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Sex differences in anxiety and depression: circuits and mechanisms

Nature Reviews Neuroscience volume 22, pages 674–684 (2021)Cite this article

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Abstract

Epidemiological sex differences in anxiety disorders and major depression are well characterized. Yet the circuits and mechanisms that contribute to these differences are understudied, because preclinical studies have historically excluded female rodents. This oversight is beginning to be addressed, and recent studies that include male and female rodents are identifying sex differences in neurobiological processes that underlie features of these disorders, including conflict anxiety, fear processing, arousal, social avoidance, learned helplessness and anhedonia. These findings allow us to conceptualize various types of sex differences in the brain, which in turn have broader implications for considering sex as a biological variable. Importantly, comparing the sexes could aid in the discovery of novel therapeutics.

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Fig. 1: Different types of sex differences in brain circuits.
Fig. 2: Sex-biased receptor signalling.
Fig. 3: Brain regions and circuits that bias male or female anxiety-like and/or depression-like behaviour.

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References

  1. Altemus, M., Sarvaiya, N. & Neill Epperson, C. Sex differences in anxiety and depression clinical perspectives. Front. Neuroendocrinol. 35, 320–330 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kessler, R. C., Petukhova, M., Sampson, N. A., Zaslavsky, A. M. & Wittchen, H. U. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int. J. Methods Psychiatr. Res. 21, 169–184 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  3. SAMHSA. National Survey on Drug Use and Health (NSDUH). US Department of Health & Human Services https://www.samhsa.gov/data/data-we-collect/nsduh-national-survey-drug-use-and-health (2018).

  4. Sramek, J. J., Murphy, M. F. & Cutler, N. R. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin. Neurosci. 18, 447–457 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kornstein, S. G. et al. Gender differences in chronic major and double depression. J. Affect. Disord. 60, 1–11 (2000).

    Article  PubMed  CAS  Google Scholar 

  6. Jalnapurkar, I., Allen, M. & Pigott, T. Sex differences in anxiety disorders: a review. J. Psychiatry Depress. Anxiety 4, 3–16 (2018).

    Google Scholar 

  7. Kornstein, S. G. et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am. J. Psychiatry 157, 1445–1452 (2000).

    Article  PubMed  CAS  Google Scholar 

  8. Marcus, S. M. et al. Gender differences in depression: findings from the STAR*D study. J. Affect. Disord. 87, 141–150 (2005).

    Article  PubMed  Google Scholar 

  9. Hildebrandt, M. G., Steyerberg, E. W., Stage, K. B., Passchier, J. & Kragh-Soerensen, P. Are gender differences important for the clinical effects of antidepressants? Am. J. Psychiatry 160, 1643–1650 (2003).

    Article  PubMed  Google Scholar 

  10. Quitkin, F. M. et al. Are there differences between women’s and men’s antidepressant responses? Am. J. Psychiatry 159, 1848–1854 (2002).

    Article  PubMed  Google Scholar 

  11. Monteggia, L. M., Heimer, H. & Nestler, E. J. Meeting report: can we make animal models of human mental illness? Biol. Psychiatry 84, 542–545 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gururajan, A., Reif, A., Cryan, J. F. & Slattery, D. A. The future of rodent models in depression research. Nat. Rev. Neurosci. 20, 686–701 (2019).

    Article  PubMed  CAS  Google Scholar 

  13. Beery, A. K. & Zucker, I. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35, 565–572 (2011).

    Article  PubMed  Google Scholar 

  14. Tannenbaum, C., Schwarz, J. M., Clayton, J. A., de Vries, G. J. & Sullivan, C. Evaluating sex as a biological variable in preclinical research: the devil in the details. Biol. Sex. Differ. 7, 13 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mamlouk, G. M., Dorris, D. M., Barrett, L. R. & Meitzen, J. Sex bias and omission in neuroscience research is influenced by research model and journal, but not reported NIH funding. Front. Neuroendocrinol. 57, 100835 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Becker, M., Pinhasov, A. & Ornoy, A. Animal models of depression: what can they teach us about the human disease? Diagnostics 11, 123 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Fernandes, C., González, M. I., Wilson, C. A. & File, S. E. Factor analysis shows that female rat behaviour is characterized primarily by activity, male rats are driven by sex and anxiety. Pharmacol. Biochem. Behav. 64, 731–736 (1999).

    Article  PubMed  CAS  Google Scholar 

  18. Riboni, F. V. & Belzung, C. Stress and psychiatric disorders: from categorical to dimensional approaches. Curr. Opin. Behav. Sci. 14, 72–77 (2017).

    Article  Google Scholar 

  19. Melchior, M. et al. Work stress precipitates depression and anxiety in young, working women and men. Psychol. Med. 37, 1119–1129 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Newman, S. C. & Bland, R. C. Life events and the 1-year prevalence of major depressive episode, generalized anxiety disorder, and panic disorder in a community sample. Compr. Psychiatry 35, 76–82 (1994).

    Article  PubMed  CAS  Google Scholar 

  21. Hodes, G. E. & Epperson, C. N. Sex differences in vulnerability and resilience to stress across the life span. Biol. Psychiatry 86, 421–432 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kokras, N., Hodes, G. E., Bangasser, D. A. & Dalla, C. Sex differences in the hypothalamic–pituitary–adrenal axis: an obstacle to antidepressant drug development? Br. J. Pharmacol. 176, 4090–4106 (2019). This review synthesizes details of how antidepressants developed only in male rodents fail clinical testing when females are included in the trials.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Bath, K. G. Synthesizing views to understand sex differences in response to early life adversity. Trends Neurosci. 43, 300–310 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Mauvais-Jarvis, F. et al. Sex and gender: modifiers of health, disease, and medicine. Lancet 396, 565–582 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  25. McCarthy, M. M. Multifaceted origins of sex differences in the brain. Phil. Trans. R. Soc. B 371, 20150106 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Maney, D. L. Perils and pitfalls of reporting sex differences. Phil. Trans. R. Soc. B 371, 20150119 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  27. McCarthy, M. M., Arnold, A. P., Ball, G. F., Blaustein, J. D. & De Vries, G. J. Sex differences in the brain: the not so inconvenient truth. J. Neurosci. 32, 2241–2247 (2012). This paper is a great primer on how to study sex differences.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Becker, J. B. & Koob, G. F. Sex differences in animal models: focus on addiction. Pharmacol. Rev. 68, 242–263 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. De Vries, G. J. Minireview: sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145, 1063–1068 (2004).

    Article  PubMed  CAS  Google Scholar 

  30. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 5th edn Vol. 5 (American Psychiatric Publishing, 2013).

  31. Ottenbreit, N. D. & Dobson, K. S. Avoidance and depression: the construction of the cognitive–behavioral avoidance scale. Behav. Res. Ther. 42, 293–313 (2004).

    Article  PubMed  Google Scholar 

  32. Orr, S. P. et al. De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. J. Abnorm. Psychol. 109, 290–298 (2000).

    Article  PubMed  CAS  Google Scholar 

  33. Milad, M. R. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Donner, N. C. & Lowry, C. A. Sex differences in anxiety and emotional behavior. Pflügers Arch. Eur. J. Physiol. 465, 601–626 (2013).

    Article  CAS  Google Scholar 

  35. Frye, C. A., Petralia, S. M. & Rhodes, M. E. Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP. Pharmacol. Biochem. Behav. 67, 587–596 (2000).

    Article  PubMed  CAS  Google Scholar 

  36. Johnston, A. L. & File, S. E. Sex differences in animal tests of anxiety. Physiol. Behav. 49, 245–250 (1991).

    Article  PubMed  CAS  Google Scholar 

  37. Miller, S. M., Piasecki, C. C. & Lonstein, J. S. Use of the light–dark box to compare the anxiety-related behavior of virgin and postpartum female rats. Pharmacol. Biochem. Behav. 100, 130–137 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Li, K., Nakajima, M., Ibanez-Tallon, I. & Heintz, N. A cortical circuit for sexually dimorphic oxytocin-dependent anxiety behaviors. Cell 167, 60–72.e11 (2016). This paper identifies a population of neurons in the PFC that mediate social behaviour in females and anxiety-like behaviour in males.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Bredewold, R., Smith, C. J., Dumais, K. M. & Veenema, A. H. Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context. Front. Behav. Neurosci. 8, 216 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. de Vries, G. J. in Progress in Brain Research Vol. 170 (eds Neumann Inga, D. & Rainer, L.) 17–27 (Elsevier, 2008).

  41. Rigney, N., Whylings, J., de Vries, G. J. & Petrulis, A. Sex differences in the control of social investigation and anxiety by vasopressin cells of the paraventricular nucleus of the hypothalamus. Neuroendocrinology 111, 521–535 (2021).

    Article  PubMed  CAS  Google Scholar 

  42. Nakajima, M., Gorlich, A. & Heintz, N. Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons. Cell 159, 295–305 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Westphal, N. J. & Seasholtz, A. F. CRH-BP: the regulation and function of a phylogenetically conserved binding protein. Front. Biosci. 11, 1878–1891 (2006).

    Article  PubMed  CAS  Google Scholar 

  44. Van Den Eede, F., Van Broeckhoven, C. & Claes, S. J. Corticotropin-releasing factor-binding protein, stress and major depression. Ageing Res. Rev. 4, 213–239 (2005).

    Article  CAS  Google Scholar 

  45. Jovanovic, T. & Norrholm, S. D. Neural mechanisms of impaired fear inhibition in posttraumatic stress disorder. Front. Behav. Neurosci. 5, 44 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Helpman, L. et al. Neural changes in extinction recall following prolonged exposure treatment for PTSD: a longitudinal fMRI study. NeuroImage Clin. 12, 715–723 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hofmann, S. G. Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clin. Psychol. Rev. 28, 199–210 (2008).

    Article  PubMed  Google Scholar 

  48. Shansky, R. M. Sex differences in PTSD resilience and susceptibility: challenges for animal models of fear learning. Neurobiol. Stress 1, 60–65 (2015).

    Article  PubMed  Google Scholar 

  49. Keiser, A. A. et al. Sex differences in context fear generalization and recruitment of hippocampus and amygdala during retrieval. Neuropsychopharmacology 42, 397–407 (2017).

    Article  PubMed  Google Scholar 

  50. Ramikie, T. S. & Ressler, K. J. Mechanisms of sex differences in fear and posttraumatic stress disorder. Biol. Psychiatry 83, 876–885 (2018).

    Article  PubMed  Google Scholar 

  51. Herry, C. & Johansen, J. P. Encoding of fear learning and memory in distributed neuronal circuits. Nat. Neurosci. 17, 1644–1654 (2014).

    Article  PubMed  CAS  Google Scholar 

  52. Duvarci, S. & Pare, D. Amygdala microcircuits controlling learned fear. Neuron 82, 966–980 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Lopez-Larson, M. P., Anderson, J. S., Ferguson, M. A. & Yurgelun-Todd, D. Local brain connectivity and associations with gender and age. Dev. Cognit. Neurosci. 1, 187–197 (2011).

    Article  Google Scholar 

  54. Cahill, L., Uncapher, M., Kilpatrick, L., Alkire, M. T. & Turner, J. Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an fMRI investigation. Learn. Mem. 11, 261–266 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Colom-Lapetina, J., Li, A. J., Pelegrina-Perez, T. C. & Shansky, R. M. Behavioral diversity across classic rodent models is sex-dependent. Front. Behav. Neurosci. 13, 45 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Gruene, T. M., Flick, K., Stefano, A., Shea, S. D. & Shansky, R. M. Sexually divergent expression of active and passive conditioned fear responses in rats. eLife 4, e11352 (2015). This study demonstrates a sex difference in freezing responses that has implications for interpreting fear conditioning studies in rats.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bangasser, D. To freeze or not to freeze. eLife 4, e13119 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kokras, N. & Dalla, C. Sex differences in animal models of psychiatric disorders. Br. J. Pharmacol. 171, 4595–4619 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Morena, M. et al. Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats. Br. J. Pharmacol. 178, 983–996 (2021).

    Article  PubMed  CAS  Google Scholar 

  60. Zygmunt, P. M. et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457 (1999).

    Article  PubMed  CAS  Google Scholar 

  61. Gunduz-Cinar, O. et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol. Psychiatry 18, 813–823 (2013).

    Article  PubMed  CAS  Google Scholar 

  62. Llorente-Berzal, A. et al. 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons. Psychopharmacology 232, 2811–2825 (2015).

    Article  PubMed  CAS  Google Scholar 

  63. Neumeister, A. et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol. Psychiatry 18, 1034–1040 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Lebron-Milad, K. & Milad, M. R. Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders. Biol. Mood Anxiety Disord. 2, 3 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Milad, M. R., Igoe, S. A., Lebron-Milad, K. & Novales, J. E. Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 164, 887–895 (2009).

    Article  PubMed  CAS  Google Scholar 

  66. Baran, S. E., Armstrong, C. E., Niren, D. C., Hanna, J. J. & Conrad, C. D. Chronic stress and sex differences on the recall of fear conditioning and extinction. Neurobiol. Learn. Mem. 91, 323–332 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hwang, M. J. et al. Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction. BMC Psychiatry 15, 295 (2015). This paper demonstrates a role for ovarian hormones in regulating fear extinction.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Rey, C. D., Lipps, J. & Shansky, R. M. Dopamine D1 receptor activation rescues extinction impairments in low-estrogen female rats and induces cortical layer-specific activation changes in prefrontal–amygdala circuits. Neuropsychopharmacology 39, 1282–1289 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Shansky, R. M. Are hormones a “female problem” for animal research? Science 364, 825–826 (2019).

    Article  PubMed  CAS  Google Scholar 

  70. Peters, L., Issakidis, C., Slade, T. I. M. & Andrews, G. Gender differences in the prevalence of DSM-IV and ICD-10 PTSD. Psychol. Med. 36, 81–89 (2005).

    Article  Google Scholar 

  71. Plante, D. T. et al. Sex-related differences in sleep slow wave activity in major depressive disorder: a high-density EEG investigation. BMC Psychiatry 12, 146 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kobayashi, I. & Mellman, T. A. Gender differences in sleep during the aftermath of trauma and the development of posttraumatic stress disorder. Behav. Sleep Med. 10, 180–190 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Murphy, S., Elklit, A., Chen, Y. Y., Ghazali, S. R. & Shevlin, M. Sex differences in PTSD symptoms: a differential item functioning approach. Psychol. Trauma 11, 319–327 (2019).

    Article  PubMed  Google Scholar 

  74. Nolen-Hoeksema, S., Larson, J. & Grayson, C. Explaining the gender difference in depressive symptoms. J. Pers. Soc. Psychol. 77, 1061–1072 (1999).

    Article  PubMed  CAS  Google Scholar 

  75. Nemeroff, C. B., Bissette, G., Akil, H. & Fink, M. Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, β-endorphin and somatostatin. Br. J. Psychiatry 158, 59–63 (1991).

    Article  PubMed  CAS  Google Scholar 

  76. Heuser, I. et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress. Anxiety 8, 71–79 (1998).

    Article  PubMed  CAS  Google Scholar 

  77. Bremner, J. D. et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am. J. Psychiatry 154, 624–629 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Baker, D. G. et al. Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder. Am. J. Psychiatry 162, 992–994 (2005).

    Article  PubMed  Google Scholar 

  79. Wang, S. S., Kamphuis, W., Huitinga, I., Zhou, J. N. & Swaab, D. F. Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: the presence of multiple receptor imbalances. Mol. Psychiatry 13, 786–799 (2008).

    Article  PubMed  CAS  Google Scholar 

  80. Valentino, R. J. & Van Bockstaele, E. J. in Hormones, Brain and Behavior Vol. 4 (eds Arnold, A. et al.) 81–102 (Academic, 2002).

  81. Valentino, R. J., Foote, S. L. & Page, M. E. The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses. Ann. N. Y. Acad. Sci. 697, 173–188 (1993).

    Article  PubMed  CAS  Google Scholar 

  82. Szabadi, E. Functional neuroanatomy of the central noradrenergic system. J. Psychopharmacol. 27, 659–693 (2013).

    Article  PubMed  CAS  Google Scholar 

  83. Aston-Jones, G. in The Rat Nervous System 3rd edn 259–294 (Academic, 2004).

  84. Berridge, C. W. & Waterhouse, B. D. The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res. Brain Res. Rev. 42, 33–84 (2003).

    Article  PubMed  Google Scholar 

  85. Berridge, C. W., Page, M. E., Valentino, R. J. & Foote, S. L. Effects of locus coeruleus inactivation on electroencephalographic activity in neocortex and hippocampus. Neuroscience 55, 381–383 (1993).

    Article  PubMed  CAS  Google Scholar 

  86. Page, M. E., Berridge, C. W., Foote, S. L. & Valentino, R. J. Corticotropin-releasing factor in the locus coeruleus mediates EEG activation associated with hypotensive stress. Neurosci. Lett. 164, 81–84 (1993).

    Article  PubMed  CAS  Google Scholar 

  87. Curtis, A. L., Grigoriadis, D. E., Page, M. E., Rivier, J. & Valentino, R. J. Pharmacological comparison of two corticotropin-releasing factor antagonists: in vivo and in vitro studies. J. Pharmacol. Exp. Ther. 268, 359–365 (1994).

    PubMed  CAS  Google Scholar 

  88. Curtis, A. L., Lechner, S. M., Pavcovich, L. A. & Valentino, R. J. Activation of the locus coeruleus noradrenergic system by intracoerulear microinfusion of corticotropin-releasing factor: effects on discharge rate, cortical norepinephrine levels and cortical electroencephalographic activity. J. Pharmacol. Exp. Ther. 281, 163–172 (1997).

    PubMed  CAS  Google Scholar 

  89. Lechner, S. M., Curtis, A. L., Brons, R. & Valentino, R. J. Locus coeruleus activation by colon distention: role of corticotropin-releasing factor and excitatory amino acids. Brain Res. 756, 114–124 (1997).

    Article  PubMed  CAS  Google Scholar 

  90. Valentino, R. J., Curtis, A. L., Page, M. E., Pavcovich, L. A. & Florin-Lechner, S. M. Activation of the locus ceruleus brain noradrenergic system during stress: circuitry, consequences, and regulation. Adv. Pharmacol. 42, 781–784 (1998).

    Article  PubMed  CAS  Google Scholar 

  91. Curtis, A. L., Bethea, T. & Valentino, R. J. Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 31, 544–554 (2006).

    Article  PubMed  CAS  Google Scholar 

  92. Bangasser, D. A. et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol. Psychiatry 15, 896–904 (2010). This paper finds that a receptor that mediates a stress neuropeptide signals differently in males versus females.

    Article  CAS  Google Scholar 

  93. Valentino, R. J., Page, M. E. & Curtis, A. L. Activation of noradrenergic locus coeruleus neurons by hemodynamic stress is due to local release of corticotropin-releasing factor. Brain Res. 555, 25–34 (1991).

    Article  PubMed  CAS  Google Scholar 

  94. Jedema, H. P. & Grace, A. A. Corticotropin-releasing hormone directly activates noradrenergic neurons of the locus ceruleus recorded in vitro. J. Neurosci. 24, 9703–9713 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Stenzel-Poore, M. P., Heinrichs, S. C., Rivest, S., Koob, G. F. & Vale, W. W. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J. Neurosci. 14, 2579–2584 (1994).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Bangasser, D. A. et al. Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer’s disease-related signaling. Mol. Psychiatry 22, 1126–1133 (2017).

    Article  PubMed  CAS  Google Scholar 

  97. Violin, J. D. & Lefkowitz, R. J. β-Arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28, 416–422 (2007).

    Article  PubMed  CAS  Google Scholar 

  98. Lefkowitz, R. J. & Shenoy, S. K. Transduction of receptor signals by β-arrestins. Science 308, 512–517 (2005).

    Article  PubMed  CAS  Google Scholar 

  99. Valentino, R. J. & Bangasser, D. A. Sex-biased cellular signaling: molecular basis for sex differences in neuropsychiatric diseases. Dialogues Clin. Neurosci. 18, 385–393 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Valentino, R. J., Bangasser, D. & Van Bockstaele, E. J. Sex-biased stress signaling: the corticotropin-releasing factor receptor as a model. Mol. Pharmacol. 83, 737–745 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Bangasser, D. A., Eck, S. R., Telenson, A. M. & Salvatore, M. Sex differences in stress regulation of arousal and cognition. Physiol. Behav. 187, 42–50 (2018).

    Article  PubMed  CAS  Google Scholar 

  102. Krupnick, J. G. & Benovic, J. L. The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annu. Rev. Pharmacol. Toxicol. 38, 289–319 (1998).

    Article  PubMed  CAS  Google Scholar 

  103. Reyes, B. A., Valentino, R. J. & Van Bockstaele, E. J. Stress-induced intracellular trafficking of corticotropin-releasing factor receptors in rat locus coeruleus neurons. Endocrinology 149, 122–130 (2008).

    Article  PubMed  CAS  Google Scholar 

  104. Bangasser, D. A. et al. Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression. Mol. Psychiatry 18, 166–173 (2013).

    Article  PubMed  CAS  Google Scholar 

  105. Murrough, J. W. & Charney, D. S. Corticotropin-releasing factor type 1 receptor antagonists for stress-related disorders: time to call it quits? Biol. Psychiatry 82, 858–860 (2017).

    Article  PubMed  Google Scholar 

  106. Ising, M. et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology 32, 1941–1949 (2007).

    Article  PubMed  CAS  Google Scholar 

  107. Valentino, R. J., Van Bockstaele, E. & Bangasser, D. Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends Pharmacol. Sci. 34, 437–444 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17, 243–260 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Seidel, E.-M. et al. Implicit and explicit behavioral tendencies in male and female depression. Psychiatry Res. 177, 124–130 (2010).

    Article  PubMed  Google Scholar 

  110. Asher, M., Asnaani, A. & Aderka, I. M. Gender differences in social anxiety disorder: a review. Clin. Psychol. Rev. 56, 1–12 (2017).

    Article  PubMed  Google Scholar 

  111. Heimberg, R. G. Social Phobia: Diagnosis, Assessment, and Treatment (Guilford Press, 1995).

  112. Newman, E. L. et al. Fighting females: neural and behavioral consequences of social defeat stress in female mice. Biol. Psychiatry 86, 657–668 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Silva, A. L., Fry, W. H. D., Sweeney, C. & Trainor, B. C. Effects of photoperiod and experience on aggressive behavior in female California mice. Behav. Brain Res. 208, 528–534 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Trainor, B. C. et al. Sex differences in stress-induced social withdrawal: independence from adult gonadal hormones and inhibition of female phenotype by corncob bedding. Horm. Behav. 63, 543–550 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Beery, A. K. Antisocial oxytocin: complex effects on social behavior. Curr. Opin. Behav. Sci. 6, 174–182 (2015).

    Article  Google Scholar 

  116. Shamay-Tsoory, S. G. & Abu-Akel, A. The social salience hypothesis of oxytocin. Biol. Psychiatry 79, 194–202 (2016).

    Article  PubMed  CAS  Google Scholar 

  117. Steinman, M. Q. et al. Sex-specific effects of stress on oxytocin neurons correspond with responses to intranasal oxytocin. Biol. Psychiatry 80, 406–414 (2016).

    Article  PubMed  CAS  Google Scholar 

  118. Duque-Wilckens, N. et al. Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance. Proc. Natl Acad. Sci. USA 117, 26406–26413 (2020). This paper demonstrates that oxytocin synthesis within the BNST is necessary for stress-induced disruptions in social approach and vigilance.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Duque-Wilckens, N. et al. Oxytocin receptors in the anteromedial bed nucleus of the stria terminalis promote stress-induced social avoidance in female california mice. Biol. Psychiatry 83, 203–213 (2018).

    Article  PubMed  CAS  Google Scholar 

  120. Lukas, M. et al. The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology 36, 2159–2168 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Kubzansky, L. D., Mendes, W. B., Appleton, A. A., Block, J. & Adler, G. K. A heartfelt response: oxytocin effects on response to social stress in men and women. Biol. Psychol. 90, 1–9 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Holt-Lunstad, J., Birmingham, W. & Light, K. C. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrinology 36, 1249–1256 (2011).

    Article  PubMed  CAS  Google Scholar 

  123. Cyranowski, J. M. et al. Evidence of dysregulated peripheral oxytocin release among depressed women. Psychosom. Med. 70, 967–975 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Maier, S. F. & Seligman, M. E. P. Learned helplessness at fifty: insights from neuroscience. Psychol. Rev. 123, 349–367 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Maier, S. F. & Watkins, L. R. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci. Biobehav. Rev. 29, 829–841 (2005).

    Article  PubMed  CAS  Google Scholar 

  126. Maier, S. F. Behavioral control blunts reactions to contemporaneous and future adverse events: medial prefrontal cortex plasticity and a corticostriatal network. Neurobiol. Stress. 1, 12–22 (2015).

    Article  PubMed  Google Scholar 

  127. Dalla, C., Edgecomb, C., Whetstone, A. S. & Shors, T. J. Females do not express learned helplessness like males do. Neuropsychopharmacology 33, 1559–1569 (2008).

    Article  PubMed  Google Scholar 

  128. Baratta, M. V. et al. Controllable stress elicits circuit-specific patterns of prefrontal plasticity in males, but not females. Brain Struct. Funct. 224, 1831–1843 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Baratta, M. V. et al. Behavioural and neural sequelae of stressor exposure are not modulated by controllability in females. Eur. J. Neurosci. 47, 959–967 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Whitton, A. E., Treadway, M. T. & Pizzagalli, D. A. Reward processing dysfunction in major depression, bipolar disorder and schizophrenia. Curr. Opin. Psychiatry 28, 7–12 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Treadway, M. T. & Zald, D. H. Parsing anhedonia: translational models of reward-processing deficits in psychopathology. Curr. Dir. Psychol. Sci. 22, 244–249 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Francis, T. C. & Lobo, M. K. Emerging role for nucleus accumbens medium spiny neuron subtypes in depression. Biol. Psychiatry 81, 645–653 (2017).

    Article  PubMed  CAS  Google Scholar 

  133. Wacker, J., Dillon, D. G. & Pizzagalli, D. A. The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques. NeuroImage 46, 327–337 (2009).

    Article  PubMed  Google Scholar 

  134. Hodes, G. E. et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J. Neurosci. 35, 16362–16376 (2015). This paper identifies an epigenetic change that contributes to female vulnerability to chronic stressor exposure.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Williams, E. S. et al. Androgen-dependent excitability of mouse ventral hippocampal afferents to nucleus accumbens underlies sex-specific susceptibility to stress. Biol. Psychiatry 87, 492–501 (2020). This paper delineates a circuit that underlies female vulnerability to stress-induced anhedonia and links male resilience to androgens.

    Article  PubMed  CAS  Google Scholar 

  136. Labonté, B. et al. Sex-specific transcriptional signatures in human depression. Nat. Med. 23, 1102–1111 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Rincón-Cortés, M. & Grace, A. A. Sex-dependent effects of stress on immobility behavior and VTA dopamine neuron activity: modulation by ketamine. Int. J. Neuropsychopharmacol. 20, 823–832 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Holly, E. N., Shimamoto, A., Debold, J. F. & Miczek, K. A. Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats. Psychopharmacology 224, 179–188 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Dalla, C. et al. Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission. Physiol. Behav. 93, 595–605 (2008).

    Article  PubMed  CAS  Google Scholar 

  140. Brancato, A. et al. Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Neuroscience 350, 180–189 (2017).

    Article  PubMed  CAS  Google Scholar 

  141. Muir, J. et al. Ventral hippocampal afferents to nucleus accumbens encode both latent vulnerability and stress-induced susceptibility. Biol. Psychiatry 88, 843–854 (2020).

    Article  PubMed  Google Scholar 

  142. Shansky, R. M. & Murphy, A. Z. Considering sex as a biological variable will require a global shift in science culture. Nat. Neurosci. 24, 457–464 (2021).

    Article  PubMed  CAS  Google Scholar 

  143. Campbell, E. J. & Marchant, N. J. The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats. Br. J. Pharmacol. 175, 994–1003 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Spiller, C., Koopman, P. & Bowles, J. Sex determination in the mammalian germline. Annu. Rev. Genet. 51, 265–285 (2017).

    Article  PubMed  CAS  Google Scholar 

  145. Disteche, C. M. Dosage compensation of the sex chromosomes and autosomes. Semin. Cell Dev. Biol. 56, 9–18 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Migeon, B. R. The role of X inactivation and cellular mosaicism in women’s health and sex-specific diseases. JAMA 295, 1428–1433 (2006).

    Article  PubMed  CAS  Google Scholar 

  148. Corre, C. et al. Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model. Brain Struct. Funct. 221, 997–1016 (2016).

    Article  PubMed  CAS  Google Scholar 

  149. Vousden, D. A. et al. Impact of X/Y genes and sex hormones on mouse neuroanatomy. NeuroImage 173, 551–563 (2018).

    Article  PubMed  CAS  Google Scholar 

  150. Seney, M. L., Ekong, K. I., Ding, Y., Tseng, G. C. & Sibille, E. Sex chromosome complement regulates expression of mood-related genes. Biol. Sex. Differ. 4, 20 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Morris, J. A., Jordan, C. L. & Breedlove, S. M. Sexual differentiation of the vertebrate nervous system. Nat. Neurosci. 7, 1034–1039 (2004).

    Article  PubMed  CAS  Google Scholar 

  152. Schulz, K. M., Molenda-Figueira, H. A. & Sisk, C. L. Back to the future: the organizational–activational hypothesis adapted to puberty and adolescence. Horm. Behav. 55, 597–604 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Jain, A., Huang, G. Z. & Woolley, C. S. Latent sex differences in molecular signaling that underlies excitatory synaptic potentiation in the hippocampus. J. Neurosci. 39, 1552–1565 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  154. Paelecke-Habermann, Y., Pohl, J. & Leplow, B. Attention and executive functions in remitted major depression patients. J. Affect. Disord. 89, 125–135 (2005).

    Article  PubMed  Google Scholar 

  155. Eck, S. R. et al. Stress regulation of sustained attention and the cholinergic attention system. Biol. Psychiatry 88, 566–575 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Seney, M. L. et al. Opposite molecular signatures of depression in men and women. Biol. Psychiatry 84, 18–27 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Seney, M. L., Glausier, J. & Sibille, E. Large-scale transcriptomics studies provide insight into sex differences in depression. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2020.12.025 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Bollinger, J. L., Bergeon Burns, C. M. & Wellman, C. L. Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav. Immun. 52, 88–97 (2016).

    Article  PubMed  CAS  Google Scholar 

  159. Torres-Platas, S. G., Cruceanu, C., Chen, G. G., Turecki, G. & Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. 42, 50–59 (2014).

    Article  PubMed  CAS  Google Scholar 

  160. Kang, H. J. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat. Med. 18, 1413–1417 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Garrett, J. E. & Wellman, C. L. Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience 162, 195–207 (2009).

    Article  PubMed  CAS  Google Scholar 

  162. Baratta, M. V. et al. Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear. Neuroscience 146, 1495–1503 (2007).

    Article  PubMed  CAS  Google Scholar 

  163. Christianson, J. P. et al. The role of prior stressor controllability and the dorsal raphé nucleus in sucrose preference and social exploration. Behav. Brain Res. 193, 87–93 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Amat, J., Paul, E., Zarza, C., Watkins, L. R. & Maier, S. F. Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J. Neurosci. 26, 13264–13272 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Valentino, R. J., Reyes, B., Van Bockstaele, E. & Bangasser, D. Molecular and cellular sex differences at the intersection of stress and arousal. Neuropharmacology 62, 13–20 (2012).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by National Science Foundation (NSF) CAREER grant IOS-1552416 (D.A.B.), NSF grant IOS-1929829 (D.A.B.) and US National Institutes of Health (NIH) DA049837 (D.A.B. with supplement to A.C.).

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    Debra A. Bangasser & Amelia Cuarenta

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Glossary

Anhedonia

A loss of or inability to feel pleasure.

Dioestrus

A period of the oestrous cycle immediately preceding pro-oestrus in which female subjects are not sexually receptive and there are relatively low levels of oestrogens and progesterone.

Extinction

A weakening of a conditioned response that yields a decrease in behaviour.

Monetary incentive delay task

An imaging paradigm used to study the neural activity of anticipatory incentive processing.

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Bangasser, D.A., Cuarenta, A. Sex differences in anxiety and depression: circuits and mechanisms. Nat Rev Neurosci 22, 674–684 (2021). https://doi.org/10.1038/s41583-021-00513-0

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