Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Resolving the neural circuits of anxiety

Abstract

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Few new pharmacotherapies for the treatment of anxiety have been developed since the 1940s.
Figure 2: Validated tests to assay anxiety and related emotional states in mice.
Figure 3: Neural circuits implicated in anxiety-related behaviors in the rodent brain.
Figure 4: Circuit organization in anxiety: a problem with interpretation.

Similar content being viewed by others

References

  1. Hull, C.L. Principles of Behavior: An Introduction to Behavior Theory (Appleton-Century-Crofts, 1943).

  2. Darwin, C. The Expression of the Emotions in Man and Animals (Impression anastalitique Culture et Civilisation, 1872).

  3. LeDoux, J. Rethinking the emotional brain. Neuron 73, 653–676 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Panksepp, J. Affective consciousness: core emotional feelings in animals and humans. Conscious. Cogn. 14, 30–80 (2005).

    Article  PubMed  Google Scholar 

  5. Anderson, D.J. & Adolphs, R. A framework for studying emotions across species. Cell 157, 187–200 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Russell, J.A. A circumplex model of affect. J. Pers. Soc. Psychol. 39, 1161–1178 (1980).

    Article  Google Scholar 

  7. Davis, M., Walker, D.L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010).

    Article  PubMed  Google Scholar 

  8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn., http://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596 (American Psychiatric Association, 2013).

  9. Bereza, B.G., Machado, M. & Einarson, T.R. Systematic review and quality assessment of economic evaluations and quality-of-life studies related to generalized anxiety disorder. Clin. Ther. 31, 1279–1308 (2009).

    Article  PubMed  Google Scholar 

  10. Mondin, T.C. et al. Anxiety disorders in young people: a population-based study. Rev. Bras. Psiquiatr. 35, 347–352 (2013).

    Article  PubMed  Google Scholar 

  11. Pagotto, L.F. et al. The impact of posttraumatic symptoms and comorbid mental disorders on the health-related quality of life in treatment-seeking PTSD patients. Compr. Psychiatry 58, 68–73 (2015).

    Article  PubMed  Google Scholar 

  12. Kessler, R.C., Chiu, W.T., Demler, O., Merikangas, K.R. & Walters, E.E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kessler, R.C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Article  PubMed  Google Scholar 

  14. Lecrubier, Y. Widespread underrecognition and undertreatment of anxiety and mood disorders: results from 3 European studies. J. Clin. Psychiatry 68 (suppl. 2): 36–41 (2007).

    PubMed  Google Scholar 

  15. Berlin, H.A., Hamilton, H. & Hollander, E. Experimental therapeutics for refractory obsessive-compulsive disorder: translational approaches and new somatic developments. Mt. Sinai J. Med. 75, 174–203 (2008).

    Article  PubMed  Google Scholar 

  16. Davidson, J.R. et al. A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J. Psychopharmacol. 24, 3–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Hoffman, E.J. & Mathew, S.J. Anxiety disorders: a comprehensive review of pharmacotherapies. Mt. Sinai J. Med. 75, 248–262 (2008).

    Article  PubMed  Google Scholar 

  18. Kinch, M.S., Haynesworth, A., Kinch, S.L. & Hoyer, D. An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

  20. Tye, K.M. Neural circuit reprogramming: a new paradigm for treating neuropsychiatric disease? Neuron 83, 1259–1261 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Allsop, S.A., Vander Weele, C.M., Wichmann, R. & Tye, K.M. Optogenetic insights on the relationship between anxiety-related behaviors and social deficits. Front. Behav. Neurosci. 8, 241 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Belzung, C. & Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res. 125, 141–149 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Cryan, J.F. & Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4, 775–790 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Sylvers, P., Lilienfeld, S.O. & LaPrairie, J.L. Differences between trait fear and trait anxiety: implications for psychopathology. Clin. Psychol. Rev. 31, 122–137 (2011).

    Article  PubMed  Google Scholar 

  25. Lister, R.G. Ethologically-based animal models of anxiety disorders. Pharmacol. Ther. 46, 321–340 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Adhikari, A. Distributed circuits underlying anxiety. Front. Behav. Neurosci. 8, 112 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Degroot, A. & Treit, D. Anxiety is functionally segregated within the septo-hippocampal system. Brain Res. 1001, 60–71 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Eden, A.S. et al. Emotion regulation and trait anxiety are predicted by the microstructure of fibers between amygdala and prefrontal cortex. J. Neurosci. 35, 6020–6027 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Etkin, A., Prater, K.E., Schatzberg, A.F., Menon, V. & Greicius, M.D. Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder. Arch. Gen. Psychiatry 66, 1361–1372 (2009).

    Article  PubMed  Google Scholar 

  30. Irle, E. et al. Reduced amygdalar and hippocampal size in adults with generalized social phobia. J. Psychiatry Neurosci. 35, 126–131 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kim, S.-Y. et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature 496, 219–223 (2013). First study to provide causal evidence that separate circuits control the behavioral and physiological features of anxiety.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Likhtik, E., Stujenske, J.M., Topiwala, M.A., Harris, A.Z. & Gordon, J.A. Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat. Neurosci. 17, 106–113 (2014). Identifies a macrocircuit-level mechanism to discern safety from threat, whereby BLA firing is tuned to mPFC oscillatory activity.

    Article  CAS  PubMed  Google Scholar 

  33. Tye, K.M. et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471, 358–362 (2011). Original optogenetic dissection of the control of anxiety by separate aspects of the BLA microcircuit and first study to employ projection-specific optogenetic manipulations of behavior.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yassa, M.A., Hazlett, R.L., Stark, C.E.L. & Hoehn-Saric, R. Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder. J. Psychiatr. Res. 46, 1045–1052 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Pellow, S., Chopin, P., File, S.E. & Briley, M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Methods 14, 149–167 (1985).

    Article  CAS  PubMed  Google Scholar 

  36. Shepherd, J.K., Grewal, S.S., Fletcher, A., Bill, D.J. & Dourish, C.T. Behavioural and pharmacological characterisation of the elevated 'zero-maze' as an animal model of anxiety. Psychopharmacology (Berl.) 116, 56–64 (1994).

    Article  CAS  Google Scholar 

  37. Hall, C. & Ballachey, E.L. A study of the rat's behavior in a field. A contribution to method in comparative psychology. Univ. Calif. Publ. Psychol. 6, 1–12 (1932).

    Google Scholar 

  38. Ambrogi Lorenzini, C., Bucherelli, C. & Giachetti, A. Passive and active avoidance behavior in the light-dark box test. Physiol. Behav. 32, 687–689 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Simiand, J., Keane, P.E. & Morre, M. The staircase test in mice: a simple and efficient procedure for primary screening of anxiolytic agents. Psychopharmacology (Berl.) 84, 48–53 (1984).

    Article  CAS  Google Scholar 

  40. Kalueff, A.V. et al. The regular and light-dark Suok tests of anxiety and sensorimotor integration: utility for behavioral characterization in laboratory rodents. Nat. Protoc. 3, 129–136 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. File, S.E. & Wardill, A.G. The reliability of the hole-board apparatus. Psychopharmacologia 44, 47–51 (1975).

    Article  CAS  PubMed  Google Scholar 

  42. Borsini, F., Podhorna, J. & Marazziti, D. Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl.) 163, 121–141 (2002).

    Article  CAS  Google Scholar 

  43. Degroot, A. & Nomikos, G.G. Genetic deletion and pharmacological blockade of CB1 receptors modulates anxiety in the shock-probe burying test. Eur. J. Neurosci. 20, 1059–1064 (2004).

    Article  PubMed  Google Scholar 

  44. Njung'e, K. & Handley, S.L. Evaluation of marble-burying behavior as a model of anxiety. Pharmacol. Biochem. Behav. 38, 63–67 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Nicolas, L.B., Kolb, Y. & Prinssen, E.P.M. A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur. J. Pharmacol. 547, 106–115 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Treit, D., Pinel, J.P.J. & Fibiger, H.C. Conditioned defensive burying: A new paradigm for the study of anxiolytic agents. Pharmacol. Biochem. Behav. 15, 619–626 (1981).

    Article  CAS  PubMed  Google Scholar 

  47. Dulawa, S.C., Holick, K.A., Gundersen, B. & Hen, R. Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 29, 1321–1330 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Merali, Z., Levac, C. & Anisman, H. Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice. Biol. Psychiatry 54, 552–565 (2003).

    Article  PubMed  Google Scholar 

  49. Sánchez, C. Stress-induced vocalisation in adult animals. A valid model of anxiety? Eur. J. Pharmacol. 463, 133–143 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gardner, C.R. Distress vocalization in rat pups. A simple screening method for anxiolytic drugs. J. Pharmacol. Methods 14, 181–187 (1985).

    Article  CAS  PubMed  Google Scholar 

  51. File, S.E. Animal models for predicting clinical efficacy of anxiolytic drugs: social behaviour. Neuropsychobiology 13, 55–62 (1985).

    Article  CAS  PubMed  Google Scholar 

  52. Viviani, D. et al. Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333, 104–107 (2011). Identification of discrete CeA efferent pathways separately regulating behavioral and physiological fear responses.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Brown, S. & Schäfer, E. An investigation into the functions of the occipital and temporal lobes of the monkey's brain. Philos. Trans. R. Soc. Lond. B 179, 303–327 (1888).

    Article  Google Scholar 

  55. McDonald, A.J. Cortical pathways to the mammalian amygdala. Prog. Neurobiol. 55, 257–332 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Janak, P.H. & Tye, K.M. From circuits to behaviour in the amygdala. Nature 517, 284–292 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Maren, S. & Quirk, G.J. Neuronal signalling of fear memory. Nat. Rev. Neurosci. 5, 844–852 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. McKernan, M.G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Rogan, M.T., Stäubli, U.V. & LeDoux, J.E. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604–607 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Tye, K.M. & Janak, P.H. Amygdala neurons differentially encode motivation and reinforcement. J. Neurosci. 27, 3937–3945 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tye, K.M., Stuber, G.D., de Ridder, B., Bonci, A. & Janak, P.H. Rapid strengthening of thalamo-amygdala synapses mediates cue-reward learning. Nature 453, 1253–1257 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Namburi, P. et al. A circuit mechanism for differentiating positive and negative associations. Nature 520, 675–678 (2015). First evidence of largely non-overlapping, projection target–defined populations of neurons in the BLA oppositely encoding valence in fear and reward learning.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tye, K.M. & Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat. Rev. Neurosci. 13, 251–266 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fox, A.S., Oler, J.A., Tromp, D.P.M., Fudge, J.L. & Kalin, N.H. Extending the amygdala in theories of threat processing. Trends Neurosci. 38, 319–329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Felix-Ortiz, A.C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013). Provides the first direct evidence of bidirectional control of anxiety via the BLA projection to vHPC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Hübner, C., Bosch, D., Gall, A., Lüthi, A. & Ehrlich, I. Ex vivo dissection of optogenetically activated mPFC and hippocampal inputs to neurons in the basolateral amygdala: implications for fear and emotional memory. Front. Behav. Neurosci. 8, 64 (2014).

    PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. Johansen, J.P. et al. Optical activation of lateral amygdala pyramidal cells instructs associative fear learning. Proc. Natl. Acad. Sci. USA 107, 12692–12697 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Quirk, G.J., Repa, C. & LeDoux, J.E. Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Ciocchi, S. et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468, 277–282 (2010) Optogenetic interrogation of amygdala microcircuits controlling learned fear on the basis of neural response profiles (see also ref. 73).

    Article  CAS  PubMed  Google Scholar 

  73. Haubensak, W. et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468, 270–276 (2010)Optogenetic dissection of the control of learned fear by genetically defined populations of neurons in the amygdala microcircuit (see also ref. 72).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cai, H., Haubensak, W., Anthony, T.E. & Anderson, D.J. Central amygdala PKC-δ+ neurons mediate the influence of multiple anorexigenic signals. Nat. Neurosci. 17, 1240–1248 (2014). Presents the first causal evidence that a population of CeL neurons mediate inhibition of feeding, and also demonstrates that activity in these cells is not anxiogenic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Li, H. et al. Experience-dependent modification of a central amygdala fear circuit. Nat. Neurosci. 16, 332–339 (2013). Presents the first evidence of fear conditioning–induced plasticity in the CeL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Penzo, M.A., Robert, V. & Li, B. Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala. J. Neurosci. 34, 2432–2437 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Penzo, M.A. et al. The paraventricular thalamus controls a central amygdala fear circuit. Nature 519, 455–459 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tovote, P., Fadok, J.P. & Lüthi, A. Neuronal circuits for fear and anxiety. Nat. Rev. Neurosci. 16, 317–331 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Wang, D.V. et al. Neurons in the amygdala with response-selectivity for anxiety in two ethologically based tests. PLoS ONE 6, e18739 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Huff, M.L., Miller, R.L., Deisseroth, K., Moorman, D.E. & LaLumiere, R.T. Posttraining optogenetic manipulations of basolateral amygdala activity modulate consolidation of inhibitory avoidance memory in rats. Proc. Natl. Acad. Sci. USA 110, 3597–3602 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Cullinan, W.E., Herman, J.P. & Watson, S.J. Ventral subicular interaction with the hypothalamic paraventricular nucleus: evidence for a relay in the bed nucleus of the stria terminalis. J. Comp. Neurol. 332, 1–20 (1993).

    Article  CAS  PubMed  Google Scholar 

  82. Dong, H.W., Petrovich, G.D. & Swanson, L.W. Topography of projections from amygdala to bed nuclei of the stria terminalis. Brain Res. Brain Res. Rev. 38, 192–246 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Stamatakis, A. M. et al. Amygdala and bed nucleus of the stria terminalis circuitry: implications for addiction-related behaviors. Neuropharmacology 76 (part B): 320–328 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Poulos, A.M., Ponnusamy, R., Dong, H.-W. & Fanselow, M.S. Compensation in the neural circuitry of fear conditioning awakens learning circuits in the bed nuclei of the stria terminalis. Proc. Natl. Acad. Sci. USA 107, 14881–14886 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Jennings, J.H. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013)Presents causal evidence of functionally opposed, neurochemically defined populations of projection neurons within a single efferent pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Christianson, J.P. et al. Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol. Psychiatry 70, 458–464 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  87. van Strien, N.M., Cappaert, N.L.M. & Witter, M.P. The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat. Rev. Neurosci. 10, 272–282 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Witter, M.P., Canto, C.B., Couey, J.J., Koganezawa, N. & O'Reilly, K.C. Architecture of spatial circuits in the hippocampal region. Phil. Trans. R. Soc. Lond. B 369, 20120515 (2014).

    Article  Google Scholar 

  89. Amaral, D. & Lavenex, P. in The Hippocampus Book (eds. Anderson, P., Morris, R., Amaral, D., Bliss, T. & O'Keefe, J.) 37–114 (Oxford Univ. Press, 2007).

  90. Sparta, D.R. et al. Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear. Front. Behav. Neurosci. 8, 129 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Kheirbek, M.A. et al. Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77, 955–968 (2013). Using optogenetics, clarifies the specific influence of dorsal and ventral dentate gyrus to exploration and encoding of fear association versus innate anxiety, respectively.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mori, M., Abegg, M.H., Gähwiler, B.H. & Gerber, U. A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit. Nature 431, 453–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Risold, P.Y. & Swanson, L.W. Structural evidence for functional domains in the rat hippocampus. Science 272, 1484–1486 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Risold, P.Y. & Swanson, L.W. Connections of the rat lateral septal complex. Brain Res. Brain Res. Rev. 24, 115–195 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Trent, N.L. & Menard, J.L. The ventral hippocampus and the lateral septum work in tandem to regulate rats' open-arm exploration in the elevated plus-maze. Physiol. Behav. 101, 141–152 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Henry, B., Vale, W. & Markou, A. The effect of lateral septum corticotropin-releasing factor receptor 2 activation on anxiety is modulated by stress. J. Neurosci. 26, 9142–9152 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Anthony, T.E. et al. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156, 522–536 (2014)First optogenetic interrogation of the septohippocampal system in anxiety, which has not been otherwise evaluated using modern tools.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gross, J.J. The emerging field of emotion regulation: an integrative review. Rev. Gen. Psychol. 2, 271–299 (1998).

    Article  Google Scholar 

  99. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Van De Werd, H.J.J.M. & Uylings, H.B.M. Comparison of (stereotactic) parcellations in mouse prefrontal cortex. Brain Struct. Funct. 219, 433–459 (2014).

    Article  PubMed  Google Scholar 

  101. Groenewegen, H.J., Wright, C.I. & Uylings, H.B. The anatomical relationships of the prefrontal cortex with limbic structures and the basal ganglia. J. Psychopharmacol. 11, 99–106 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Kim, M.J. et al. The structural and functional connectivity of the amygdala: from normal emotion to pathological anxiety. Behav. Brain Res. 223, 403–410 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Ochsner, K.N., Bunge, S.A., Gross, J.J. & Gabrieli, J.D.E. Rethinking feelings: an fMRI study of the cognitive regulation of emotion. J. Cogn. Neurosci. 14, 1215–1229 (2002).

    Article  PubMed  Google Scholar 

  104. Livneh, U. & Paz, R. Amygdala-prefrontal synchronization underlies resistance to extinction of aversive memories. Neuron 75, 133–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Senn, V. et al. Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81, 428–437 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Burgos-Robles, A., Vidal-Gonzalez, I. & Quirk, G.J. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. J. Neurosci. 29, 8474–8482 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Courtin, J. et al. Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014)Original causal demonstration that mPFC microcircuit dynamics locally produce the mPFC theta rhythm to control the timing of fear behaviors.

    Article  CAS  PubMed  Google Scholar 

  108. Milad, M.R. & Quirk, G.J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Baeg, E.H. et al. Fast spiking and regular spiking neural correlates of fear conditioning in the medial prefrontal cortex of the rat. Cereb. Cortex 11, 441–451 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Chang, C., Berke, J.D. & Maren, S. Single-unit activity in the medial prefrontal cortex during immediate and delayed extinction of fear in rats. PLoS ONE 5, e11971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Holmes, A. et al. Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat. Neurosci. 15, 1359–1361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Maroun, M., Kavushansky, A., Holmes, A., Wellman, C. & Motanis, H. Enhanced extinction of aversive memories by high-frequency stimulation of the rat infralimbic cortex. PLoS ONE 7, e35853 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Arruda-Carvalho, M. & Clem, R.L. Pathway-selective adjustment of prefrontal-amygdala transmission during fear encoding. J. Neurosci. 34, 15601–15609 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Do-Monte, F.H., Quiñones-Laracuente, K. & Quirk, G.J. A temporal shift in the circuits mediating retrieval of fear memory. Nature 519, 460–463 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Likhtik, E. & Paz, R. Amygdala-prefrontal interactions in (mal)adaptive learning. Trends Neurosci. 38, 158–166 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Grace, A.A. & Rosenkranz, J.A. Regulation of conditioned responses of basolateral amygdala neurons. Physiol. Behav. 77, 489–493 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Likhtik, E., Pelletier, J.G., Paz, R. & Paré, D. Prefrontal control of the amygdala. J. Neurosci. 25, 7429–7437 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Rosenkranz, J.A., Moore, H. & Grace, A.A. The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J. Neurosci. 23, 11054–11064 (2003). Early demonstration, using technically challenging in vivo intracellular recordings, that mPFC can regulate affective processing via inhibition of amygdala activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Calhoon, G.G. & O'Donnell, P. Closing the gate in the limbic striatum: prefrontal suppression of hippocampal and thalamic inputs. Neuron 78, 181–190 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Britt, J.P. et al. Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 76, 790–803 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mackintosh, N.J. Neurobiology, psychology and habituation. Behav. Res. Ther. 25, 81–97 (1987).

    Article  CAS  PubMed  Google Scholar 

  122. Byrne, J.H., Castellucci, V.F., Carew, T.J. & Kandel, E.R. Stimulus-response relations and stability of mechanoreceptor and motor neurons mediating defensive gill-withdrawal reflex in Aplysia. J. Neurophysiol. 41, 402–417 (1978).

    Article  CAS  PubMed  Google Scholar 

  123. Balleine, B.W. Neural bases of food-seeking: affect, arousal and reward in corticostriatolimbic circuits. Physiol. Behav. 86, 717–730 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Orsini, C.A., Moorman, D.E., Young, J.W., Setlow, B. & Floresco, S.B. Neural mechanisms regulating different forms of risk-related decision-making: insights from animal models. Neurosci. Biobehav. Rev. doi:10.1016/j.neubiorev.2015.04.009 (2015).

  125. Phillips, P.E.M., Walton, M.E. & Jhou, T.C. Calculating utility: preclinical evidence for cost-benefit analysis by mesolimbic dopamine. Psychopharmacology (Berl.) 191, 483–495 (2007).

    Article  CAS  Google Scholar 

  126. Opland, D.M., Leinninger, G.M. & Myers, M.G. Modulation of the mesolimbic dopamine system by leptin. Brain Res. 1350, 65–70 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sternson, S.M. Hypothalamic survival circuits: blueprints for purposive behaviors. Neuron 77, 810–824 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nieh, E.H. et al. Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Adhikari, A., Topiwala, M.A. & Gordon, J.A. Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron 65, 257–269 (2010). Early demonstration that vHPC (but not dorsal HPC) theta rhythm synchrony with mPFC increases during anxiety.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Vertes, R.P. & Kocsis, B. Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 81, 893–926 (1997).

    Article  CAS  PubMed  Google Scholar 

  131. McNaughton, N., Kocsis, B. & Hajós, M. Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function? Behav. Pharmacol. 18, 329–346 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Sirota, A. et al. Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm. Neuron 60, 683–697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Seidenbecher, T., Laxmi, T.R., Stork, O. & Pape, H.-C. Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval. Science 301, 846–850 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Lesting, J. et al. Directional theta coherence in prefrontal cortical to amygdalo-hippocampal pathways signals fear extinction. PLoS ONE 8, e77707 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Schoenfeld, T.J. et al. Gap junctions in the ventral hippocampal-medial prefrontal pathway are involved in anxiety regulation. J. Neurosci. 34, 15679–15688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Adhikari, A., Topiwala, M.A. & Gordon, J.A. Single units in the medial prefrontal cortex with anxiety-related firing patterns are preferentially influenced by ventral hippocampal activity. Neuron 71, 898–910 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lesting, J. et al. Patterns of coupled theta activity in amygdala-hippocampal-prefrontal cortical circuits during fear extinction. PLoS ONE 6, e21714 (2011). Initial investigation of the macrocircuit dynamics underlying fear learning, characterized by coordinated oscillatory activity among the amygdala, hippocampus and PFC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Stujenske, J.M., Likhtik, E., Topiwala, M.A. & Gordon, J.A. Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala. Neuron 83, 919–933 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tejeda, H.A. & O'Donnell, P. Amygdala inputs to the prefrontal cortex elicit heterosynaptic suppression of hippocampal inputs. J. Neurosci. 34, 14365–14374 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mogenson, G.J., Jones, D.L. & Yim, C.Y. From motivation to action: functional interface between the limbic system and the motor system. Prog. Neurobiol. 14, 69–97 (1980).

    Article  CAS  PubMed  Google Scholar 

  141. Carvalho, M.C., Albrechet-Souza, L., Masson, S. & Brandão, M.L. Changes in the biogenic amine content of the prefrontal cortex, amygdala, dorsal hippocampus, and nucleus accumbens of rats submitted to single and repeated sessions of the elevated plus-maze test. Braz. J. Med. Biol. Res. 38, 1857–1866 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Collier, D.A. et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol. Psychiatry 1, 453–460 (1996).

    CAS  PubMed  Google Scholar 

  143. Lesch, K.-P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996).

    Article  CAS  PubMed  Google Scholar 

  144. Corbetta, M. & Shulman, G.L. Control of goal-directed and stimulus-driven attention in the brain. Nat. Rev. Neurosci. 3, 201–215 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Houk, J.C., Adams, J.L. & Barto, A.G. in Models of Information Processing in the Basal Ganglia (eds. Houk, J.C., Davis, J.L. & Beiser, D.G.) 249–270 (MIT Press, 1995).

  146. Joel, D., Niv, Y. & Ruppin, E. Actor-critic models of the basal ganglia: new anatomical and computational perspectives. Neural Netw. 15, 535–547 (2002).

    Article  PubMed  Google Scholar 

  147. Sugrue, L.P., Corrado, G.S. & Newsome, W.T. Choosing the greater of two goods: neural currencies for valuation and decision making. Nat. Rev. Neurosci. 6, 363–375 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Nabavi, S. et al. Engineering a memory with LTD and LTP. Nature 511, 348–352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Butler, A.C., Chapman, J.E., Forman, E.M. & Beck, A.T. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin. Psychol. Rev. 26, 17–31 (2006).

    Article  PubMed  Google Scholar 

  150. Sporns, O., Tononi, G. & Kötter, R. The human connectome: a structural description of the human brain. PLoS Comput. Biol. 1, e42 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Kinch and M. Kheirbek for correspondence, C. Vander Weele and R. Wichmann for reading and comments on our text, and the entire Tye laboratory for discussion. K.M.T. is a New York Stem Cell Foundation – Robertson Investigator, and this work was supported by funding from the JPB Foundation, PIIF, PNDRF, JFDP, Whitehall Foundation, Klingenstein Foundation, McKnight Foundation, NARSAD Young Investigator Award, Alfred P Sloan Foundation, New York Stem Cell Foundation, Whitehead Career Development Chair, US National Institutes of Health (NIH) R01-MH102441-01 (National Institute of Mental Health) and NIH Director's New Innovator Award DP2-DK-102256-01 (National Institute of Diabetes and Digestive and Kidney Diseases). G.G.C. is supported by the JFDP Postdoctoral Fellowship from the JPB Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kay M Tye.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calhoon, G., Tye, K. Resolving the neural circuits of anxiety. Nat Neurosci 18, 1394–1404 (2015). https://doi.org/10.1038/nn.4101

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4101

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing