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Cited by 42Stress Responses and CortisolTreatment of Major DepressionNeuroscience and Neuropharmacology Research

Excitation-inhibition imbalance in medial preoptic area circuits underlies chronic stress-induced depression-like states

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Tao, Can, Zhang, Guang-Wei, Sun, Wen-Jian, Huang, Junxiang J., Zhang, Li I., Tao, Huizhong Whit·2024·Nature Communications
DOI 10.1038/s41467-024-52727-2PMC PMC11452203
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Abstract

Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors. Whether excitatory and inhibitory neural populations in the medial preoptic area of hypothalamus (MPOA) respond differentially under different chronic stress conditions is not fully understood. Here, the authors show that chronic stress induces a disruption of excitation-inhibition balance in mouse MPOA, leading to depression-like states.

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  1. [1]Nelson, S. B. & Valakh, V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015). 26291155 PMC4567857 · DOI · Paper page
  2. [2]Sohal, V. S. & Rubenstein, J. L. R. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol. Psychiatry 24, 1248–1257 (2019). 31089192 PMC6742424 · DOI · Paper page
  3. [3]Rubenstein, J. L. R. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003). 14606691 PMC6748642 · DOI · Paper page
  4. [4]Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011). 21796121 PMC4155501 · DOI · Paper page
  5. [5]Lisman, J. Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Curr. Opin. Neurobiol. 22, 537–544 (2012). 22079494 PMC3302967 · DOI
  6. [7]Krishnan, V. & Nestler, E. J. The molecular neurobiology of depression. Nature 455, 894–902 (2008). 18923511 PMC2721780 · DOI · Paper page
  7. [8]Kanner, A. M. & Balabanov, A. Depression and epilepsy: how closely related are they? Neurology 58, S27–S39 (2002). 11971130 · DOI
  8. [9]Serafini, G. et al. The role of ketamine in treatment-resistant depression: a systematic review. Curr. Neuropharmacol. 12, 444–461 (2014). 25426012 PMC4243034 · DOI · Paper page
  9. [11]Luscher, B., Shen, Q. & Sahir, N. The GABAergic deficit hypothesis of major depressive disorder. Mol. Psychiatry16, 383–406 (2011). PMC3412149 21079608
  10. [12]Moffitt, J. R. et al. Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science 362, eaau5324 (2018). 30385464 PMC6482113 · DOI · Paper page
  11. [13]Zhang, G.-W. et al. Medial preoptic area antagonistically mediates stress-induced anxiety and parental behavior. Nat. Neurosci. 24, 516–528 (2021). 33526942 PMC8328037 · DOI
  12. [14]Fang, Y.-Y., Yamaguchi, T., Song, S. C., Tritsch, N. X. & Lin, D. A hypothalamic midbrain pathway essential for driving maternal behaviors. Neuron 98, 192–207.e10 (2018). 29621487 PMC5890946 · DOI
  13. [15]Wu, Z., Autry, A. E., Bergan, J. F., Watabe-Uchida, M. & Dulac, C. G. Galanin neurons in the medial preoptic area govern parental behaviour. Nature 509, 325–330 (2014). 24828191 PMC4105201 · DOI
  14. [16]McHenry, J. A. et al. Hormonal gain control of a medial preoptic area social reward circuit. Nat. Neurosci. 20, 449–458 (2017). 28135243 PMC5735833 · DOI
  15. [18]Santollo, J., Torregrossa, A.-M. & Eckel, L. A. Estradiol acts in the medial preoptic area, arcuate nucleus, and dorsal raphe nucleus to reduce food intake in ovariectomized rats. Horm. Behav. 60, 86–93 (2011). 21439964 PMC3112293 · DOI
  16. [19]Tao, C. et al. The medial preoptic area mediates depressive-like behaviors induced by ovarian hormone withdrawal through distinct GABAergic projections. Nat. Neurosci. 26, 1529–1540 (2023). PMC11037266 37524978
  17. [21]Xiao, C. et al. Glutamatergic and GABAergic neurons in pontine central gray mediate opposing valence-specific behaviors through a global network. Neuron 111, 1486–1503.e7 (2023). 36893756 PMC10164086 · DOI
  18. [22]Shen, L. et al. A bottom-up reward pathway mediated by somatostatin neurons in the medial septum complex underlying appetitive learning. Nat. Commun. 13, 1194 (2022). 35256596 PMC8901785 · DOI
  19. [23]Smith, J. et al. Regulation of stress-induced sleep fragmentation by preoptic glutamatergic neurons. Curr. Biol. 34, 12–23.e5 (2023). PMC10872481 38096820
  20. [24]Dimén, D. et al. Sex-specific parenting and depression evoked by preoptic inhibitory neurons. iScience24, 103090 (2021). PMC8463871 34604722
  21. [25]Li, Z. et al. Corticostriatal control of defense behavior in mice induced by auditory looming cues. Nat. Commun. 12, 1040 (2021). 33589613 PMC7884702 · DOI
  22. [26]Emiliani, V. et al. Optogenetics for light control of biological systems. Nat. Rev. Methods Prim. 2, 1–25 (2022). PMC10627578 37933248
  23. [27]Kaneda, K. et al. Selective optical control of synaptic transmission in the subcortical visual pathway by activation of viral vector-expressed halorhodopsin. PLoS ONE 6, e18452 (2011). 21483674 PMC3071716 · DOI
  24. [28]Pollak Dorocic, I. et al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron 83, 663–678 (2014). 25102561 · DOI · Paper page
  25. [29]Becker, C. et al. Repeated social defeat-induced depression-like behavioral and biological alterations in rats: involvement of cholecystokinin. Mol. Psychiatry13, 1079–1092 (2008). 17893702
  26. [30]Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006). 16469931 · DOI · Paper page
  27. [31]Sanacora, G., Zarate, C. A., Krystal, J. H. & Manji, H. K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 7, 426–437 (2008). PMC2715836 18425072
  28. [32]Hashimoto, K., Sawa, A. & Iyo, M. Increased levels of glutamate in brains from patients with mood disorders. Biol. Psychiatry 62, 1310–1316 (2007). 17574216 · DOI
  29. [33]Duman, R. S., Aghajanian, G. K., Sanacora, G. & Krystal, J. H. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238–249 (2016). 26937618 PMC5405628 · DOI · Paper page
  30. [34]Chen, F. et al. Hippocampal volume and cell number in depression, schizophrenia, and suicide subjects. Brain Res. 1727, 146546 (2020). 31715144 · DOI
  31. [35]Covington, H. E. et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082–16090 (2010). 21123555 PMC3004756 · DOI · Paper page
  32. [36]Holtzheimer, P. E. & Mayberg, H. S. Deep brain stimulation for treatment-resistant depression. AJP 167, 1437–1444 (2010). PMC4413473 21131410 · DOI
  33. [37]Northoff, G. & Sibille, E. Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings. Mol. Psychiatry19, 966–977 (2014). PMC4169738 25048001
  34. [38]Nagy, C. et al. Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nat. Neurosci. 23, 771–781 (2020). 32341540 · DOI · Paper page
  35. [39]Heshmati, M. et al. Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc. Natl Acad. Sci. USA 115, 1111–1116 (2018). 29339486 PMC5798379 · DOI · Paper page
  36. [40]Motta, S. C. & Canteras, N. S. Restraint stress and social defeat: what they have in common. Physiol. Behav. 146, 105–110 (2015). 26066716 · DOI
  37. [41]Hamon, M. & Blier, P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog. Neuropsychopharmacol. Biol. Psychiatry 45, 54–63 (2013). 23602950 · DOI
  38. [42]Bayless, D. W. et al. A neural circuit for male sexual behavior and reward. Cell 186, 3862–3881.e28 (2023). 37572660 PMC10615179 · DOI
  39. [43]Li, Z. et al. Enhancement and contextual modulation of visuospatial processing by thalamocollicular projections from ventral lateral geniculate nucleus. Nat. Commun. 14, 7278 (2023). 37949869 PMC10638288 · DOI
  40. [44]Kohl, J. et al. Functional circuit architecture underlying parental behaviour. Nature 556, 326–331 (2018). 29643503 PMC5908752 · DOI
  41. [45]Ryoo, J., Park, S. & Kim, D. An inhibitory medial preoptic circuit mediates innate exploration. Front. Neurosci. 15, 716147 (2021). PMC8419349 34497488
  42. [50]Wallace, D. D., Boynton, M. H. & Lytle, L. A. Multilevel analysis exploring the links between stress, depression, and sleep problems among two-year college students. J. Am. Coll. Health 65, 187–196 (2017). 27937737 PMC5373919 · DOI
  43. [52]Chaudhury, D. et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013). 23235832 PMC3554860 · DOI · Paper page
  44. [53]Warden, M. R. et al. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492, 428–432 (2012). 23160494 PMC5929119 · DOI · Paper page
  45. [54]Ramirez, S. et al. Activating positive memory engrams suppresses depression-like behaviour. Nature 522, 335–339 (2015). 26085274 PMC5583720 · DOI
  46. [55]Proulx, C. D. et al. A neural pathway controlling motivation to exert effort. Proc. Natl Acad. Sci. USA 115, 5792–5797 (2018). 29752382 PMC5984527 · DOI · Paper page
  47. [57]Challis, C., Beck, S. G. & Berton, O. Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat. Front. Behav. Neurosci. 8, 43 (2014). 24596546 PMC3925846 · DOI
  48. [58]Ohmura, Y. et al. Different roles of distinct serotonergic pathways in anxiety-like behavior, antidepressant-like, and anti-impulsive effects. Neuropharmacology 167, 107703 (2020). 31299228 · DOI
  49. [59]Cai, Y.-Q., Wang, W., Paulucci-Holthauzen, A. & Pan, Z. Z. Brain circuits mediating opposing effects on emotion and pain. J. Neurosci. 38, 6340–6349 (2018). 29941444 PMC6041794 · DOI
  50. [60]Johnson, S. B. et al. A basal forebrain site coordinates the modulation of endocrine and behavioral stress responses via divergent neural pathways. J. Neurosci. 36, 8687–8699 (2016). 27535914 PMC4987438 · DOI
  51. [61]Knowland, D. et al. Distinct ventral pallidal neural populations mediate separate symptoms of depression. Cell 170, 284–297.e18 (2017). 28689640 PMC5621481 · DOI · Paper page
  52. [62]Wei, Y.-C. et al. Medial preoptic area in mice is capable of mediating sexually dimorphic behaviors regardless of gender. Nat. Commun. 9, 279–279 (2018). 29348568 PMC5773506 · DOI
  53. [64]Berkhout, J. B. et al. An integrated single-cell RNA-seq atlas of the mouse hypothalamic paraventricular nucleus links transcriptomic and functional types. J. Neuroendocrinol. 36, e13367 (2024). 38281730 · DOI
  54. [65]Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000). 11027914 · DOI · Paper page
  55. [66]Pnevmatikakis, E. A. & Giovannucci, A. NoRMCorre: an online algorithm for piecewise rigid motion correction of calcium imaging data. J. Neurosci. Methods 291, 83–94 (2017). 28782629 · DOI
  56. [67]Zhou, P. et al. Efficient and accurate extraction of in vivo calcium signals from microendoscopic video data. eLife 7, e28728 (2018). 29469809 PMC5871355 · DOI
  57. [68]Sheintuch, L. et al. Tracking the same neurons across multiple days in Ca 2+ imaging data. Cell Rep. 21, 1102–1115 (2017). 29069591 PMC5670033 · DOI
  58. [69]Mei, L., Yan, R., Yin, L., Sullivan, R. M. & Lin, D. Antagonistic circuits mediating infanticide and maternal care in female mice. Nature 618, 1006–1016 (2023). 37286598 PMC10648307 · DOI

Cited by

Sorted by citations

Authors
Tao, C., Zhang, G.-W., Sun, W.-J., Huang, J. J., Zhang, L. I., & Tao, H. W.
Affiliations
University of Southern California (US)
Corresponding author
  • Zhang, Li I.
  • Tao, Huizhong Whit
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-10-03
Volume
15
Issue
1
Pages
8575-8575
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-52727-2
PMC
PMC11452203
OpenAlex
W4403096276
Cited by
42
References
11
Citations by year
2026: 19 · 2025: 23
FWCI
12.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Eye Institute (EY019049)
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH116990)
  • U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (R01DC008983)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (RF1NS132912)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
excitatory-inhibitory imbalance, medial preoptic area, chronic restraint stress, social defeat stress, depression-like behavior, major depressive disorder, glutamatergic neurons, GABAergic neurons, paraventricular hypothalamus, ventral tegmental area, periaqueductal gray, dorsal raphe nucleus, dopaminergic activity, serotonergic activity, neural circuits
MeSH terms
Social Defeat, Animals, Behavior, Animal, Depression, Disease Models, Animal, Male, Mice, Inbred C57BL, Neural Pathways, Neurons, Paraventricular Hypothalamic Nucleus, Preoptic Area, Restraint, Physical, Stress, Psychological, Ventral Tegmental Area, Mice, GABAergic Neurons

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