Journal Home > Volume 2 , Issue 3

The hypothalamic paraventricular nucleus (PVN) expresses multiple neuropeptides and plays an essential role in several physiological processes. Among the brain areas directly projecting to the PVN are deep brain structures closely related to instinctive behavior. Moreover, the PVN neurons can project abundant axons to multiple downstream brain regions and are key components of the stress response. Accordingly, PVN malfunction is implicated in stress-related psychiatric diseases. When facing stressors, the PVN releases neuropeptides into the pituitary, activating the hypothalamic–pituitary–adrenocortical axis to regulate blood pressure, energy metabolism, and electrolyte balance. This review summarizes the physiological functions of PVN-related neural circuits and neuropeptides, as well as their role in anxiety, which may provide insights into the mechanism of stress-related psychiatric disorders assisting in the development of new treatments.

Full text
About this article

Role of the hypothalamic paraventricular nucleus in anxiety disorders

Show Author's information Chen Wu1,2( )Mario A. Zetter3
Department of Neurology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
Department of Physiology, School of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico


The hypothalamic paraventricular nucleus (PVN) expresses multiple neuropeptides and plays an essential role in several physiological processes. Among the brain areas directly projecting to the PVN are deep brain structures closely related to instinctive behavior. Moreover, the PVN neurons can project abundant axons to multiple downstream brain regions and are key components of the stress response. Accordingly, PVN malfunction is implicated in stress-related psychiatric diseases. When facing stressors, the PVN releases neuropeptides into the pituitary, activating the hypothalamic–pituitary–adrenocortical axis to regulate blood pressure, energy metabolism, and electrolyte balance. This review summarizes the physiological functions of PVN-related neural circuits and neuropeptides, as well as their role in anxiety, which may provide insights into the mechanism of stress-related psychiatric disorders assisting in the development of new treatments.

Keywords: neural circuit, anxiety disorders, hypothalamic paraventricular nucleus, hypothalamic–pituitary–adrenocortical axis, neuropeptide



Kessler, R. C. The global burden of anxiety and mood disorders: Putting the European Study of the Epidemiology of Mental Disorders (ESEMeD) findings into perspective. The Journal of Clinical Psychiatry, 2007, 68(Suppl 2): 10–19.


Wittchen, H. U., Jacobi, F., Rehm, J., Gustavsson, A., Svensson, M., Jönsson, B., Olesen, J., Allgulander, C., Alonso, J., Faravelli, C. et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology, 2011, 21(9): 655–679.


Kessler, R. C., Ormel, J., Petukhova, M., McLaughlin, K. A., Green, J. G., Russo, L. J., Stein, D. J., Zaslavsky, A. M., Aguilar-Gaxiola, S., Alonso, J. et al. Development of lifetime comorbidity in the World Health Organization world mental health surveys. Archives of General Psychiatry, 2011, 68(1): 90–100.


Ormel, J., Petukhova, M., Chatterji, S., Aguilar-Gaxiola, S., Alonso, J., Angermeyer, M. C., Bromet, E. J., Burger, H., Demyttenaere, K., de Girolamo, G. et al. Disability and treatment of specific mental and physical disorders across the world. The British Journal of Psychiatry, 2008, 192(5): 368–375.


López-Muñoz, F., Srinivasan, V., de Berardis, D., Álamo, C., Kato, T. A. Melatonin, Neuroprotective Agents and Antidepressant Therapy. 1st edn. Springer India: New Delhi, 2016.


Daviu, N., Bruchas. M. R., Moghaddam. B., Sandi, C., Beyeler, A. Neurobiological links between stress and anxiety. Neurobiology of Stress, 2019, 11: 100191.


de Jonge, P., Roest, A. M., Lim, C. C. W., Florescu, S. E., Bromet, E. J., Stein, D. J., Harris, M., Nakov, V., Caldas-de-Almeida, J. M., Viana, M. C. et al. Cross-national epidemiology of panic disorder and panic attacks in the world mental health surveys. Depression and Anxiety, 2016, 33(12): 1155–1177.


Wardenaar, K. J., Lim, C. C. W., Al-Hamzawi, A. O., Alonso, J., Benjet, C., Bunting, B., de Girolamo, G., Demyttenaere, K., Florescu, S. E., Gureje, O. et al. The cross-national epidemiology of specific phobia in the World Mental Health Surveys. Psychological Medicine, 2017, 47(10): 1744–1760.


Daly, M., Robinson, E. Depression and anxiety during COVID-19. Lancet, 2022, 399(10324): 518.


Penninx, B. W. J. H., Pine. D. S., Holmes, E. A., Reif, A. Anxiety disorders. The Lancet, 2021, 397(10277): 914–927.


Griebel, G., Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nature Reviews Drug Discovery, 2013, 12(9): 667–687.


Saper, C. B., Lowell, B. B. The hypothalamus. Current Biology, 2014, 24(23): R1111–R1116.


Herman, J. P., Flak, J., Jankord, R. Chronic stress plasticity in the hypothalamic paraventricular nucleus. Progress in Brain Research, 2008, 170: 353–364.


Armstrong, W. E., Warach, S., Hatton, G. I., McNeill, T. H. Subnuclei in the rat hypothalamic paraventricular nucleus: A cytoarchitectural, horseradish peroxidase and immunocytochemical analysis. Neuroscience, 1980, 5(11): 1931–1958.


Ramot, A., Jiang, Z. Y., Tian, J. B., Nahum, T., Kuperman, Y., Justice, N., Chen, A. Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress. Nature Neuroscience, 2017, 20(3): 385–388.


Mobbs, D., Petrovic, P., Marchant, J. L., Hassabis, D., Weiskopf, N., Seymour, B., Dolan, R. J., Frith, C. D. When fear is near: Threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science, 2007, 317(5841): 1079–1083.


Takagi, Y., Sakai, Y., Abe, Y., Nishida, S., Harrison, B. J., Martínez-Zalacaín, I., Soriano-Mas, C., Narumoto, J., Tanaka, S. C. A common brain network among state, trait, and pathological anxiety from whole-brain functional connectivity. NeuroImage, 2018, 172: 506–516.


Nusbaum, M. P., Blitz, D. M. Neuropeptide modulation of microcircuits. Current Opinion in Neurobiology, 2012, 22(4): 592–601.


Son, S. J., Filosa, J. A., Potapenko, E. S., Biancardi, V. C., Zheng, H., Patel, K. P., Tobin, V. A., Ludwig, M., Stern, J. E. Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron, 2013, 78(6): 1036–1049.


Tang, Y., Benusiglio, D., Lefevre, A., Hilfiger, L., Althammer, F., Bludau, A., Hagiwara, D., Baudon, A., Darbon, P., Schimmer, J. et al. Social touch promotes interfemale communication via activation of parvocellular oxytocin neurons. Nat Neurosci, 2020, 23(9): 1125–1137.


Herman, J. P., Tasker, J. G., Ziegler, D. R., Cullinan, W. E. Local circuit regulation of paraventricular nucleus stress integration: Glutamate–GABA connections. Pharmacology, Biochemistry, and Behavior, 2002, 71(3): 457–468.


Jiang, Z., Rajamanickam, S., Justice, N. J. Local corticotropin-releasing factor signaling in the hypothalamic paraventricular nucleus. The Journal of Neuroscience, 2018, 38(8): 1874–1890.


Justice, N. J., Yuan, Z. F., Sawchenko, P. E., Vale, W. Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: Implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. The Journal of Comparative Neurology, 2008, 511(4): 479–496.


Myers, B., Mark Dolgas, C., Kasckow, J., Cullinan, W. E., Herman, J. P. Central stress-integrative circuits: Forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. Brain Structure and Function, 2014, 219(4): 1287–1303.


Hernández, V. S., Hernández, O. R., Perez de la Mora, M., Gómora, M. J., Fuxe, K., Eiden, L. E., Zhang, L. Hypothalamic vasopressinergic projections innervate central amygdala GABAergic neurons: Implications for anxiety and stress coping. Frontiers in Neural Circuits, 2016, 10: 92.


Mulders, W. H., Meek, J., Hafmans, T. G., Cools, A. R. Plasticity in the stress-regulating circuit: Decreased input from the bed nucleus of the stria terminalis to the hypothalamic paraventricular nucleus in Wistar rats following adrenalectomy. Frontiers in Oncology, 1997, 9(11): 2462–2471.


Yuan, Y., Wu, W., Chen, M., Cai, F., Fan, C., Shen, W., Sun, W., Hu, J. Reward inhibits paraventricular CRH neurons to relieve stress. Current Biology, 2019, 29(7): 1243–1251.e4.


Betley, J. N., Cao, Z. F., Ritola, K. D., Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell, 2013, 155(6): 1337–1350.


Atasoy, D., Betley, J. N., Su, H. H., Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature, 2012, 488(7410): 172–177.


Kuzmiski, J. B., Marty, V., Baimoukhametova, D. V., Bains, J. S. Stress-induced priming of glutamate synapses unmasks associative short-term plasticity. Nature Neuroscience, 2010, 13(10): 1257–1264.


Marty, V., Kuzmiski, J. B., Baimoukhametova, D. V., Bains, J. S. Short-term plasticity impacts information transfer at glutamate synapses onto parvocellular neuroendocrine cells in the paraventricular nucleus of the hypothalamus. The Journal of Physiology, 2011, 589(17): 4259–4270.


Miklós, I. H., Kovács, K. J. Reorganization of synaptic inputs to the hypothalamic paraventricular nucleus during chronic psychogenic stress in rats. Biological Psychiatry, 2012, 71(4): 301–308.


Huang, S. -T., Song, Z. -J., Liu, Y., Luo, W. -C., Yin, Q., Zhang, Y. -M. BNSTAV GABA-PVNCRF circuit regulates visceral hypersensitivity induced by maternal separation in Vgat-Cre mice. Frontiers in Pharmacology, 2021, 12(19): 615202.


Stoop, R. Neuromodulation by oxytocin and vasopressin in the central nervous system as a basis for their rapid behavioral effects. Current Opinion in Neurobiology, 2014, 29: 187–193.


Otero-García, M., Agustín-Pavón, C., Lanuza, E., Martínez-García, F. Distribution of oxytocin and co-localization with arginine vasopressin in the brain of mice. Brain Structure and Function, 2016, 221(7): 3445–3473.


Zhang, L., Hernández, V. S. Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei. Neuroscience, 2013, 228: 139–162.


Onaka, T., Takayanagi, Y., Yoshida, M. Roles of oxytocin neurones in the control of stress, energy metabolism, and social behaviour. Journal of Neuroendocrinology, 2012, 24(4): 587–598.


Zaninetti, M., Raggenbass, M. Oxytocin receptor agonists enhance inhibitory synaptic transmission in the rat hippocampus by activating interneurons in stratum pyramidale. The European Journal of Neuroscience, 2000, 12(11): 3975–3984.


Knobloch, H. S., Charlet, A., Hoffmann, L. C., Eliava, M., Khrulev, S., Cetin, A. H., Osten, P., Schwarz, M. K., Seeburg, P. H., Stoop, R. et al. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron, 2012, 73(3): 553–566.


Zhong, Y., Chen, C, Xu, W., Xu, P., Yang, M., Yang, F., Chen, A., Huang, Z. Vasopressin mediates anxiety-like behavior, glutamatergic neuron engages insomnia circuit in the paraventricular hypothalamic nucleus (PVH). Sleep Medicine, 2019, 64(Suppl 1): S441.


Liu, Y., Rao, B., Li, S., Zheng, N., Wang, J., Bi, L., Xu, H. Distinct hypothalamic paraventricular nucleus inputs to the cingulate cortex and paraventricular thalamic nucleus modulate anxiety and arousal. Frontiers in Pharmacology, 2022, 13: 814623.


Vale, W., Spiess, J., Rivier, C., Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Acta Neurochirurgica, 1981, 213(4514): 1394–1397.


Bale, T. L., Vale, W. W. CRF and CRF receptors: Role in stress responsivity and other behaviors. Annual Review of Pharmacology and Toxicology, 2004, 44: 525–557.


Hauger, R. L., Grigoriadis, D. E., Dallman, M. F., Plotsky, P. M., Vale, W. W., Dautzenberg, F. M. International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. eLife, 2003, 55(1): 21–26.


Valentino, R. J., Van Bockstaele, E. Convergent regulation of locus coeruleus activity as an adaptive response to stress. European Journal of Pharmacology, 2008, 583(2–3): 194–203.


Gunn, B. G., Cox, C. D., Chen, Y., Frotscher, M., Gall, C. M., Baram, T. Z., Lynch, G. The endogenous stress hormone CRH modulates excitatory transmission and network physiology in hippocampus. Cerebral Cortex, 2017, 27(8): 1–17.


Swanson, L. W., Sawchenko, P. E., Rivier, J., Vale, W. W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: An immunohistochemical study. Proceedings of the National Academy of Sciences of the United States of America, 1983, 36(3): 165–186.


Koob, G. F. A role for brain stress systems in addiction. Neuron, 2008, 59(1): 11–34.


Gunn, B. G., Sanchez, G. A., Lynch, G., Baram, T. Z., Chen, Y. C. Hyper-diversity of CRH interneurons in mouse hippocampus. Brain Structure and Function, 2019, 224(2): 583–598.


Aguilera, G., Liu, Y. The molecular physiology of CRH neurons. Front Neuroendocrinol, 2012, 33(1): 67–84.


Kim, J. S., Han, S. Y., Iremonger, K. J. Stress experience and hormone feedback tune distinct components of hypothalamic CRH neuron activity. Nature Communications, 2019, 10(1): 5696.


Herman, J. P., Tasker, J. G. Paraventricular hypothalamic mechanisms of chronic stress adaptation. Frontiers in Endocrinology, 2016, 7: 137.


Walther, C., Caetano, F. A., Dunn, H. A., Ferguson, S. S. PDZK1/NHERF3 differentially regulates corticotropin-releasing factor receptor 1 and serotonin 2A receptor signaling and endocytosis. Cellular Signalling, 2015, 27(3): 519–531.


Retson, T. A., Reyes, B. A., Van Bockstaele, E. J. Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2015, 56: 66–74.


Tsigos, C., Chrousos, G. P. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of Psychosomatic Research, 2002, 53(4): 865–871.


Koshimizu, T. A., Nakamura, K., Egashira, N., Hiroyama, M., Nonoguchi, H., Tanoue, A. Vasopressin V1a and V1b receptors: From molecules to physiological systems. Physiological Reviews, 2012, 92(4): 1813–1864.


Joëls, M., Baram, T. Z. The neuro-symphony of stress. Academic Pediatrics, 2009, 10(6): 459–466.


Frank, E., Landgraf, R. The vasopressin system—from antidiuresis to psychopathology. European Journal of Pharmacology, 2008, 583(2–3): 226–242.


Reppert, S. M., Artman, H. G., Swaminathan, S., Fisher, D. A. Vasopressin exhibits a rhythmic daily pattern in cerebrospinal fluid but not in blood. Reproductive Health, 1981, 213(4513): 1256–1257.


Laycock, J. F. Perspectives on Vasopressin. London: Imperial College Press, 2009.


Lake, D., Corrêa, S. A. L., Müller, J. NMDA receptor-dependent signalling pathways regulate arginine vasopressin expression in the paraventricular nucleus of the rat. Brain Research, 2019, 1722: 146357.


Fujiwara, Y., Tanoue, A., Tsujimoto, G., Koshimizu, T. A. The roles of V1a vasopressin receptors in blood pressure homeostasis: A review of studies on V1a receptor knockout mice. Clinical and Experimental Nephrology, 2012, 16(1): 30–34.


Hernando, F., Schoots, O., Lolait, S. J., Burbach, J. P. H. Immunohistochemical localization of the vasopressin V1b receptor in the rat brain and pituitary gland: Anatomical support for its involvement in the central effects of vasopressin. Endocrinology, 2001, 142(4): 1659–1668.


Bielsky, I. F., Hu, S. B., Szegda, K. L., Westphal, H., Young, L. J. Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology, 2004, 29(3): 483–493.


Egashira, N., Tanoue, A., Matsuda, T., Koushi, E., Harada, S., Takano, Y., Tsujimoto, G., Mishima, K., Iwasaki, K., Fujiwara, M. Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice. Behavioural Brain Research, 2007, 178(1): 123–127.


Angoa-Pérez, M., Kane, M. J., Briggs, D. I., Francescutti, D. M., Kuhn, D. M. Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. Journal of Visualized Experiments, 2013(82): 50978.


Egashira, N., Mishima, K., Iwasaki, K., Oishi, R., Fujiwara, M. New topics in vasopressin receptors and approach to novel drugs: Role of the vasopressin receptor in psychological and cognitive functions. Journal of Pharmacological Sciences, 2009, 109(1): 44–49.


Egashira, N., Tanoue, A., Higashihara, F., Fuchigami, H., Sano, K., Mishima, K., Fukue, Y., Nagai, H., Takano, Y., Tsujimoto, G. et al. Disruption of the prepulse inhibition of the startle reflex in vasopressin V1b receptor knockout mice: Reversal by antipsychotic drugs. Neuropsychopharmacology, 2005, 30(11): 1996–2005.


Wersinger, S. R., Ginns, E. I., O'Carroll, A. M., Lolait, S. J., Young, W. S. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol Psychiatry, 2002, 7(9): 975–984.


Surget, A., Belzung, C. Involvement of vasopressin in affective disorders. European Journal of Pharmacology, 2008, 583(2–3): 340–349.


Pinnock, S. B., Herbert, J. Corticosterone differentially modulates expression of corticotropin releasing factor and arginine vasopressin mRNA in the hypothalamic paraventricular nucleus following either acute or repeated restraint stress. The European Journal of Neuroscience, 2001, 13(3): 576–584.


Lightman, S. L. The neuroendocrinology of stress: A never ending story. Journal of Neuroendocrinology, 2008, 20(6): 880–884.


Vaidyanathan, R., Hammock, E. A. Oxytocin receptor dynamics in the brain across development and species. Developmental Neurobiology, 2017, 77(2): 143–157.


Pierce, M. L., French, J. A., Murray, T. F. Comparison of the pharmacological profiles of arginine vasopressin and oxytocin analogs at marmoset, macaque, and human vasopressin 1a receptor. Biomedicine & Pharmacotherapy, 2020, 126: 110060.


Herman, J. P., Flak, J., Jankord, R. Chronic stress plasticity in the hypothalamic paraventricular nucleus. Progress in Brain Research, 2008, 170: 353–364.


Veenema, A. H., Neumann, I. D. Central vasopressin and oxytocin release: Regulation of complex social behaviours. Progress in Brain Research, 2008, 170: 261–276.


Olff, M., Frijling, J. L., Kubzansky, L. D., Bradley, B., Ellenbogen, M. A., Cardoso, C., Bartz, J. A., Yee, J. R., van Zuiden, M. The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology, 2013, 38(9): 1883–1894.


Hoge, E. A., Pollack, M. H., Kaufman, R. E., Zak, P. J., Simon, N. M. Oxytocin levels in social anxiety disorder. CNS Neuroscience & Therapeutics, 2008, 14(3): 165–170.


Blume, A., Bosch, O. J., Miklos, S., Torner, L., Wales, L., Waldherr, M., Neumann, I. D. Oxytocin reduces anxiety via ERK1/2 activation: Local effect within the rat hypothalamic paraventricular nucleus. The European Journal of Neuroscience, 2008, 27(8): 1947–1956.


Smith, A. S., Tabbaa, M., Lei, K., Eastham, P., Butler, M. J., Linton, L., Altshuler, R., Liu, Y., Wang, Z. Local oxytocin tempers anxiety by activating GABAA receptors in the hypothalamic paraventricular nucleus. Psychoneuroendocrinology, 2016, 63: 50–58.


Chaviaras, S., Mak, P., Ralph, D., Krishnan, L., Broadbear, J. H. Assessing the antidepressant-like effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test. Psychopharmacology, 2010, 210(1): 35–43.


Petersson, M., Uvnäs-Moberg, K. Effects of an acute stressor on blood pressure and heart rate in rats pretreated with intracerebroventricular oxytocin injections. Psychoneuroendocrinology, 2007, 32(8–10): 959–965.


Zhang, Z., Boelen, A., Bisschop, P. H., Kalsbeek, A., Fliers, E. Hypothalamic effects of thyroid hormone. Molecular and Cellular Endocrinology, 2017, 458: 143–148.


Moog, N. K., Entringer, S., Heim, C., Wadhwa, P. D., Kathmann, N., Buss, C. Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience, 2017, 342: 68–100.


Valdés-Moreno, M. I., Alcántara-Alonso, V., Estrada-Camarena, E., Mengod, G., Amaya, M. I., Matamoros-Trejo, G., de Gortari, P. Phosphodiesterase-7 inhibition affects accumbal and hypothalamic thyrotropin-releasing hormone expression, feeding and anxiety behavior of rats. Behavioural Brain Research, 2017, 319: 165–173.


Vinogradova, E. P., Kargin, A. V., Zhukov, D. A., Markov, A. G. Intranasal application of a thyrotropin-releasing hormone attenuates state-anxiety of the rats. Zhurnal Vysshei Nervnoi Deiatelnosti Imeni I P Pavlova, 2014, 64(6): 660–667.


Stahl, C. E., Redei, E., Wang, Y., Borlongan, C. V. Behavioral, hormonal and histological stress markers of anxiety-separation in postnatal rats are reduced by prepro-thyrotropin-releasing hormone 178-199. Membranes, 2002, 321(1–2): 85–89.


Choi, J., Kim, J. E., Kim, T. K., Park, J. Y., Lee, J. E., Kim, H., Lee, E. H., Han, P. L. TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors. Neuropharmacology, 2015, 97: 346–356.


Zeng, H. K., Schimpf, B. A., Rohde, A. D., Pavlova, M. N., Gragerov, A., Bergmann, J. E. Thyrotropin-releasing hormone receptor 1-deficient mice display increased depression and anxiety-like behavior. Molecular Endocrinology, 2007, 21(11): 2795–2804.


Cleare, A., Pariante, C. M., Young, A. H., Anderson, I. M., Christmas, D., Cowen, P. J., Dickens, C., Ferrier, I. N., Geddes, J., Gilbody, S. et al. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. Journal of Psychopharmacology (Oxford, England), 2015, 29(5): 459–525.


Li, S. B., de Lecea, L. The hypocretin (orexin) system: From a neural circuitry perspective. Neuropharmacology, 2020, 167: 107993.


Johnson, P. L., Truitt, W., Fitz, S. D., Minick, P. E., Dietrich, A., Sanghani, S., Träskman-Bendz, L., Goddard, A. W., Brundin, L., Shekhar, A. A key role for orexin in panic anxiety. Nature Medicine, 2010, 16(1): 111–115.


Suzuki, M., Beuckmann, C. T., Shikata, K., Ogura, H., Sawai, T. Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior. Brain Research, 2005, 1044(1): 116–121.


Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Sakurai, T., Yanagisawa, M., Nakazato, M. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. PNAS, 1999, 96(2): 748–753.


Heydendael, W., Sengupta, A., Beck, S., Bhatnagar, S. Optogenetic examination identifies a context-specific role for orexins/hypocretins in anxiety-related behavior. Physiology & Behavior, 2014, 130: 182–190.


Heydendael, W., Sharma, K., Iyer, V., Luz, S., Piel, D., Beck, S., Bhatnagar, S. Orexins/hypocretins act in the posterior paraventricular thalamic nucleus during repeated stress to regulate facilitation to novel stress. ACS Applied Materials & Interfaces, 2011, 152(12): 4738–4752.


Li, Y. H., Li, S., Wei, C. G., Wang, H. Y., Sui, N., Kirouac, G. J. Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology, 2010, 212(2): 251–265.


Han, D., Shi, Y., Han, F. The effects of orexin-A and orexin receptors on anxiety- and depression-related behaviors in a male rat model of post-traumatic stress disorder. The Journal of Comparative Neurology, 2022, 530(3): 592–606.


Schroeder, M., Weller, A. Anxiety-like behavior and locomotion in CCK1 knockout rats as a function of strain, sex and early maternal environment. Behavioural Brain Research, 2010, 211(2): 198–207.


Daugé, V., Léna, I. CCK in anxiety and cognitive processes. Neuroscience and Biobehavioral Reviews, 1998, 22(6): 815–825.


Rex, A., Marsden, C. A., Fink, H. Cortical 5-HT-CCK interactions and anxiety-related behaviour of Guinea-pigs: A microdialysis study. Neuroscience Letters, 1997, 228(2): 79–82.


Li, H., Ohta, H., Izumi, H., Matsuda, Y., Seki, M., Toda, T., Akiyama, M., Matsushima, Y., Goto, Y., Kaga, M. et al. Behavioral and cortical EEG evaluations confirm the roles of both CCKA and CCKB receptors in mouse CCK-induced anxiety. Behavioural Brain Research, 2013, 237: 325–332.


Cohen, H., Kaplan, Z., Matar, M. A., Buriakovsky, I., Bourin, M., Kotler, M. Different pathways mediated by CCK1 and CCK2 receptors: Effect of intraperitonal mrna antisense oligodeoxynucleotides to cholecystokinin on anxiety-like and learning behaviors in rats. Depression and Anxiety, 2004, 20(3): 139–152.

Publication history
Rights and permissions

Publication history

Received: 02 September 2022
Revised: 14 September 2022
Accepted: 26 September 2022
Published: 26 October 2022
Issue date: September 2022


© The Author(s) 2022



We thank Prof. Xiao-Dong Wang from Zhejiang University School of Medicine for his critical reading of the manuscript. This work was supported by the UNAM-DGAPA-POSDOC program.

Rights and permissions

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attributtion-NonCommercial 4.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission.