Animals have sophisticated mechanisms for coping with danger. Freezing is a unique state that, upon threat detection, allows evidence to be gathered, response possibilities to be previsioned and preparations to be made for worst-case fight or flight. We propose that — rather than reflecting a passive fear state — the particular somatic and cognitive characteristics of freezing help to conceal overt responses, while optimizing sensory processing and action preparation. Critical for these functions are the neurotransmitters noradrenaline and acetylcholine, which modulate neural information processing and also control the sympathetic and parasympathetic branches of the autonomic nervous system. However, the interactions between autonomic systems and the brain during freezing, and the way in which they jointly coordinate responses, remain incompletely explored. We review the joint actions of these systems and offer a novel computational framework to describe their temporally harmonized integration. This reconceptualization of freezing has implications for its role in decision-making under threat and for psychopathology.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Stimulation of the ventromedial prefrontal cortex blocks the return of subcortically mediated fear responses
Translational Psychiatry Open Access 20 September 2022
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Blanchard, D. C., Griebel, G., Pobbe, R. & Blanchard, R. J. Risk assessment as an evolved threat detection and analysis process. Neurosci. Biobehav. Rev. 35, 991–998 (2011).
Fanselow, M. S., Lester, L. S. & Helmstetter, F. J. Changes in feeding and foraging patterns as an antipredator defensive strategy: a laboratory simulation using aversive stimulation in a closed economy. J. Exp. Anal. Behav. 50, 361–374 (1988).
McNaughton, N. & Corr, P. J. A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci. Biobehav. Rev. 28, 285–305 (2004).
Mobbs, D. & Kim, J. J. Neuroethological studies of fear, anxiety, and risky decision-making in rodents and humans. Curr. Opin. Behav. Sci. 5, 8–15 (2015).
Bach, D. R. & Dayan, P. Algorithms for survival: a comparative perspective on emotions. Nat. Rev. Neurosci. 18, 311–319 (2017).
Hagenaars, M. A., Oitzl, M. & Roelofs, K. Updating freeze: aligning animal and human research. Neurosci. Biobehav. Rev. 47, 165–176 (2014).
Mobbs, D., Headley, D. B., Ding, W. & Dayan, P. Space, time, and fear: survival computations along defensive circuits. Trends Cogn. Sci. 24, 228–241 (2020).
Roelofs, K. Freeze for action: neurobiological mechanisms in animal and human freezing. Philos. Trans. R. Soc. B Biol. Sci. 372, 20160206 (2017).
Gozzi, A. et al. A neural switch for active and passive fear. Neuron 67, 656–666 (2010).
Moscarello, J. M. & LeDoux, J. E. Active avoidance learning requires prefrontal suppression of amygdala-mediated defensive reactions. J. Neurosci. 33, 3815–3823 (2013).
Fadok, J. P. et al. A competitive inhibitory circuit for selection of active and passive fear responses. Nature 542, 96–100 (2017).
Brandão, M. L., Zanoveli, J. M., Ruiz-Martinez, R. C., Oliveira, L. C. & Landeira-Fernandez, J. Different patterns of freezing behavior organized in the periaqueductal gray of rats: association with different types of anxiety. Behav. Brain Res. 188, 1–13 (2008).
Fanselow, M. S., Hoffman, A. N. & Zhuravka, I. Timing and the transition between modes in the defensive behavior system. Behav. Process. 166, 103890 (2019).
Smith, R., Thayer, J. F., Khalsa, S. S. & Lane, R. D. The hierarchical basis of neurovisceral integration. Neurosci. Biobehav. Rev. 75, 274–296 (2017).
Thayer, J. F. & Lane, R. D. A model of neurovisceral integration in emotion regulation and dysregulation. J. Affect. Disord. 61, 201–216 (2000).
Thayer, J. F. & Lane, R. D. Claude Bernard and the heart–brain connection: further elaboration of a model of neurovisceral integration. Neurosci. Biobehav. Rev. 33, 81–88 (2009).
Marr, H. Vision (W.H. Freeman, 1982).
Bolles, R. C. Avoidance and escape learning: simultaneous acquisition of different responses. J. Comp. Physiol. Psychol. 68, 355 (1969).
LeDoux J. E. in Handbook of Physiology. 1: The Nervous System. Volume V, Higher Functions of the Brain (ed. Plum, F.) 419–460 (American Physiological Society, 1987).
Samuels, E. R. & Szabadi, E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr. Neuropharmacol. 6, 235–253 (2008).
Bouret, S. & Sara, S. J. Network reset: a simplified overarching theory of locus coeruleus noradrenaline function. Trends Neurosci. 28, 574–582 (2005).
Dayan, P. & Yu, A. J. Phasic norepinephrine: a neural interrupt signal for unexpected events. Netw. Comput. Neural Syst. 17, 335–350 (2006).
Bockstaele, E. J. V., Pieribone, V. A. & Aston-Jones, G. Diverse afferents converge on the nucleus paragigantocellularis in the rat ventrolateral medulla: retrograde and anterograde tracing studies. J. Comp. Neurol. 290, 561–584 (1989).
Van Bockstaele, E. J., Bajic, D., Proudfit, H. & Valentino, R. J. Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus. Physiol. Behav. 73, 273–283 (2001).
Petrov, T., Krukoff, T. L. & Jhamandas, J. H. Branching projections of catecholaminergic brainstem neurons to the paraventricular hypothalamic nucleus and the central nucleus of the amygdala in the rat. Brain Res. 609, 81–92 (1993).
Zardetto-Smith, A. M. & Gray, T. S. Organization of peptidergic and catecholaminergic efferents from the nucleus of the solitary tract to the rat amygdala. Brain Res. Bull. 25, 875–887 (1990).
Resstel, L. B. M., Fernandes, K. B. P. & Corrêa, F. M. A. Medial prefrontal cortex modulation of the baroreflex parasympathetic component in the rat. Brain Res. 1015, 136–144 (2004).
Ulrich-Lai, Y. M. & Herman, J. P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10, 397–409 (2009).
Lima, J. D. et al. Cholinergic neurons in the pedunculopontine tegmental nucleus modulate breathing in rats by direct projections to the retrotrapezoid nucleus. J. Physiol. 597, 1919–1934 (2019).
Mena-Segovia, J. & Bolam, J. P. Rethinking the pedunculopontine nucleus: from cellular organization to function. Neuron 94, 7–18 (2017).
Pahapill, P. A. & Lozano, A. M. The pedunculopontine nucleus and Parkinson’s disease. Brain 123, 1767–1783 (2000).
Sarter, M., Hasselmo, M. E., Bruno, J. P. & Givens, B. Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection. Brain Res. Rev. 48, 98–111 (2005).
Sarter, M. & Lustig, C. Forebrain cholinergic signaling: wired and phasic, not tonic, and causing behavior. J. Neurosci. 40, 712–719 (2020).
Hasselmo, M. E. The role of acetylcholine in learning and memory. Curr. Opin. Neurobiol. 16, 710–715 (2006).
LeDoux, J. & Daw, N. D. Surviving threats: neural circuit and computational implications of a new taxonomy of defensive behaviour. Nat. Rev. Neurosci. 19, 269–282 (2018).
McFadyen, J. Investigating the subcortical route to the amygdala across species and in disordered fear responses. J. Exp. Neurosci. 13, 1179069519846445 (2019).
Pitkänen, A., Savander, V. & LeDoux, J. E. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci. 20, 517–523 (1997).
Terburg, D. et al. The basolateral amygdala is essential for rapid escape: a human and rodent study. Cell 175, 723–735.e16 (2018).
Evans, D. A. et al. A synaptic threshold mechanism for computing escape decisions. Nature 558, 590–594 (2018).
Jones, B. E. & Yang, T. Z. The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J. Comp. Neurol. 242, 56–92 (1985).
Smith, M. S., Schambra, U. B., Wilson, K. H., Page, S. O. & Schwinn, D. A. α1-Adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding α1-adrenergic receptor subtypes at four distinct levels. Mol. Brain Res. 63, 254–261 (1999).
Li, L. et al. Stress accelerates defensive responses to looming in mice and involves a locus coeruleus–superior colliculus projection. Curr. Biol. 28, 859–871.e5 (2018).
Liu, Y., Rodenkirch, C., Moskowitz, N., Schriver, B. & Wang, Q. Dynamic lateralization of pupil dilation evoked by locus coeruleus activation results from sympathetic not parasympathetic contributions. Cell Rep. 20, 3099–3112 (2017).
Deolindo, M. V., Pelosi, G. G., Busnardo, C., Resstel, L. B. M. & Corrêa, F. M. A. Cardiovascular effects of acetylcholine microinjection into the ventrolateral and dorsal periaqueductal gray of rats. Brain Res. 1371, 74–81 (2011).
Koba, S., Inoue, R. & Watanabe, T. Role played by periaqueductal gray neurons in parasympathetically mediated fear bradycardia in conscious rats. Physiol. Rep. 4, e12831 (2016).
LeDoux, J. E., Iwata, J., Cicchetti, P. & Reis, D. J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988).
Hermans, E. J., Henckens, M. J. A. G., Roelofs, K. & Fernández, G. Fear bradycardia and activation of the human periaqueductal grey. NeuroImage 66, 278–287 (2013).
Carrive, P., Bandler, R. & Dampney, R. A. Somatic and autonomic integration in the midbrain of the unanesthetized decerebrate cat: a distinctive pattern evoked by excitation of neurones in the subtentorial portion of the midbrain periaqueductal grey. Brain Res. 483, 251–258 (1989).
Keay, K. A., Li, Q. F. & Bandler, R. Muscle pain activates a direct projection from ventrolateral periaqueductal gray to rostral ventrolateral medulla in rats. Neurosci. Lett. 290, 157–160 (2000).
Lovick, T. A. Midbrain influences on ventrolateral medullo-spinal neurones in the rat. Exp. Brain Res. 90, 147–152 (1992).
Verberne, A. J. M. & Struyker Boudier, H. A. J. Midbrain central gray: regional haemodynamic control and excitatory amino acidergic mechanisms. Brain Res. 550, 86–94 (1991).
Alves, F. H. F., Crestani, C. C., Resstel, L. B. M. & Corrêa, F. M. A. Cardiovascular effects of carbachol microinjected into the bed nucleus of the stria terminalis of the rat brain. Brain Res. 1143, 161–168 (2007).
Crestani, C. C. et al. Mechanisms in the bed nucleus of the stria terminalis involved in control of autonomic and neuroendocrine functions: a review. Curr. Neuropharmacol. 11, 141–159 (2013).
Wong, S. W., Massé, N., Kimmerly, D. S., Menon, R. S. & Shoemaker, J. K. Ventral medial prefrontal cortex and cardiovagal control in conscious humans. NeuroImage 35, 698–708 (2007).
Crippa, G. E., Peres-Polon, V. L., Kuboyama, R. H. & Corrêa, F. M. A. Cardiovascular response to the injection of acetylcholine into the anterior cingulate region of the medial prefrontal cortex of unanesthetized rats. Cereb. Cortex 9, 362–365 (1999).
Mallios, V. J., Lydic, R. & Baghdoyan, H. A. Muscarinic receptor subtypes are differentially distributed across brain stem respiratory nuclei. Am. J. Physiol. Lung Cell. Mol. Physiol. https://doi.org/10.1152/ajplung.1995.268.6.L941 (1995).
Ghali, M. G. Z. Midbrain control of breathing and blood pressure: the role of periaqueductal gray matter and mesencephalic collicular neuronal microcircuit oscillators. Eur. J. Neurosci. 52, 3879–3902 (2020).
Castegnetti, G., Tzovara, A., Staib, M., Gerster, S. & Bach, D. R. Assessing fear learning via conditioned respiratory amplitude responses. Psychophysiology 54, 215–223 (2017).
Fokkema, D. S. The psychobiology of strained breathing and its cardiovascular implications: a functional system review. Psychophysiology 36, 164–175 (1999).
Van Diest, I., Bradley, M. M., Guerra, P., Van den Bergh, O. & Lang, P. J. Fear conditioned respiration and its association to cardiac reactivity. Biol. Psychol. 80, 212–217 (2009).
Yasuma, F. & Hayano, J. Respiratory sinus arrhythmia: why does the heartbeat synchronize with respiratory rhythm? Chest 125, 683–690 (2004).
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).
Schipper, P. et al. The association between serotonin transporter availability and the neural correlates of fear bradycardia. Proc. Natl Acad. Sci. USA 116, 25941–25947 (2019).
Tovote, P. et al. Midbrain circuits for defensive behaviour. Nature 534, 206–212 (2016).
Nuseir, K., Heidenreich, B. A. & Proudfit, H. K. The antinociception produced by microinjection of a cholinergic agonist in the ventromedial medulla is mediated by noradrenergic neurons in the A7 catecholamine cell group. Brain Res. 822, 1–7 (1999).
Power, A. E. & McGaugh, J. L. Cholinergic activation of the basolateral amygdala regulates unlearned freezing behavior in rats. Behav. Brain Res. 134, 307–315 (2002).
Winkler, J., Ramirez, G. A., Thal, L. J. & Waite, J. J. Nerve growth factor (NGF) augments cortical and hippocampal cholinergic functioning after p75NGF receptor-mediated deafferentation but impairs inhibitory avoidance and induces fear-related behaviors. J. Neurosci. 20, 834–844 (2000).
Aitta-aho, T. et al. Basal forebrain and brainstem cholinergic neurons differentially impact amygdala circuits and learning-related behavior. Curr. Biol. 28, 2557–2569.e4 (2018).
Monassi, C. R., Hoffmann, A. & Menescal-de-Oliveira, L. Involvement of the cholinergic system and periaqueductal gray matter in the modulation of tonic immobility in the guinea pig. Physiol. Behav. 62, 53–59 (1997).
Burnstock, G. Do some sympathetic neurones synthesize and release both noradrenaline and acetylcholine? Prog. Neurobiol. 11, 205–222 (1978).
Bagur, S. et al. Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation. Nat. Commun. 12, 2605 (2021).
Corcoran, A. W., Pezzulo, G. & Hohwy, J. Commentary: respiration-entrained brain rhythms are global but often overlooked. Front. Syst. Neurosci. 12, 25 (2018).
Tort, A. B. L., Brankačk, J. & Draguhn, A. Respiration-entrained brain rhythms are global but often overlooked. Trends Neurosci. 41, 186–197 (2018).
Karalis, N. et al. 4-Hz oscillations synchronize prefrontal–amygdala circuits during fear behavior. Nat. Neurosci. 19, 605–612 (2016).
Zelano, C. et al. Nasal respiration entrains human limbic oscillations and modulates cognitive function. J. Neurosci. 36, 12448–12467 (2016).
Walker, P. & Carrive, P. Role of ventrolateral periaqueductal gray neurons in the behavioral and cardiovascular responses to contextual conditioned fear and poststress recovery. Neuroscience 116, 897–912 (2003).
Allen, M., Levy, A., Parr, T. & Friston, K. J. In the body’s eye: the computational anatomy of interoceptive inference. Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/603928v1 (2019).
Corcoran, A. W., Macefield, V. G. & Hohwy, J. Be still my heart: cardiac regulation as a mode of uncertainty reduction. Psychon. Bull. Rev. https://doi.org/10.3758/s13423-021-01888-y (2021).
Lang, P. J., Bradley, M. M. & Cuthbert, B. N. Emotion, motivation, and anxiety: brain mechanisms and psychophysiology. Biol. Psychiatry 44, 1248–1263 (1998).
Wiens, S. & Ohman, A. Unawareness is more than a chance event: comment on Lovibond and Shanks (2002). J. Exp. Psychol. Anim. Behav. Process. 28, 27–31 (2002).
Garfinkel, S. N. & Critchley, H. D. Threat and the body: how the heart supports fear processing. Trends Cogn. Sci. 20, 34–46 (2016).
Rösler, L. & Gamer, M. Freezing of gaze during action preparation under threat imminence. Sci. Rep. 9, 17215 (2019).
Lojowska, M., Gladwin, T. E., Hermans, E. J. & Roelofs, K. Freezing promotes perception of coarse visual features. J. Exp. Psychol. Gen. 144, 1080–1088 (2015).
Lojowska, M., Ling, S., Roelofs, K. & Hermans, E. J. Visuocortical changes during a freezing-like state in humans. NeuroImage 179, 313–325 (2018).
De Voogd L., Hagenberg E., Zhou Y., De Lange F., Roelofs K. Acute threat enhances perceptual sensitivity without affecting the decision criterion. Sci. Rep. 12, 9071 (2022).
Ribeiro, M. J. & Castelo-Branco, M. Neural correlates of anticipatory cardiac deceleration and its association with the speed of perceptual decision-making, in young and older adults. NeuroImage 199, 521–533 (2019).
Rothermel, M., Carey, R. M., Puche, A., Shipley, M. T. & Wachowiak, M. Cholinergic inputs from basal forebrain add an excitatory bias to odor coding in the olfactory bulb. J. Neurosci. 34, 4654–4664 (2014).
D’Souza, R. D. & Vijayaraghavan, S. Paying attention to smell: cholinergic signaling in the olfactory bulb. Front. Synaptic Neurosci. 6, 21 (2014).
Koch, M. The neurobiology of startle. Prog. Neurobiol. 59, 107–128 (1999).
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).
Szeska, C., Richter, J., Wendt, J., Weymar, M. & Hamm, A. O. Attentive immobility in the face of inevitable distal threat — startle potentiation and fear bradycardia as an index of emotion and attention. Psychophysiology 58, e13812 (2021).
van Ast, V. A., Klumpers, F., Grasman, R. P. P. P., Krypotos, A.-M. & Roelofs, K. Postural freezing relates to startle potentiation in a human fear-conditioning paradigm. Psychophysiology 59, e13983 (2022).
Leaton, R. N. & Borszcz, G. S. Potentiated startle: its relation to freezing and shock intensity in rats. J. Exp. Psychol. Anim. Behav. Process. 11, 421–428 (1985).
Plappert, C. F., Pilz, P. K. D. & Schnitzler, H.-U. Acoustic startle response and habituation in freezing and nonfreezing rats. Behav. Neurosci. 107, 981–987 (1993).
Greba, Q., Munro, L. J. & Kokkinidis, L. The involvement of ventral tegmental area cholinergic muscarinic receptors in classically conditioned fear expression as measured with fear-potentiated startle. Brain Res. 870, 135–141 (2000).
Schwienbacher, I., Schnitzler, H.-U., Westbrook, R. F., Richardson, R. & Fendt, M. Carbachol injections into the nucleus accumbens disrupt acquisition and expression of fear-potentiated startle and freezing in rats. Neuroscience 140, 769–778 (2006).
Grillon, C. et al. Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am. J. Psychiat. 165, 898–904 (2008).
Kozlowska, K., Walker, P., McLean, L. & Carrive, P. Fear and the defense cascade: clinical implications and management. Harv. Rev. Psychiat. 23, 263–287 (2015).
Hashemi, M. M. et al. Neural dynamics of shooting decisions and the switch from freeze to fight. Sci. Rep. 9, 4240 (2019).
Paton, J. F. R., Boscan, P., Pickering, A. E. & Nalivaiko, E. The yin and yang of cardiac autonomic control: vago-sympathetic interactions revisited. Brain Res. Brain Res. Rev. 49, 555–565 (2005).
Vila, J. et al. Cardiac defense: from attention to action. Int. J. Psychophysiol. 66, 169–182 (2007).
Mobbs, D. et al. From threat to fear: the neural organization of defensive fear systems in humans. J. Neurosci. 29, 12236–12243 (2009).
Ongür, D. & Price, J. L. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb. Cortex 10, 206–219 (2000).
Arnsten, A. F. T. & Goldman-Rakic, P. S. Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey. Brain Res. 306, 9–18 (1984).
Koga, K. et al. Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex. Mol. Brain 13, 49 (2020).
Tervo, D. G. R. et al. Behavioral variability through stochastic choice and its gating by anterior cingulate cortex. Cell 159, 21–32 (2014).
Etkin, A., Egner, T. & Kalisch, R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn. Sci. 15, 85–93 (2011).
Holroyd, C. B. & Verguts, T. The best laid plans: computational principles of anterior cingulate cortex. Trends Cogn. Sci. 25, 316–329 (2021).
Ridderinkhof, K. R., Ullsperger, M., Crone, E. A. & Nieuwenhuis, S. The role of the medial frontal cortex in cognitive control. Science 306, 443–447 (2004).
Shenhav, A., Botvinick, M. M. & Cohen, J. D. The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron 79, 217–240 (2013).
Kennerley, S. W., Walton, M. E., Behrens, T. E. J., Buckley, M. J. & Rushworth, M. F. S. Optimal decision making and the anterior cingulate cortex. Nat. Neurosci. 9, 940–947 (2006).
Kolling, N., Behrens, T. E. J., Mars, R. B. & Rushworth, M. F. S. Neural mechanisms of foraging. Science 336, 95–98 (2012).
Klaassen, F. H. et al. Defensive freezing and its relation to approach–avoidance decision-making under threat. Sci. Rep. 11, 12030 (2021).
Blanchard, D. C. Translating dynamic defense patterns from rodents to people. Neurosci. Biobehav. Rev. 76, 22–28 (2017).
Blanchard, R. J., Blanchard, D. C., Rodgers, J. & Weiss, S. M. The characterization and modelling of antipredator defensive behavior. Neurosci. Biobehav. Rev. 14, 463–472 (1990).
Caroline Blanchard, D., Hynd, A. L., Minke, K. A., Minemoto, T. & Blanchard, R. J. Human defensive behaviors to threat scenarios show parallels to fear- and anxiety-related defense patterns of non-human mammals. Neurosci. Biobehav. Rev. 25, 761–770 (2001).
Lloyd, K. & Dayan, P. Interrupting behaviour: minimizing decision costs via temporal commitment and low-level interrupts. PLoS Comput. Biol. 14, e1005916 (2018).
Vale, R., Evans, D. A. & Branco, T. Rapid spatial learning controls instinctive defensive behavior in mice. Curr. Biol. 27, 1342–1349 (2017).
Mattar, M. G. & Daw, N. D. Prioritized memory access explains planning and hippocampal replay. Nat. Neurosci. 21, 1609–1617 (2018).
Sutton, R. S. Dyna, an integrated architecture for learning, planning, and reacting. ACM SIGART Bull. 2, 160–163 (1991).
Wise, T., Liu, Y., Chowdhury, F. & Dolan, R. J. Model-based aversive learning in humans is supported by preferential task state reactivation. Sci. Adv. 7, eabf9616 (2021).
Cazé, R., Khamassi, M., Aubin, L. & Girard, B. Hippocampal replays under the scrutiny of reinforcement learning models. J. Neurophysiol. 120, 2877–2896 (2018).
Findlay, G., Tononi, G. & Cirelli, C. The evolving view of replay and its functions in wake and sleep. Sleep. Adv. 1, zpab002 (2020).
Foster, D. J. Replay comes of age. Annu. Rev. Neurosci. 40, 581–602 (2017).
Tambini, A. & Davachi, L. Awake reactivation of prior experiences consolidates memories and biases cognition. Trends Cogn. Sci. 23, 876–890 (2019).
Buhry, L., Azizi, A. H. & Cheng, S. Reactivation, replay, and preplay: how it might all fit together. Neural Plast. 2011, e203462 (2011).
Chen, Z. & Wilson, M. A. Deciphering neural codes of memory during sleep. Trends Neurosci. 40, 260–275 (2017).
Shea-Brown, E., Gilzenrat, M. S. & Cohen, J. D. Optimization of decision making in multilayer networks: the role of locus coeruleus. Neural Comput. 20, 2863–2894 (2008).
Ratcliff, R., Smith, P. L., Brown, S. D. & McKoon, G. Diffusion decision model: current issues and history. Trends Cogn. Sci. 20, 260–281 (2016).
Livermore, J. J. A. Approach-avoidance decisions under threat: the role of autonomic psychophysiological states. Front. Neurosci. 15, 12 (2021).
Worringer, B. et al. Common and distinct neural correlates of dual-tasking and task-switching: a meta-analytic review and a neuro-cognitive processing model of human multitasking. Brain Struct. Funct. 224, 1845–1869 (2019).
Mobbs, D., Trimmer, P. C., Blumstein, D. T. & Dayan, P. Foraging for foundations in decision neuroscience: insights from ethology. Nat. Rev. Neurosci. 19, 419–427 (2018).
Robbins, T. W. Arousal systems and attentional processes. Biol. Psychol. 45, 57–71 (1997).
Sarter, M., Gehring, W. J. & Kozak, R. More attention must be paid: the neurobiology of attentional effort. Brain Res. Rev. 51, 145–160 (2006).
Qi, S. et al. How cognitive and reactive fear circuits optimize escape decisions in humans. Proc. Natl Acad. Sci. USA 115, 3186–3191 (2018).
Al, E. et al. Heart–brain interactions shape somatosensory perception and evoked potentials. Proc. Natl Acad. Sci. USA 117, 10575–10584 (2020).
Sandman, C. A., McCanne, T. R., Kaiser, D. N. & Diamond, B. Heart rate and cardiac phase influences on visual perception. J. Comp. Physiol. Psychol. 91, 189–202 (1977).
Dayan, P., Niv, Y., Seymour, B. & Daw, N. D. The misbehavior of value and the discipline of the will. Neural Netw. 19, 1153–1160 (2006).
Hasselmo, M. E. & Giocomo, L. M. Cholinergic modulation of cortical function. J. Mol. Neurosci. 30, 133–135 (2006).
Rokem, A., Landau, A. N., Garg, D., Prinzmetal, W. & Silver, M. A. Cholinergic enhancement increases the effects of voluntary attention but does not affect involuntary attention. Neuropsychopharmacology 35, 2538–2544 (2010).
Dayan, P., Kakade, S. & Montague, P. R. Learning and selective attention. Nat. Neurosci. 3, 1218–1223 (2000).
Kaelbling, L. P., Littman, M. L. & Cassandra, A. R. Planning and acting in partially observable stochastic domains. Artif. Intell. 101, 99–134 (1998).
Papadimitriou, C. H. & Tsitsiklis, J. N. The complexity of Markov decision processes. Math. Oper. Res. 12, 441–450 (1987).
Eppinger, B., Goschke, T. & Musslick, S. Meta-control: from psychology to computational neuroscience. Cogn. Affect. Behav. Neurosci. https://doi.org/10.3758/s13415-021-00919-4 (2021).
Cools, R. Chemistry of the adaptive mind: lessons from dopamine. Neuron 104, 113–131 (2019).
Ratcliff, R. & Smith, P. L. A comparison of sequential sampling models for two-choice reaction time. Psychol. Rev. 111, 333–367 (2004).
Gold, J. I. & Shadlen, M. N. Banburismus and the brain: decoding the relationship between sensory stimuli, decisions, and reward. Neuron 36, 299–308 (2002).
Hauser, T. U., Moutoussis, M., Purg, N., Dayan, P. & Dolan, R. J. Beta-blocker propranolol modulates decision urgency during sequential information gathering. J. Neurosci. 38, 7170–7178 (2018).
Sutton, R. S. & Barto, A. G. Reinforcement Learning: An Introduction (MIT Press, 2018).
Kahneman, D. Thinking, Fast and Slow (Farrar, Straus and Giroux, 2011).
Tolman, E. C. Cognitive maps in rats and men. Psychol. Rev. 55, 189–208 (1948).
Johnson, A. & Redish, A. D. Neural ensembles in CA3 transiently encode paths forward of the animal at a decision point. J. Neurosci. 27, 12176–12189 (2007).
Pfeiffer, B. E. & Foster, D. J. Hippocampal place-cell sequences depict future paths to remembered goals. Nature 497, 74–79 (2013).
Coulom, R. in Computers and Games (eds van den Herik, H. J., Ciancarini, P. & Donkers, H. H. L. M.) 72–83 (Springer, 2007).
Daw, N. D., Niv, Y. & Dayan, P. Uncertainty-based competition between prefrontal and dorsolateral striatal systems for behavioral control. Nat. Neurosci. 8, 1704–1711 (2005).
Sutton, R. S. Learning to predict by the methods of temporal differences. Mach. Learn. 3, 9–44 (1988).
Montague, P. R., Dayan, P. & Sejnowski, T. J. A framework for mesencephalic dopamine systems based on predictive Hebbian learning. J. Neurosci. 16, 1936–1947 (1996).
Killcross, S. & Coutureau, E. Coordination of actions and habits in the medial prefrontal cortex of rats. Cereb. Cortex 13, 400–408 (2003).
Dayan, P. How to set the switches on this thing. Curr. Opin. Neurobiol. 22, 1068–1074 (2012).
Pezzulo, G., Rigoli, F. & Chersi, F. The mixed instrumental controller: using value of information to combine habitual choice and mental simulation. Front. Psychol. 4, 92 (2013).
Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117–126 (2016).
Mazzoni, P., Hristova, A. & Krakauer, J. W. Why don’t we move faster? Parkinson’s disease, movement vigor, and implicit motivation. J. Neurosci. 27, 7105–7116 (2007).
Niv, Y., Daw, N. D., Joel, D. & Dayan, P. Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology 191, 507–520 (2007).
Blanchard, T. C. & Hayden, B. Y. Neurons in dorsal anterior cingulate cortex signal postdecisional variables in a foraging task. J. Neurosci. 34, 646–655 (2014).
Brown, J. W. & Alexander, W. H. Foraging value, risk avoidance, and multiple control signals: how the anterior cingulate cortex controls value-based decision-making. J. Cogn. Neurosci. 29, 1656–1673 (2017).
Mobbs, D. et al. When fear is near: threat imminence elicits prefrontal–periaqueductal gray shifts in humans. Science 317, 1079–1083 (2007).
Porges, S. W. Orienting in a defensive world: mammalian modifications of our evolutionary heritage. A polyvagal theory. Psychophysiology 32, 301–318 (1995).
Porges, S. W. The polyvagal theory: phylogenetic substrates of a social nervous system. Int. J. Psychophysiol. 42, 123–146 (2001).
Porges, S. W. The polyvagal perspective. Biol. Psychol. 74, 116–143 (2007).
Katz, P. S. & Lillvis, J. L. Reconciling the deep homology of neuromodulation with the evolution of behavior. Curr. Opin. Neurobiol. 29, 39–47 (2014).
Menegas, W., Akiti, K., Amo, R., Uchida, N. & Watabe-Uchida, M. Dopamine neurons projecting to the posterior striatum reinforce avoidance of threatening stimuli. Nat. Neurosci. 21, 1421–1430 (2018).
Verharen, J. P. H., Zhu, Y. & Lammel, S. Aversion hot spots in the dopamine system. Curr. Opin. Neurobiol. 64, 46–52 (2020).
Gentry, R. N., Lee, B. & Roesch, M. R. Phasic dopamine release in the rat nucleus accumbens predicts approach and avoidance performance. Nat. Commun. 7, 13154 (2016).
Gentry, R. N., Schuweiler, D. R. & Roesch, M. R. Dopamine signals related to appetitive and aversive events in paradigms that manipulate reward and avoidability. Brain Res. 1713, 80–90 (2019).
Wenzel, J. M., Rauscher, N. A., Cheer, J. F. & Oleson, E. B. A role for phasic dopamine release within the nucleus accumbens in encoding aversion: a review of the neurochemical literature. ACS Chem. Neurosci. 6, 16–26 (2015).
Boureau, Y.-L. & Dayan, P. Opponency revisited: competition and cooperation between dopamine and serotonin. Neuropsychopharmacology 36, 74–97 (2011).
Deakin, J. The origins of ‘5-HT and mechanisms of defence’ by Deakin and Graeff: a personal perspective. J. Psychopharmacol. 27, 1084–1089 (2013).
Paul, E. D., Johnson, P. L., Shekhar, A. & Lowry, C. A. The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic. Neurosci. Biobehav. Rev. 46, 379–396 (2014).
Deakin, J. F. W. & Graeff, F. G. 5-HT and mechanisms of defence. J. Psychopharmacol. 5, 305–315 (1991).
Graeff, F. G., Guimarães, F. S., De Andrade, T. G. C. S. & Deakin, J. F. W. Role of 5-HT in stress, anxiety, and depression. Pharmacol. Biochem. Behav. 54, 129–141 (1996).
Cools, R., Robinson, O. J. & Sahakian, B. Acute tryptophan depletion in healthy volunteers enhances punishment prediction but does not affect reward prediction. Neuropsychopharmacology 33, 2291–2299 (2008).
Crockett, M. J., Clark, L. & Robbins, T. W. Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans. J. Neurosci. 29, 11993–11999 (2009).
Lottem, E. et al. Activation of serotonin neurons promotes active persistence in a probabilistic foraging task. Nat. Commun. 9, 1000 (2018).
Miyazaki, K., Miyazaki, K. W. & Doya, K. The role of serotonin in the regulation of patience and impulsivity. Mol. Neurobiol. 45, 213–224 (2012).
Miyazaki, K. W. et al. Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards. Curr. Biol. 24, 2033–2040 (2014).
Soubrié, P. Reconciling the role of central serotonin neurons in human and animal behavior. Behav. Brain Sci. 9, 319–335 (1986).
Seo, C. et al. Intense threat switches dorsal raphe serotonin neurons to a paradoxical operational mode. Science 363, 538–542 (2019).
Campese, V. D. et al. Noradrenergic regulation of central amygdala in aversive pavlovian-to-instrumental transfer. eNeuro 4, ENEURO.0224-17.2017 (2017).
Hamm, A. O. & Vaitl, D. Affective learning: awareness and aversion. Psychophysiology 33, 698–710 (1996).
Hodes, R. L., Cook, E. W. & Lang, P. J. Individual differences in autonomic response: conditioned association or conditioned fear? Psychophysiology 22, 545–560 (1985).
Moratti, S. & Keil, A. Cortical activation during Pavlovian fear conditioning depends on heart rate response patterns: an MEG study. Cogn. Brain Res. 25, 459–471 (2005).
Obrist, W. The cardiac–somatic relationship: some reformulations. Psychophysiology 6, 569–587 (1970).
Aylward, J. & Robinson, O. J. Towards an emotional ‘stress test’: a reliable, non-subjective cognitive measure of anxious responding. Sci. Rep. 7, 40094 (2017).
Mobbs, D. et al. Promises and challenges of human computational ethology. Neuron 14, 2224–2238 (2021).
Chandler, D. J., Lamperski, C. S. & Waterhouse, B. D. Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. Brain Res. 1522, 38–58 (2013).
Gielow, M. R. & Zaborszky, L. The input–output relationship of the cholinergic basal forebrain. Cell Rep. 18, 1817–1830 (2017).
Wang, H.-L. & Morales, M. Pedunculopontine and laterodorsal tegmental nuclei contain distinct populations of cholinergic, glutamatergic and GABAergic neurons in the rat. Eur. J. Neurosci. 29, 340–358 (2009).
Spann, B. M. & Grofova, I. Origin of ascending and spinal pathways from the nucleus tegmenti pedunculopontinus in the rat. J. Comp. Neurol. 283, 13–27 (1989).
Ballinger, E., Ananth, M., Talmage, D. A. & Role, L. Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline. Neuron 91, 1199–1218 (2016).
Gladwin, T. E., Hashemi, M. M., van Ast, V. & Roelofs, K. Ready and waiting: freezing as active action preparation under threat. Neurosci. Lett. 619, 182–188 (2016).
Kalin, N. H. & Shelton, S. E. Nonhuman primate models to study anxiety, emotion regulation, and psychopathology. Ann. N. Y. Acad. Sci. 1008, 189–200 (2003).
Qi, C. et al. Anxiety-related behavioral inhibition in rats: a model to examine mechanisms underlying the risk to develop stress-related psychopathology. Genes Brain Behav. 9, 974–984 (2010).
Hashemi, M. M. Exploring Defensive Freeze–Fight Reaction in Humans: From Adaptive Defence to Stress Vulnerability. Doctoral dissertation (Radboud University Nijmegen, The Netherlands, 2021).
Hagenaars, M. A., Stins, J. F. & Roelofs, K. Aversive life events enhance human freezing responses. J. Exp. Psychol. Gen. 141, 98–105 (2012).
Niermann, H. C. M. et al. Infant attachment predicts bodily freezing in adolescence: evidence from a prospective longitudinal study. Front. Behav. Neurosci. 9, 263 (2015).
Niermann, H. C. M. et al. The relation between infant freezing and the development of internalizing symptoms in adolescence: a prospective longitudinal study. Dev. Sci. 22, e12763 (2019).
Brosschot, J. F., Verkuil, B. & Thayer, J. F. The default response to uncertainty and the importance of perceived safety in anxiety and stress: an evolution-theoretical perspective. J. Anxiety Disord. 41, 22–34 (2016).
Hartley, C. A. & Phelps, E. A. Anxiety and decision-making. Biol. Psychiat. 72, 113–118 (2012).
Ly, V., Huys, Q. J. M., Stins, J. F., Roelofs, K. & Cools, R. Individual differences in bodily freezing predict emotional biases in decision making. Front. Behav. Neurosci. 8, 237 (2014).
Garfinkel, S. N. et al. Interoceptive dimensions across cardiac and respiratory axes. Philos. Trans. R. Soc. B Biol. Sci. 371, 20160014 (2016).
Owens, A. P., Allen, M., Ondobaka, S. & Friston, K. J. Interoceptive inference: from computational neuroscience to clinic. Neurosci. Biobehav. Rev. 90, 174–183 (2018).
Mkrtchian, A., Roiser, J. P. & Robinson, O. J. Threat of shock and aversive inhibition: induced anxiety modulates Pavlovian–instrumental interactions. J. Exp. Psychol. Gen. 146, 1694–1704 (2017).
Robinson, O. J., Krimsky, M. & Grillon, C. The impact of induced anxiety on response inhibition. Front. Hum. Neurosci. 7, 69 (2013).
Fung, B. J., Qi, S., Hassabis, D., Daw, N. & Mobbs, D. Slow escape decisions are swayed by trait anxiety. Nat. Hum. Behav. 3, 702–708 (2019).
Robinson, O. J. et al. Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal–amygdala ‘aversive amplification’ circuit in unmedicated generalized and social anxiety disorders. Lancet Psychiat. 1, 294–302 (2014).
Maier, S. F. & Seligman, M. E. P. Learned helplessness at fifty: insights from neuroscience. Psychol. Rev. 123, 349–367 (2016).
K.R. was supported by a consolidator grant from the European Research Council (ERC_CoG-2017_772337). P.D. was supported by the Max Planck Society and the Alexander von Humboldt Foundation. The authors thank A. Cleeremans, R. Cools, F. Klumpers, D. Mobbs, O. Robinson and T. Wise for their most helpful comments on an earlier draft, and S. Sara and L. de Voogd for discussions.
The authors declare no competing interest.
Peer review information
Nature Reviews Neuroscience thanks J. Herman, J. LeDoux and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Roelofs, K., Dayan, P. Freezing revisited: coordinated autonomic and central optimization of threat coping. Nat Rev Neurosci 23, 568–580 (2022). https://doi.org/10.1038/s41583-022-00608-2
This article is cited by
Stimulation of the ventromedial prefrontal cortex blocks the return of subcortically mediated fear responses
Translational Psychiatry (2022)