Role of Neuroglia in the Habenular Connection Hub of the Dorsal Diencephalic Conduction System
Abstract
:1. Introduction
2. Theoretical Background for a Role of the DDCS
3. Anatomy of the DDCS
4. Putative Role of Neuroglia in the Habenula
4.1. Astroglia
4.2. Microglia
5. Cytokines, Habenula and Psychiatric Diseases
5.1. Limitations of Peripheral Cytokine Levels
5.2. Peripheral Cytokine Levels in Depression and Addiction
5.3. Peripheral Cytokine Levels and Metabolic Syndrome
5.4. Involvement of the Lateral Habenula (LHb)
5.5. Involvement of the Medial Habenula (MHb)
6. Personal Commentary
7. Conclusions and Future Prospects
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Gurdjian, E.S. Olfactory connections in the albino rat, with special reference to the stria medullaris and the anterior commissure. J. Comp. Neurol. 1925, 38, 127–163. [Google Scholar] [CrossRef] [Green Version]
- Jansen, J. The brain of myxine glutinosa. J. Comp. Neurol. 1930, 49, 359–507. [Google Scholar] [CrossRef]
- Loonen, A.J.M.; Ivanova, S.A. Circuits regulating pleasure and happiness: Evolution and role in mental disorders. Acta Neuropsychiatr. 2018, 30, 29–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bartrop, R.W.; Luckhurst, E.; Lazarus, L.; Kiloh, L.G.; Penny, R. Depressed lymphocyte function after bereavement. Lancet 1977, 1, 834–836. [Google Scholar] [CrossRef]
- Leonard, B.E. Psychoneuroimmunology: An area of interest for the psychopharmacologist? J. Psychopharmacol. 1990, 4, 1–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zachariae, R. Psychoneuroimmunology: A bio-psycho-social approach to health and disease. Scand. J. Psychol. 2009, 50, 645–651. [Google Scholar] [CrossRef]
- Soria, V.; Uribe, J.; Salvat-Pujol, N.; Palao, D.; Menchón, J.M.; Labad, J. Psychoneuroimmunology of mental disorders. Rev. Psiquiatr. Salud. Ment. 2018, 11, 115–124. [Google Scholar] [CrossRef]
- Calcia, M.A.; Bonsall, D.R.; Bloomfield, P.S.; Selvaraj, S.; Barichello, T.; Howes, O.D. Stress and neuroinflammation: A systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology 2016, 233, 1637–1650. [Google Scholar] [CrossRef] [Green Version]
- Mattei, D.; Notter, T. Basic Concept of Microglia Biology and Neuroinflammation in Relation to Psychiatry. Curr. Top. Behav Neurosci. 2020, 44, 9–34. [Google Scholar] [CrossRef] [PubMed]
- Thylur, D.S.; Goldsmith, D.R. Brick by Brick: Building a Transdiagnostic Understanding of Inflammation in Psychiatry. Harv. Rev. Psychiatry 2022, 30, 40–53. [Google Scholar] [CrossRef]
- Bottaccioli, A.G.; Bologna, M.; Bottaccioli, F. Psychic Life-Biological Molecule Bidirectional Relationship: Pathways, Mechanisms, and Consequences for Medical and Psychological Sciences-A Narrative Review. Int. J. Mol. Sci. 2022, 23, 3932. [Google Scholar] [CrossRef] [PubMed]
- Leonard, B.E.; Myint, A. The psychoneuroimmunology of depression. Hum. Psychopharmacol. 2009, 24, 165–175. [Google Scholar] [CrossRef]
- Kim, Y.K.; Na, K.S.; Myint, A.M.; Leonard, B.E. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 64, 277–284. [Google Scholar] [CrossRef]
- Loonen, A.J.M.; Ivanova, S.A. Circuits Regulating Pleasure and Happiness-Mechanisms of Depression. Front. Hum. Neurosci. 2016, 10, 571. [Google Scholar] [CrossRef] [Green Version]
- Peña-Vargas, C.; Armaiz-Peña, G.; Castro-Figueroa, E. A Biopsychosocial Approach to Grief, Depression, and the Role of Emotional Regulation. Behav. Sci. 2021, 11, 110. [Google Scholar] [CrossRef]
- Sperner-Unterweger, B.; Fuchs, D. Schizophrenia and psychoneuroimmunology: An integrative view. Curr. Opin. Psychiatry 2015, 28, 201–206. [Google Scholar] [CrossRef]
- Müller, N.; Weidinger, E.; Leitner, B.; Schwarz, M.J. The role of inflammation in schizophrenia. Front. Neurosci. 2015, 9, 372. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rodrigues-Amorim, D.; Rivera-Baltanás, T.; Spuch, C.; Caruncho, H.J.; González-Fernandez, Á.; Olivares, J.M.; Agís-Balboa, R.C. Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship. Schizophr. Res. 2018, 197, 19–33. [Google Scholar] [CrossRef] [PubMed]
- Wong, C.M. Post-traumatic stress disorder: Advances in psychoneuroimmunology. Psychiatr. Clin. North Am. 2002, 25, 369–383, vii. [Google Scholar] [CrossRef]
- Pace, T.W.; Heim, C.M. A short review on the psychoneuroimmunology of posttraumatic stress disorder: From risk factors to medical comorbidities. Brain Behav. Immun. 2011, 25, 6–13. [Google Scholar] [CrossRef]
- Furtado, M.; Katzman, M.A. Neuroinflammatory pathways in anxiety, posttraumatic stress, and obsessive compulsive disorders. Psychiatry Res. 2015, 229, 37–48. [Google Scholar] [CrossRef] [PubMed]
- 2013 Five Theories of the Mechanism of Depression. Prof. dr. Anton J.M. Loonen Foundation. Available online: https://antonloonen.nl/presentations/ (accessed on 5 October 2022).
- Loonen, A.J.M.; Ivanova, S.A. Circuits regulating pleasure and happiness—focus on potential biomarkers for circuitry including the habenuloid complex. Acta Neuropsychiatr. 2022, 34, 229–239. [Google Scholar] [CrossRef]
- Loonen, A.J.M.; Ivanova, S.A. Evolution of circuits regulating pleasure and happiness with the habenula in control. CNS Spectr. 2019, 24, 233–238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loonen, A.J.M.; Ochi, T.; Geers, L.M.; Simutkin, G.G.; Bokhan, N.A.; Touw, D.J.; Wilffert, B.; Kornetov, A.N.; Ivanova, S.A. A New Paradigm to Indicate Antidepressant Treatments. Pharmaceuticals 2021, 14, 1288. [Google Scholar] [CrossRef]
- Nieuwenhuys, R.; Voogd, J.; Huijzen, C. The Human Central Nervous System—A Synopsis and Atlas, 3rd ed.; Springer: Berlin/Heidelberg, Germany, 2013. [Google Scholar]
- Loonen, A.J.M. Het Beweeglijke Brein—De Neurowetenschappelijke Achtergrond van de Psychische Functies, 3rd ed.; Mension: Haarlem, The Netherlands, 2021. [Google Scholar]
- Ochi, T.; Vyalova, N.M.; Losenkov, I.S.; Paderina, D.Z.; Pozhidaev, I.V.; Loonen, A.J.M.; Simutkin, G.G.; Bokhan, N.A.; Wilffert, B.; Ivanova, S.A. Polymorphisms in the adrenergic neurotransmission pathway impact antidepressant response in depressed patients. Neurosci. Appl. 2023, 2, 101016. [Google Scholar] [CrossRef]
- Batalla, A.; Homberg, J.R.; Lipina, T.V.; Sescousse, G.; Luijten, M.; Ivanova, S.A.; Schellekens, A.F.A.; Loonen, A.J.M. The role of the habenula in the transition from reward to misery in substance use and mood disorders. Neurosci. Biobehav. Rev. 2017, 80, 276–285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loonen, A.J.M.; Ivanova, S.A. Circuits regulating pleasure and happiness in major depression. Med. Hypotheses 2016, 87, 14–21. [Google Scholar] [CrossRef]
- Zahm, D.S.; Root, D.H. Review of the cytology and connections of the lateral habenula, an avatar of adaptive behaving. Pharmacol. Biochem. Behav. 2017, 162, 3–21. [Google Scholar] [CrossRef]
- Fakhoury, M. The dorsal diencephalic conduction system in reward processing: Spotlight on the anatomy and functions of the habenular complex. Behav. Brain Res. 2018, 348, 115–126. [Google Scholar] [CrossRef]
- Aizawa, H.; Zhu, M. Toward an understanding of the habenula’s various roles in human depression. Psychiatry Clin. Neurosci. 2019, 73, 607–612. [Google Scholar] [CrossRef] [Green Version]
- Metzger, M.; Souza, R.; Lima, L.B.; Bueno, D.; Gonçalves, L.; Sego, C.; Donato, J., Jr.; Shammah-Lagnado, S.J. Habenular connections with the dopaminergic and serotonergic system and their role in stress-related psychiatric disorders. Eur. J. Neurosci. 2021, 53, 65–88. [Google Scholar] [CrossRef]
- Roman, E.; Weininger, J.; Lim, B.; Roman, M.; Barry, D.; Tierney, P.; O’Hanlon, E.; Levins, K.; O’Keane, V.; Roddy, D. Untangling the dorsal diencephalic conduction system: A review of structure and function of the stria medullaris, habenula and fasciculus retroflexus. Brain Struct. Funct. 2020, 225, 1437–1458. [Google Scholar] [CrossRef]
- Gouveia, F.V.; Ibrahim, G.M. Habenula as a Neural Substrate for Aggressive Behavior. Front. Psychiatry 2022, 13, 817302. [Google Scholar] [CrossRef]
- Hétu, S.; Luo, Y.; Saez, I.; D’Ardenne, K.; Lohrenz, T.; Montague, P.R. Asymmetry in functional connectivity of the human habenula revealed by high-resolution cardiac-gated resting state imaging. Hum. Brain Mapp. 2016, 37, 2602–2615. [Google Scholar] [CrossRef] [Green Version]
- Ahumada-Galleguillos, P.; Lemus, C.G.; Díaz, E.; Osorio-Reich, M.; Härtel, S.; Concha, M.L. Directional asymmetry in the volume of the human habenula. Brain Struct. Funct. 2017, 222, 1087–1092. [Google Scholar] [CrossRef]
- Morley, B.J. The interpeduncular nucleus. Int. Rev. Neurobiol. 1986, 28, 157–182. [Google Scholar] [CrossRef] [PubMed]
- Lima, L.B.; Bueno, D.; Leite, F.; Souza, S.; Gonçalves, L.; Furigo, I.C.; Donato, J., Jr.; Metzger, M. Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei. J. Comp. Neurol. 2017, 525, 2411–2442. [Google Scholar] [CrossRef] [PubMed]
- Khatami, L.; Khodagholi, F.; Motamedi, F. Reversible inactivation of interpeduncular nucleus impairs memory consolidation and retrieval but not learning in rats: A behavioral and molecular study. Behav. Brain Res. 2018, 342, 79–88. [Google Scholar] [CrossRef] [PubMed]
- Khatami, L.; Safari, V.; Motamedi, F. Temporary inactivation of interpeduncular nucleus impairs long but not short term plasticity in the perforant-path dentate gyrus synapses in rats. Behav. Brain Res. 2020, 377, 112212. [Google Scholar] [CrossRef]
- Watanabe, K.; Irie, K.; Hanashima, C.; Takebayashi, H.; Sato, N. Diencephalic progenitors contribute to the posterior septum through rostral migration along the hippocampal axonal pathway. Sci. Rep. 2018, 8, 11728. [Google Scholar] [CrossRef]
- Watanabe, K.; Takebayashi, H.; Sato, N. The fornix acts as a permissive corridor for septal neuron migration beyond the diencephalic-telencephalic boundary. Sci. Rep. 2020, 10, 8315. [Google Scholar] [CrossRef]
- McNaughton, N. The role of the subiculum within the behavioural inhibition system. Behav. Brain Res. 2006, 174, 232–250. [Google Scholar] [CrossRef] [PubMed]
- McNaughton, N.; Department of Psychology and Brain Health Research Centre, University of Otago, Dunedin, New Zealand. Personal communication, 2022.
- Stephenson-Jones, M.; Kardamakis, A.A.; Robertson, B.; Grillner, S. Independent circuits in the basal ganglia for the evaluation and selection of actions. Proc. Natl. Acad. Sci. USA 2013, 110, E3670–E3679. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gampe, K.; Hammer, K.; Kittel, Á.; Zimmermann, H. The medial habenula contains a specific nonstellate subtype of astrocyte expressing the ectonucleotidase NTPDase2. Glia 2012, 60, 1860–1870. [Google Scholar] [CrossRef]
- Sperlágh, B.; Kittel, A.; Lajtha, A.; Vizi, E.S. ATP acts as fast neurotransmitter in rat habenula: Neurochemical and enzymecytochemical evidence. Neuroscience 1995, 66, 915–920. [Google Scholar] [CrossRef]
- Ferré, S.; Agnati, L.F.; Ciruela, F.; Lluis, C.; Woods, A.S.; Fuxe, K.; Franco, R. Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: The striatal spine module. Brain Res. Rev. 2007, 55, 55–67. [Google Scholar] [CrossRef] [Green Version]
- Loonen, A.J.M.; Wilffert, B.; Ivanova, S.A. Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia. Pharmacogenomics 2019, 20, 1199–1223. [Google Scholar] [CrossRef] [Green Version]
- Savtchenko, L.P.; Rusakov, D.A. The optimal height of the synaptic cleft. Proc. Natl. Acad. Sci. USA 2007, 104, 1823–1828. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Derouiche, A.; Anlauf, E.; Aumann, G.; Mühlstädt, B.; Lavialle, M. Anatomical aspects of glia-synapse interaction: The perisynaptic glial sheath consists of a specialized astrocyte compartment. J. Physiol. Paris 2002, 96, 177–182. [Google Scholar] [CrossRef]
- Ghézali, G.; Dallérac, G.; Rouach, N. Perisynaptic astroglial processes: Dynamic processors of neuronal information. Brain Struct. Funct. 2016, 221, 2427–2442. [Google Scholar] [CrossRef]
- Saint-Martin, M.; Goda, Y. Astrocyte-synapse interactions and cell adhesion molecules. FEBS J. 2022. [Google Scholar] [CrossRef]
- Chen, T.; Lennon, V.A.; Liu, Y.U.; Bosco, D.B.; Li, Y.; Yi, M.H.; Zhu, J.; Wei, S.; Wu, L.J. Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion. J. Clin. Investig. 2020, 130, 4025–4038. [Google Scholar] [CrossRef]
- Frizzo, M.E.; Ohno, Y. Perisynaptic astrocytes as a potential target for novel antidepressant drugs. J. Pharmacol. Sci. 2021, 145, 60–68. [Google Scholar] [CrossRef] [PubMed]
- Lalo, U.; Koh, W.; Lee, C.J.; Pankratov, Y. The tripartite glutamatergic synapse. Neuropharmacology 2021, 199, 108758. [Google Scholar] [CrossRef]
- Kruyer, A.; Kalivas, P.W.; Scofield, M.D. Astrocyte regulation of synaptic signaling in psychiatric disorders. Neuropsychopharmacology 2022, 48, 21–36. [Google Scholar] [CrossRef] [PubMed]
- Paniccia, J.E.; Otis, J.M.; Scofield, M.D. Looking to the stars for answers: Strategies for determining how astrocytes influence neuronal activity. Comput. Struct. Biotechnol. J. 2022, 20, 4146–4156. [Google Scholar] [CrossRef] [PubMed]
- Ricci, G.; Volpi, L.; Pasquali, L.; Petrozzi, L.; Siciliano, G. Astrocyte-neuron interactions in neurological disorders. J. Biol. Phys. 2009, 35, 317–336. [Google Scholar] [CrossRef] [Green Version]
- Soung, A.; Klein, R.S. Astrocytes: Initiators of and Responders to Inflammation. In Glia in Health and Disease; Spohr, T., Ed.; IntechOpen: London, UK, 2019. [Google Scholar] [CrossRef]
- Bernaus, A.; Blanco, S.; Sevilla, A. Glia Crosstalk in Neuroinflammatory Diseases. Front. Cell Neurosci. 2020, 14, 209. [Google Scholar] [CrossRef]
- Linnerbauer, M.; Wheeler, M.A.; Quintana, F.J. Astrocyte Crosstalk in CNS Inflammation. Neuron 2020, 108, 608–622. [Google Scholar] [CrossRef]
- Rauf, A.; Badoni, H.; Abu-Izneid, T.; Olatunde, A.; Rahman, M.M.; Painuli, S.; Semwal, P.; Wilairatana, P.; Mubarak, M.S. Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules 2022, 27, 3194. [Google Scholar] [CrossRef]
- Leonard, B.E. Inflammation, depression and dementia: Are they connected? Neurochem. Res. 2007, 32, 1749–1756. [Google Scholar] [CrossRef] [PubMed]
- Sugama, S.; Cho, B.P.; Baker, H.; Joh, T.H.; Lucero, J.; Conti, B. Neurons of the superior nucleus of the medial habenula and ependymal cells express IL-18 in rat CNS. Brain Res. 2002, 958, 1–9. [Google Scholar] [CrossRef]
- Aizawa, H.; Kobayashi, M.; Tanaka, S.; Fukai, T.; Okamoto, H. Molecular characterization of the subnuclei in rat habenula. J. Comp. Neurol. 2012, 520, 4051–4066. [Google Scholar] [CrossRef]
- Yasuda, K.; Nakanishi, K.; Tsutsui, H. Interleukin-18 in Health and Disease. Int. J. Mol. Sci. 2019, 20, 649. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alboni, S.; Cervia, D.; Sugama, S.; Conti, B. Interleukin 18 in the CNS. J. Neuroinflammation 2010, 7, 9. [Google Scholar] [CrossRef] [Green Version]
- Kettenmann, H.; Hanisch, U.K.; Noda, M.; Verkhratsky, A. Physiology of microglia. Physiol. Rev. 2011, 91, 461–553. [Google Scholar] [CrossRef] [PubMed]
- Wolf, S.A.; Boddeke, H.W.; Kettenmann, H. Microglia in Physiology and Disease. Annu. Rev. Physiol. 2017, 79, 619–643. [Google Scholar] [CrossRef]
- Li, Q.; Barres, B.A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 2018, 18, 225–242. [Google Scholar] [CrossRef]
- Deng, S.L.; Chen, J.G.; Wang, F. Microglia: A Central Player in Depression. Curr. Med. Sci. 2020, 40, 391–400. [Google Scholar] [CrossRef]
- Ginhoux, F.; Greter, M.; Leboeuf, M.; Nandi, S.; See, P.; Gokhan, S.; Mehler, M.F.; Conway, S.J.; Ng, L.G.; Stanley, E.R.; et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010, 330, 841–845. [Google Scholar] [CrossRef] [Green Version]
- Tay, T.L.; Mai, D.; Dautzenberg, J.; Fernandez-Klett, F.; Lin, G.; Sagar; Datta, M.; Drougard, A.; Stempfl, T.; Ardura-Fabregat, A.; et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 2017, 20, 793–803. [Google Scholar] [CrossRef] [PubMed]
- Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308, 1314–1318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eyo, U.B.; Wu, L.J. Microglia: Lifelong patrolling immune cells of the brain. Prog. Neurobiol. 2019, 179, 101614. [Google Scholar] [CrossRef]
- Hickman, S.E.; Kingery, N.D.; Ohsumi, T.K.; Borowsky, M.L.; Wang, L.C.; Means, T.K.; El Khoury, J. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 2013, 16, 1896–1905. [Google Scholar] [CrossRef] [Green Version]
- Kettenmann, H.; Kirchhoff, F.; Verkhratsky, A. Microglia: New roles for the synaptic stripper. Neuron 2013, 77, 10–18. [Google Scholar] [CrossRef] [Green Version]
- Sancho, L.; Contreras, M.; Allen, N.J. Glia as sculptors of synaptic plasticity. Neurosci. Res. 2021, 167, 17–29. [Google Scholar] [CrossRef] [PubMed]
- Saijo, K.; Glass, C.K. Microglial cell origin and phenotypes in health and disease. Nat. Rev. Immunol. 2011, 11, 775–787. [Google Scholar] [CrossRef] [PubMed]
- Boche, D.; Perry, V.H.; Nicoll, J.A. Review: Activation patterns of microglia and their identification in the human brain. Neuropathol. Appl. Neurobiol. 2013, 39, 3–18. [Google Scholar] [CrossRef]
- Tang, Y.; Le, W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol. Neurobiol. 2016, 53, 1181–1194. [Google Scholar] [CrossRef] [PubMed]
- Chai, M.; Su, G.; Gao, J.; Chen, W.; Wu, Q.; Dong, Y.; Wang, H.; Chen, D.; Li, Y.; Gao., X.; et al. Molecular Mechanism of the Protective Effects of M2 Microglia on Neurons: A Review Focused on Exosomes and Secretory Proteins. Neurochem. Res. 2022, 47, 3556–3564. [Google Scholar] [CrossRef]
- Jia, X.; Gao, Z.; Hu, H. Microglia in depression: Current perspectives. Sci. China Life Sci. 2021, 64, 911–925. [Google Scholar] [CrossRef] [PubMed]
- Guo, X.; Rao, Y.; Mao, R.; Cui, L.; Fang, Y. Common cellular and molecular mechanisms and interactions between microglial activation and aberrant neuroplasticity in depression. Neuropharmacology 2020, 181, 108336. [Google Scholar] [CrossRef]
- Nieto-Quero, A.; Chaves-Peña, P.; Santín, L.J.; Pérez-Martín, M.; Pedraza, C. Do changes in microglial status underlie neurogenesis impairments and depressive-like behaviours induced by psychological stress? A systematic review in animal models. Neurobiol. Stress 2021, 15, 100356. [Google Scholar] [CrossRef]
- Alexaki, V.I. The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives. Cells 2021, 10, 1584. [Google Scholar] [CrossRef] [PubMed]
- Woodburn, S.C.; Bollinger, J.L.; Wohleb, E.S. The semantics of microglia activation: Neuroinflammation, homeostasis, and stress. J. Neuroinflammation 2021, 18, 258. [Google Scholar] [CrossRef]
- Carloni, E.; Ramos, A.; Hayes, L.N. Developmental Stressors Induce Innate Immune Memory in Microglia and Contribute to Disease Risk. Int. J. Mol. Sci. 2021, 22, 13035. [Google Scholar] [CrossRef]
- Rahimian, R.; Wakid, M.; O’Leary, L.A.; Mechawar, N. The emerging tale of microglia in psychiatric disorders. Neurosci. Biobehav. Rev. 2021, 131, 1–29. [Google Scholar] [CrossRef]
- Brisch, R.; Wojtylak, S.; Saniotis, A.; Steiner, J.; Gos, T.; Kumaratilake, J.; Henneberg, M.; Wolf, R. The role of microglia in neuropsychiatric disorders and suicide. Eur. Arch. Psychiatry Clin. Neurosci. 2022, 272, 929–945. [Google Scholar] [CrossRef] [PubMed]
- Leal, G.C.; Bandeira, I.D.; Correia-Melo, F.S.; Telles, M.; Mello, R.P.; Vieira, F.; Lima, C.S.; Jesus-Nunes, A.P.; Guerreiro-Costa, L.N.F.; Marback, R.F.; et al. Intravenous arketamine for treatment-resistant depression: Open-label pilot study. Eur. Arch. Psychiatry Clin. Neurosci. 2020, 271, 577–582. [Google Scholar] [CrossRef]
- Jelen, L.A.; Young, A.H.; Stone, J.M. Ketamine: A tale of two enantiomers. J. Psychopharmacol. 2021, 35, 109–123. [Google Scholar] [CrossRef]
- Zhang, J.C.; Yao, W.; Hashimoto, K. Arketamine, a new rapid-acting antidepressant: A historical review and future directions. Neuropharmacology 2022, 218, 109219. [Google Scholar] [CrossRef]
- Wei, Y.; Chang, L.; Hashimoto, K. Molecular mechanisms underlying the antidepressant actions of arketamine: Beyond the NMDA receptor. Mol. Psychiatry 2022, 27, 559–573. [Google Scholar] [CrossRef]
- Leng, L.; Zhuang, K.; Liu, Z.; Huang, C.; Gao, Y.; Chen, G.; Lin, H.; Hu, Y.; Wu, D.; Shi, M.; et al. Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation. Neuron 2018, 100, 551–563. [Google Scholar] [CrossRef] [Green Version]
- Guan, Y.-F.; Huang, G.-B.; Xu, M.-D.; Gao, F.; Lin, S.; Huang, J.; Wang, J.; Li, Y.-Q.; Wu, C.-H.; Yao, S.; et al. Anti-depression effects of ketogenic diet are mediated via the restoration of microglial activation and neuronal excitability in the lateral habenula. Brain, Behav. Immun. 2020, 88, 748–762. [Google Scholar] [CrossRef] [PubMed]
- Valentinova, K.; Tchenio, A.; Trusel, M.; Clerke, J.A.; Lalive, A.L.; Tzanoulinou, S.; Matera, A.; Moutkine, I.; Maroteaux, L.; Paolicelli, R.C.; et al. Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability. Nat. Neurosci. 2019, 22, 1053–1056. [Google Scholar] [CrossRef]
- Mednova, I.A.; Levchuk, L.A.; Boiko, A.S.; Roschina, O.V.; Simutkin, G.G.; Bokhan, N.A.; Loonen, A.J.M.; Ivanova, S.A. Cytokine level in patients with mood disorder, alcohol use disorder and their comorbidity. World J. Biol. Psychiatry 2022, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Miller, A.H.; Raison, C.L. The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 2016, 16, 22–34. [Google Scholar] [CrossRef] [Green Version]
- Erickson, M.A.; Banks, W.A. Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions. Pharmacol. Rev. 2018, 70, 278–314. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gonçalves, R.A.; De Felice, F.G. The crosstalk between brain and periphery: Implications for brain health and disease. Neuropharmacology 2021, 197, 108728. [Google Scholar] [CrossRef] [PubMed]
- Banks, W.A.; Kastin, A.J.; Durham, D.A. Bidirectional transport of interleukin-1 alpha across the blood-brain barrier. Brain Res. Bull. 1989, 23, 433–437. [Google Scholar] [CrossRef]
- Hikosaka, O. The habenula: From stress evasion to value-based decision-making. Nat. Rev. Neurosci. 2010, 11, 503–513. [Google Scholar] [CrossRef] [PubMed]
- Lawson, R.P.; Seymour, B.; Loh, E.; Lutti, A.; Dolan, R.J.; Dayan, P.; Weiskopf, N.; Roiser, J.P. The habenula encodes negative motivational value associated with primary punishment in humans. Proc. Natl. Acad. Sci. USA 2014, 111, 11858–11863. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Proulx, C.D.; Hikosaka, O.; Malinow, R. Reward processing by the lateral habenula in normal and depressive behaviors. Nat. Neurosci. 2014, 17, 1146–1152. [Google Scholar] [CrossRef]
- Koob, G.F.; Volkow, N.D. Neurocircuitry of addiction. Neuropsychopharmacology 2010, 35, 217–238, Erratum in: Neuropsychopharmacology 2010, 35, 1051. [Google Scholar] [CrossRef] [Green Version]
- Koob, G.F.; Buck, C.L.; Cohen, A.; Edwards, S.; Park, P.E.; Schlosburg, J.E.; Schmeichel, B.; Vendruscolo, L.F.; Wade, C.L.; Whitfield, T.W.; et al. Addiction as a stress surfeit disorder. Neuropharmacology 2014, 76 Pt B, 370–382. [Google Scholar] [CrossRef] [Green Version]
- Dowlati, Y.; Herrmann, N.; Swardfager, W.; Liu, H.; Sham, L.; Reim, E.K.; Lanctôt, K.L. A meta-analysis of cytokines in major depression. Biol. Psychiatry 2010, 67, 446–457. [Google Scholar] [CrossRef] [PubMed]
- Köhler, C.A.; Freitas, T.H.; Maes, M.; De Andrade, N.Q.; Liu, C.S.; Fernandes, B.S.; Stubbs, B.; Solmi, M.; Veronese, N.; Herrmann, N.; et al. Peripheral cytokine and chemokine alterations in depression: A meta-analysis of 82 studies. Acta Psychiatr. Scand. 2017, 135, 373–387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adams, C.; Conigrave, J.H.; Lewohl, J.; Haber, P.; Morley, K.C. Alcohol use disorder and circulating cytokines: A systematic review and meta-analysis. Brain Behav. Immun. 2020, 89, 501–512. [Google Scholar] [CrossRef] [PubMed]
- Wei, Z.X.; Chen, L.; Zhang, J.J.; Cheng, Y. Aberrations in peripheral inflammatory cytokine levels in substance use disorders: A meta-analysis of 74 studies. Addiction 2020, 115, 2257–2267. [Google Scholar] [CrossRef]
- Doggui, R.; Elsawy, W.; Conti, A.A.; Baldacchino, A. Association between chronic psychoactive substances use and systemic inflammation: A systematic review and meta-analysis. Neurosci. Biobehav. Rev. 2021, 125, 208–220. [Google Scholar] [CrossRef]
- Vallée, A. Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway. Int. J. Mol. Sci. 2022, 23, 2810. [Google Scholar] [CrossRef]
- Fišar, Z. Biological hypotheses, risk factors, and biomarkers of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2022, 120, 110626. [Google Scholar] [CrossRef]
- Mednova, I.A.; Boiko, A.S.; Kornetova, E.G.; Semke, A.V.; Bokhan, N.A.; Ivanova, S.A. Cytokines as potential biomarkers of clinical characteristics of schizophrenia. Life 2022, 12, 1972. [Google Scholar] [CrossRef]
- Miller, B.J.; Buckley, P.; Seabolt, W.; Mellor, A.; Kirkpatrick, B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol. Psychiatry 2011, 70, 663–671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, X.; Tian, B.; Han, H.B. Serum interleukin-6 in schizophrenia: A system review and meta-analysis. Cytokine 2021, 141, 155441. [Google Scholar] [CrossRef] [PubMed]
- Çakici, N.; Sutterland, A.L.; Penninx, B.W.J.H.; de Haan, L.; van Beveren, N.J.M. Changes in peripheral blood compounds following psychopharmacological treatment in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: A meta-analysis. Psychol. Med. 2021, 51, 538–549. [Google Scholar] [CrossRef] [PubMed]
- Jackson, A.J.; Miller, B.J. Meta-analysis of total and differential white blood cell counts in schizophrenia. Acta Psychiatr. Scand. 2020, 142, 18–26. [Google Scholar] [CrossRef] [PubMed]
- Alberti, K.G.M.M.; Zimmet, P.; Shaw, J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet ed. 2006, 23, 469–480. [Google Scholar] [CrossRef] [PubMed]
- Mitchell, A.J.; Vancampfort, D.; Sweers, K.; van Winkel, R.; Yu, W.; De Hert, M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr. Bull. 2013, 39, 306–318. [Google Scholar] [CrossRef] [Green Version]
- Kornetova, E.; Kornetov, A.; Mednova, I.; Lobacheva, O.; Gerasimova, V.; Dubrovskaya, V.; Tolmachev, I.; Semke, A.; Loonen, A.; Bokhan, N.; et al. Body Fat Parameters, Glucose and Lipid Profiles, and Thyroid Hormone Levels in Schizophrenia Patients with or without Metabolic Syndrome. Diagnostics 2020, 10, 683. [Google Scholar] [CrossRef]
- Kornetova, E.G.; Kornetov, A.N.; Mednova, I.A.; Goncharova, A.A.; Gerasimova, V.I.; Pozhidaev, I.V.; Boiko, A.S.; Semke, A.V.; Loonen, A.J.M.; Bokhan, N.A.; et al. Comparative Characteristics of the Metabolic Syndrome Prevalence in Patients With Schizophrenia in Three Western Siberia Psychiatric Hospitals. Front. Psychiatry 2021, 12, 661174. [Google Scholar] [CrossRef] [PubMed]
- Ringen, P.A.; Engh, J.A.; Birkenaes, A.B.; Dieset, I.; Andreassen, O.A. Increased mortality in schizophrenia due to cardiovascular disease—A non-systematic review of epidemiology, possible causes, and interventions. Front. Psychiatry 2014, 5, 137. [Google Scholar] [CrossRef]
- Correll, C.U.; Solmi, M.; Croatto, G.; Schneider, L.K.; Rohani-Montez, S.C.; Fairley, L.; Smith, N.; Bitter, I.; Gorwood, P.; Taipale, H.; et al. Mortality in people with schizophrenia: A systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry 2022, 21, 248–271. [Google Scholar] [CrossRef]
- Li, H.; Peng, S.; Li, S.; Liu, S.; Lv, Y.; Yang, N.; Yu, L.; Deng, Y.-H.; Zhang, Z.; Fang, M.; et al. Chronic olanzapine administration causes metabolic syndrome through inflammatory cytokines in rodent models of insulin resistance. Sci. Rep. 2019, 9, 1582. [Google Scholar] [CrossRef] [PubMed]
- Boiko, A.S.; Mednova, I.A.; Kornetova, E.G.; Gerasimova, V.I.; Kornetov, A.N.; Loonen, A.J.M.; Bokhan, N.A.; Ivanova, S.A. Cytokine Level Changes in Schizophrenia Patients with and without Metabolic Syndrome Treated with Atypical Antipsychotics. Pharmaceuticals 2021, 14, 446. [Google Scholar] [CrossRef]
- Rocha, A.R.d.F.; Morais, N.d.S.; Priore, S.E.; Franceschini, S.d.C.C. Inflammatory Biomarkers and Components of Metabolic Syndrome in Adolescents: A Systematic Review. Inflammation 2022, 45, 14–30. [Google Scholar] [CrossRef] [PubMed]
- Mednova, I.A.; Boiko, A.S.; Kornetova, E.G.; Parshukova, D.A.; Semke, A.V.; Bokhan, N.A.; Loonen, A.J.M.; Ivanova, S.A. Adipocytokines and Metabolic Syndrome in Patients with Schizophrenia. Metabolites 2020, 10, 410. [Google Scholar] [CrossRef]
- Enache, D.; Pariante, C.M.; Mondelli, V. Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue. Brain Behav. Immun. 2019, 81, 24–40. [Google Scholar] [CrossRef] [PubMed]
- Trépanier, M.O.; Hopperton, K.E.; Mizrahi, R.; Mechawar, N.; Bazinet, R.P. Postmortem evidence of cerebral inflammation in schizophrenia: A systematic review. Mol. Psychiatry 2016, 21, 1009–1026. [Google Scholar] [CrossRef]
- Marques, T.R.; Ashok, A.H.; Pillinger, T.; Veronese, M.; Turkheimer, F.E.; Dazzan, P.; Sommer, I.E.C.; Howes, O.D. Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies. Psychol. Med. 2019, 49, 2186–2196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Picker, L.J.; Morrens, M.; Chance, S.A.; Boche, D. Microglia and Brain Plasticity in Acute Psychosis and Schizophrenia Illness Course: A Meta-Review. Front. Psychiatry 2017, 8, 238. [Google Scholar] [CrossRef] [Green Version]
- Loonen, A.J.M.; Ivanova, S.A. Circuits Regulating Pleasure and Happiness: The Evolution of the Amygdalar-Hippocampal-Habenular Connectivity in Vertebrates. Front. Neurosci. 2016, 10, 539. [Google Scholar] [CrossRef] [Green Version]
- Xia, Q.P.; Cheng, Z.Y.; He, L. The modulatory role of dopamine receptors in brain neuroinflammation. Int. Immunopharmacol. 2019, 76, 105908. [Google Scholar] [CrossRef]
- Gu, C.; Chen, Y.; Chen, Y.; Liu, C.F.; Zhu, Z.; Wang, M. Role of G Protein-Coupled Receptors in Microglial Activation: Implication in Parkinson’s Disease. Front. Aging Neurosci. 2021, 13, 768156. [Google Scholar] [CrossRef]
- Won, E.; Kim, Y.K. Stress, the Autonomic Nervous System, and the Immune-kynurenine Pathway in the Etiology of Depression. Curr. Neuropharmacol. 2016, 14, 665–673. [Google Scholar] [CrossRef] [Green Version]
- Kim, Y.K.; Won, E. The influence of stress on neuroinflammation and alterations in brain structure and function in major depressive disorder. Behav. Brain Res. 2017, 329, 6–11. [Google Scholar] [CrossRef]
- Ishikawa, Y.; Furuyashiki, T. The impact of stress on immune systems and its relevance to mental illness. Neurosci. Res. 2022, 175, 16–24. [Google Scholar] [CrossRef] [PubMed]
- Olmos, G.; Lladó, J. Tumor necrosis factor alpha: A link between neuroinflammation and excitotoxicity. Mediators Inflamm. 2014, 2014, 861231. [Google Scholar] [CrossRef] [Green Version]
- Shabel, S.J.; Proulx, C.D.; Piriz, J.; Malinow, R. Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 2014, 345, 1494–1498. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wallace, M.L.; Saunders, A.; Huang, K.W.; Philson, A.C.; Goldman, M.; Macosko, E.Z.; McCarroll, S.A.; Sabatini, B.L. Genetically Distinct Parallel Pathways in the Entopeduncular Nucleus for Limbic and Sensorimotor Output of the Basal Ganglia. Neuron 2017, 94, 138–152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meye, F.J.; Soiza-Reilly, M.; Smit, T.; Diana, M.A.; Schwarz, M.K.; Mameli, M. Shifted pallidal co-release of GABA and glutamate in habenula drives cocaine withdrawal and relapse. Nat. Neurosci. 2016, 19, 1019–1024, Erratum in: Nat. Neurosci. 2020, 23, 594. [Google Scholar] [CrossRef] [PubMed]
- Han, R.T.; Kim, R.D.; Molofsky, A.V.; Liddelow, S.A. Astrocyte-immune cell interactions in physiology and pathology. Immunity 2021, 54, 211–224. [Google Scholar] [CrossRef] [PubMed]
- Boiko, A.S.; Mednova, I.A.; Kornetova, E.G.; Semke, A.V.; Bokhan, N.A.; Loonen, A.J.M.; Ivanova, S.A. Apolipoprotein serum levels related to metabolic syndrome in patients with schizophrenia. Heliyon 2019, 5, e02033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carniglia, L.; Ramírez, D.; Durand, D.; Saba, J.; Turati, J.; Caruso, C.; Scimonelli, T.N.; Lasaga, M. Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases. Mediators Inflamm. 2017, 2017, 5048616. [Google Scholar] [CrossRef] [Green Version]
- Polito, R.; Nigro, E.; Messina, A.; Monaco, M.L.; Monda, V.; Scudiero, O.; Cibelli, G.; Valenzano, A.; Picciocchi, E.; Zammit, C.; et al. Adiponectin and Orexin-A as a Potential Immunity Link Between Adipose Tissue and Central Nervous System. Front. Physiol. 2018, 9, 982. [Google Scholar] [CrossRef] [Green Version]
- Nicolas, S.; Cazareth, J.; Zarif, H.; Guyon, A.; Heurteaux, C.; Chabry, J.; Petit-Paitel, A. Globular Adiponectin Limits Microglia Pro-Inflammatory Phenotype through an AdipoR1/NF-κB Signaling Pathway. Front. Cell Neurosci. 2017, 11, 352. [Google Scholar] [CrossRef] [Green Version]
- Zhao, L.; Chen, S.; Sherchan, P.; Ding, Y.; Zhao, W.; Guo, Z.; Yu, J.; Tang, J.; Zhang, J.H. Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice. J. Neuroinflammation 2018, 15, 215. [Google Scholar] [CrossRef] [Green Version]
- Peng, J.; Yin, L.; Wang, X. Central and peripheral leptin resistance in obesity and improvements of exercise. Horm. Behav. 2021, 133, 105006. [Google Scholar] [CrossRef]
- Khaledi, M.; Haghighatdoost, F.; Feizi, A.; Aminorroaya, A. The prevalence of comorbid depression in patients with type 2 diabetes: An updated systematic review and meta-analysis on huge number of observational studies. Acta Diabetol. 2019, 56, 631–650. [Google Scholar] [CrossRef]
- Wang, F.; Wang, S.; Zong, Q.Q.; Zhang, Q.; Ng, C.H.; Ungvari, G.S.; Xiang, Y.T. Prevalence of comorbid major depressive disorder in Type 2 diabetes: A meta-analysis of comparative and epidemiological studies. Diabet. Med. 2019, 36, 961–969. [Google Scholar] [CrossRef]
- Viswanath, H.; Carter, A.Q.; Baldwin, P.R.; Molfese, D.L.; Salas, R. The medial habenula: Still neglected. Front. Hum. Neurosci. 2014, 7, 931. [Google Scholar] [CrossRef] [PubMed]
- Antolin-Fontes, B.; Ables, J.L.; Görlich, A.; Ibañez-Tallon, I. The habenulo-interpeduncular pathway in nicotine aversion and withdrawal. Neuropharmacology 2015, 96 Pt B, 213–222. [Google Scholar] [CrossRef] [Green Version]
- Wilhelm, M. Neuro-immune interactions in the dove brain. Gen. Comp. Endocrinol. 2011, 172, 173–180. [Google Scholar] [CrossRef] [PubMed]
- Mayberg, H.S. Limbic-cortical dysregulation: A proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 1997, 9, 471–481. [Google Scholar] [CrossRef] [PubMed]
- Mayberg, H.S. Modulating dysfunctional limbic-cortical circuits in depression: Towards development of brain-based algorithms for diagnosis and optimised treatment. Br. Med. Bull. 2003, 65, 193–207. [Google Scholar] [CrossRef] [Green Version]
- Giacobbe, P.; Mayberg, H.S.; Lozano, A.M. Treatment resistant depression as a failure of brain homeostatic mechanisms: Implications for deep brain stimulation. Exp. Neurol. 2009, 219, 44–52. [Google Scholar] [CrossRef] [PubMed]
- Riva-Posse, P.; Holtzheimer, P.E.; Garlow, S.J.; Mayberg, H.S. Practical considerations in the development and refinement of subcallosal cingulate white matter deep brain stimulation for treatment-resistant depression. World Neurosurg. 2013, 80, S27.e25–S27.e34. [Google Scholar] [CrossRef] [PubMed]
- Stephenson-Jones, M.; Yu, K.; Ahrens, S.; Tucciarone, J.M.; van Huijstee, A.N.; Mejia, L.A.; Penzo, M.A.; Tai, L.H.; Wilbrecht, L.; Li, B. A basal ganglia circuit for evaluating action outcomes. Nature 2016, 539, 289–293. [Google Scholar] [CrossRef] [Green Version]
- Hong, S.; Amemori, S.; Chung, E.; Gibson, D.J.; Amemori, K.I.; Graybiel, A.M. Predominant Striatal Input to the Lateral Habenula in Macaques Comes from Striosomes. Curr. Biol. 2019, 29, 51–61.e5. [Google Scholar] [CrossRef] [Green Version]
- Hamani, C.; Mayberg, H.; Stone, S.; Laxton, A.; Haber, S.; Lozano, A.M. The subcallosal cingulate gyrus in the context of major depression. Biol. Psychiatry 2011, 69, 301–308. [Google Scholar] [CrossRef]
Anatomical Components | Circuits | Role | |
---|---|---|---|
Primary forebrain * | Corticoid amygdala Extended amygdala Hippocampal complex Posterior septum Hypothalamus | DDCS | Initiates the emotional response |
Habenuloid complex | |||
Secondary forebrain | Limbic cortex | ||
Nucleus accumbens Ventral pallidum Thalamus Hypothalamus Habenuloid complex | Ventral CSTC (aCg re-entry) (sCg re-entry) DDCS | Regulates intensity of the emotional response | |
Tertiary forebrain | Isocortex | Cortical | |
Putamen Caudate nucleus | Dorsal CSTC | Initiates and regulates of the voluntary and planned response | |
Globus pallidus | Intracerebral | ||
Dorsal thalamus | Cerebrospinal |
Primary | Secondary | Likelihood |
---|---|---|
Cortical activation |
| Unlikely |
LHb activation |
| possible |
| ||
Peripheral cytokines (TNFα, IL-6) |
| likely |
|
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Loonen, A.J.M. Role of Neuroglia in the Habenular Connection Hub of the Dorsal Diencephalic Conduction System. Neuroglia 2023, 4, 34-51. https://doi.org/10.3390/neuroglia4010004
Loonen AJM. Role of Neuroglia in the Habenular Connection Hub of the Dorsal Diencephalic Conduction System. Neuroglia. 2023; 4(1):34-51. https://doi.org/10.3390/neuroglia4010004
Chicago/Turabian StyleLoonen, Anton J. M. 2023. "Role of Neuroglia in the Habenular Connection Hub of the Dorsal Diencephalic Conduction System" Neuroglia 4, no. 1: 34-51. https://doi.org/10.3390/neuroglia4010004