.org/10.1111/j.1467-789X.2009.00677.x CrossRefPubMed

Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443:289–295PubMedCrossRef

Munzberg H (2010) Leptin-signaling pathways and leptin resistance. Forum Nutr 63:123–132PubMedCrossRef

Nakamura Y, Takahashi H, Shoya Y, Nakaya T, Watanabe M, Tomonaga K, Iwahashi K, Ameno K, Momiyama N, Taniyama H, Sata T, Kurata T, de la Torre JC, Ikuta K (2000) Isolation of Borna disease virus from human brain tissue. J Virol 74(10):4601–4611PubMedPubMedCentralCrossRef

Narayan O, Herzog S, Frese K, Scheefers H, Rott R (1983a) Behavioral disease in rats caused by immunopathological responses to persistent Borna virus in the brain. Science 220:1401–1403PubMedCrossRef

Narayan O, Herzog S, Frese K, Scheefers H, Rott R (1983b) Pathogenesis of Borna disease in rats: Immune-mediated viral ophthalmoencephalopathy causing blindness and behavioral abnormalities. J Infect Dis 148:305–315PubMedCrossRef

Ng M, Fleming T, Robinson M, Thomson B, Graetz N et al (2014) Global, regional and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781PubMedPubMedCentralCrossRef

Nicolau S, Galloway IA (1927) Preliminary note on the experimental study of the enzootic encephalo-myelitis (Borna disease). Brit J Exp Pathol 8:336–341

Niller HH, Angstwurm K, Rubbenstroth D, Schlottau K, Ebinger A, Giese S et al (2020) Zoonotic spillover infections with Borna disease virus 1 leading to fatal human encephalitis, 1999–2019: an epidemiological investigation. Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(19)30546-8 CrossRefPubMed

Nitzschke E (1963) Untersuchungen über die experimentelle Bornavirus-Infektion bei der Ratte. Zentralbl Vet Med B 10:470–527CrossRef

Nobili A, Krashia P, Cordella A, La Barbela L et al (2018) Ambra 1 shapes hippocampal inhibition/excitation balance: role in neurodevelopmental disorders. Mol Neurobiol 55:7921–7940. https://doi.org/10.1007/s12035-018-0911-5(Epub 2018 Feb 27) CrossRefPubMedPubMedCentral

Norrild B (ed) (2008) The International Berlin Symposium on bornavirus infections—from animals to men—50 years of development. In: APMIS suppl. no 124, vol 116

Norsted E, Gömüc B, Meister B (2008) Protein components of the blood-brain barrier (BBB) in the mediobasal hypothalamus. J Chem Neuroanat 36:107–121PubMedCrossRef

Ohlmeier MD, Zhang Y, Bode L, Sieg S, Feutl S, Ludwig H, Emrich HM, Dietrich DE (2008) Amantadine reduces mania in Borna disease virus-infected non-psychotic bipolar patients. Pharmacopsychiatry 41:1–2CrossRef

Oswal A, Yeo GS (2007) The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics. Obes Rev 8:293–306PubMedCrossRef

Page RB, Dovey-Hartman BJ (1984) Resistance vessels supplying the median eminence of the rabbit, rat and cat. Anat Rec 210:647–655PubMedCrossRef

Palkovits M (1982) Neuropeptides in the median eminence: Their sources and destinations. Peptides 3:299–303PubMedCrossRef

Palkovits M (1984) Role of the central nervous system neuropeptides in body fluid homeostasis. J Physiol (Paris) 79:428–431

Palkovits M (2003) Hypothalamic regulation of food intake. Clin Neurosci/Ideggy Szle 56:288–302

Palkovits M (2008) Stress-induced activation of neurons in the ventromedial arcuate nucleus: A blood-brain-CSF interface of the hypothalamus. Ann N Y Acad Sci 1148:57–63PubMedCrossRef

Paxinos G, Watson CH (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, Sydney

Pinto S, Roseberry AG, Liu H, Diano S, Shana Brough M, Cai X, Frriedman JM, Horvath TL (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110–115PubMedCrossRef

Pi-Sunyer FX (1993) Medical hazards of obesity. Ann Intern Med 119:655–660PubMedCrossRef

Poteracki J, Walsh KM (1998) Spontaneous neoplasms in control Wistar rats: a comparison of reviews. Toxicol Sci 45:1–8PubMedCrossRef

Pratt LA, Brody DJ (2014) Depression and obesity in the U.S. adult household population, 2005–2010. NCHS Data Brief 167:1–8

Preiss K, Brenan L, Clarke D (2013) A systematic review of variables associated with the relationship between obesity and depression. Obes Rev 14(906):918

Pringle CR (1996) Virus taxonomy—a bulletin from the Xth International Congress of Virology in Jerusalem. Arch Virol 141:2251–2256PubMedPubMedCentralCrossRef

Rackova S, Janu L, Kubickova H (2010) Borna disease virus (BDV) circulating immuncomplex positivity in addicted patients in the Czech Republic: a prospective cohort analysis. BMC Psychiatry 10:70–78PubMedPubMedCentralCrossRef

Rethorst CD, Bernstein I, Trivedi MH (2014) Inflammation, obesity, and metabolic syndrome in depression: Analysis of the 2009–2010 National Health and Nutrition Examination Survey (NHANES). J Clin Psychiatry 75:e1428–1432PubMedPubMedCentralCrossRef

Rihmer Z, Purebl G, Faludi G, Halmy L (2008) Association of obesity and depression. Neuropsychopharmacol Hung 10:183–189PubMed

Rosetti C, Halfon O, Boutrel B (2014) Controversies about a common etiology for eating and mood disorders. Front Psychol 5:1205

Rosmond R (2004) Obesity and depression: same disease, different names? Med Hypothes 62:976–979CrossRef

Rott R, Herzog S, Fleischer B, Winokur A, Amsterdam J, Dyson W, Koprowski H (1985) Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228:755–756PubMedCrossRef

Saper CB, Chou TC, Elmquist JK (2002) The need to feed: Homeostatic and hedonic control of eating. Neuron 36:199–211PubMedCrossRef

Schaeffer M, Langlet F, Lafont C, Molino F, Hodson DJ, Roux T, Lamarque L, Verdié P, Bourrier E, Dehouck B, Banères JL, Martinez J, Méry PF, Marie J, Trinquet E, Fehrentz JA, Prévot V, Mollard P (2013) Rapid sensing of circulating ghrelin by hypothalamic appetite-modulating neurons. Proc Natl Acad Sci USA 110:1512–1517PubMedCrossRef

Schlottau K, Forth L, Angstwurm K, Höper D, Zecher D, Liesche F et al (2018) Fatal encephalitic Borna disease virus 1 in solid-organ transplant recipients. N Engl J Med 379:1377–1379PubMedCrossRef

Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671PubMedCrossRef

Shaver SW, Pang JJ, Wainman DS, Wall KM, Gross PM (1992) Morphology and function of capillary networks in subregions of the rat tuber cinereum. Cell Tissue Res 267:437–448PubMedCrossRef

Shelton RC, Falola M, Li L, Zajecka J, Fava M, Papakostas GI (2015) The pro-inflammatory profile of depressed patients is (partly) related to obesity. J Psychiatr Res 70:91–97PubMedPubMedCentralCrossRef

Slavich GM, Irwin MR (2014) From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull 140:774–815. https://doi.org/10.1037/a0035302 CrossRefPubMedPubMedCentral

Somogyi P, Takagi H (1982) A note on the use of picric acid-paraformaldehyde-glutaraldehyde fixative for correlated light and electron microsopic immunochemistry. Neuroscience 7:1779–1783PubMedCrossRef

Stunkard AJ, Faith MS, Allison KC (2003) Depression and obesity. Biol Psychiatry 54:330–337PubMedCrossRef

Szentágothai J, Flerkó B, Mess B, Halász B (1972) Hypothalamic control of the anterior pituitary. An experimental-morphological study. Akadémiai Kiadó, Budapest

Thaler JP, Guyenet SJ, Dorfman MD, Wisse BE, Schwartz MW (2013) Hypothalamic inflammation: marker of mechanism of obesity pathogenesis? Diabetes 62:2629–2634PubMedPubMedCentralCrossRef

Valtonen MK, Laaksonen DE, Tolmunen T, Viinamaki H, Lakka HM, Lakka TA, Niskanen L, Kauhanen J (2012) Low-grade inflammation and depressive symptoms as predictors of abdominal obesity. Scand J Public Health 40:674–680PubMedCrossRef

van den Pol AN (2003) Weighing the role of hypothalamic feeding neurotransmitters. Neuron 40:1059–1061PubMedCrossRef

van den Pol AN, Trombley PQ (1993) Glutamate neurons in hypothalamus regulate excitatory transmission. J Neurosci 13:2829–2836PubMedPubMedCentralCrossRef

van den Pol AN, Wuarin JP, Dudek FE (1990) Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science 250:1276–1278PubMedCrossRef

Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13:1079–1086PubMedPubMedCentralCrossRef

Vasilakopoulou A, le Roux CW (2007) Could a virus contribute to weight gain? Int J Obes 31:1350–1356CrossRef

Vetter ML, Wadden TA, Vinnard C, Moore RH, Khan Z, Volger S, Sarver DB, Faulconbridge LF, POWER UP Research Group (2013) Gender differences in the relationship between symptoms of depression and high-sensitivity CRP. Int J Obes (Lond) 37(Suppl 1):S38–43PubMedCentralCrossRef

Vida I, Halasy K, Szinyei C, Somogyi P, Buhl EH (1998) Unitary IPSPs evoked by interneurons at the stratum radiatum-stratum lacunosum-moleculare border in the CA1 area of the rat hippocampus in vitro. J Physiol 506:755–773PubMedPubMedCentralCrossRef

Walley AJ, Asher JE, Froguel P (2009) The genetic contribution ot non-syndromic human obesity. Nat Rev Genet 10:431–442PubMedCrossRef

Wang Y, Beydoun MA, Liang L, Caballero B, Kumanyika SK (2008) Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic. Obesity 16:2323–2330PubMedCrossRef

WHO Media Centre (2015) Obesity and overweight. Fact sheet N^o311

Williams EP, Mesidor M, Winter K, Dubbert PM, Wyatt SB (2015) Overweight and obbesity: prevalence, consequences, and causes of a growing public health problem. Curr Obes Rep 4:363–370PubMedCrossRef

World Health Organ Tech Rep Ser 894:i-xii, pp 1–123 (2000)

Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137:1225–1234PubMedPubMedCentralCrossRef

Wu Q, Clark MS, Palmiter RD (2012) Deciphering a neuronal circuit that mediates appetite. Nature 483:594–597PubMedPubMedCentralCrossRef

Wu Q, Howell MP, Cowley MA, Palmiter RD (2008) Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc Natl Acad Sci USA 105:2687–2692PubMedCrossRef

Wu Q, Palmiter RD (2011) GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur J Pharmacol 660:21–27PubMedPubMedCentralCrossRef

Yin W, Gore AC (2010) The hypothalamic median eminence and its role in reproductive aging. Ann NY Acad Sci 1204:113–122PubMedCrossRef

Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ et al (2011) Neocortical excitation/inhibition processing and social dysfunction. Nature 477:171–178PubMedPubMedCentralCrossRef

Yu JH, Kim MS (2012) Moleculat mechanisms of appetite regulation. Diabetes Metab J 36:391–398. https://doi.org/10.4093/dmj.2012.36.6.391 CrossRefPubMedPubMedCentral

Zaliunaite V, Steibliene V, Bode L, Podlipskyte A, Bunevicius R, Ludwig H (2016) Primary psychosis and Borna disease virus infection in Lithuania: a case control study. BMC Psychiatry 16:369PubMedPubMedCentralCrossRef

Zhang L, Xu MM, Zeng L, Liu S, Liu X, Wang X, Li D et al (2014) Evidence for Borna disease virus infection in neuropsychiatric patients in three western China provinces. Eur J Clin Microbiol Infect Dis 33:621–627PubMedCrossRef

Zwick W (1939) Bornasche Krankheit und Encephalomyelitis der Tiere. In: Gildenmeister, Haagen, Waldmann: Handbuch der Viruskrankheiten II, pp 254–354 (Fischer, Jena)

Zwick W, Seifried O, Witte J (1929) Weitere Beiträge zur Erforschung der Bornaschen Krankheit des Pferdes. Arch Wiss Prakt Tierheilkd 59:511–545

Title: Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates
Authors: Georg Gosztonyi
Hanns Ludwig
Liv Bode
Moujahed Kao
Manfred Sell
Peter Petrusz
Béla Halász
Publication date: 01-06-2020
Publisher: Springer Berlin Heidelberg
Keywords: Obesity
Obesity
Overweight
Published in: Brain Structure and Function / Issue 5/2020
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-020-02063-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2020

Spatiotemporal dynamics of auditory information processing in the insular cortex: an intracranial EEG study using an oddball paradigm

Dorsal prefrontal and premotor cortex of the ferret as defined by distinctive patterns of thalamo-cortical projections

The occipital face area is causally involved in identity-related visual-semantic associations

White matter characteristics of motor, sensory and interhemispheric tracts underlying impaired upper limb function in children with unilateral cerebral palsy

Personality factors and cerebral glucose metabolism in community-dwelling older adults

The effect of intrinsic and extrinsic motivation on memory formation: insight from behavioral and imaging study