Neuronal circuits for fear and anxiety

Journal name:
Nature Reviews Neuroscience
Volume:
16,
Pages:
317–331
Year published:
DOI:
doi:10.1038/nrn3945
Published online

Abstract

Decades of research has identified the brain areas that are involved in fear, fear extinction, anxiety and related defensive behaviours. Newly developed genetic and viral tools, optogenetics and advanced in vivo imaging techniques have now made it possible to characterize the activity, connectivity and function of specific cell types within complex neuronal circuits. Recent findings that have been made using these tools and techniques have provided mechanistic insights into the exquisite organization of the circuitry underlying internal defensive states. This Review focuses on studies that have used circuit-based approaches to gain a more detailed, and also more comprehensive and integrated, view on how the brain governs fear and anxiety and how it orchestrates adaptive defensive behaviours.

At a glance

Figures

  1. The fear and extinction network.
    Figure 1: The fear and extinction network.

    a | Fear states are mediated by long-range excitatory and inhibitory connections between multiple brain areas. b | Several amygdala nuclei receive sensory input from cortical and thalamic centres and are major sites of fear-related neuronal plasticity. This plasticity is modulated by reciprocal connections between the basal amygdala (BA) and the ventral hippocampus (vHC) as well as between the BA and the prelimbic cortex (PL). In turn, central nuclei of the amygdala project to hypothalamic and brainstem centres to promote fear behaviour. Extinction of fear is mediated by different circuit elements within the same structures. Input from the infralimbic cortex (IL) to the BA and to the intercalated (ITC) cells is instrumental in dampening fear output from lateral central amygdala (CEl) nuclei to the hypothalamus (HYP) and the periaqueductal grey (PAG). The identity, connectivity and function of important forebrain-to-brainstem fear pathways remain to be characterized by modern circuit-based approaches. CEm, medial central amygdala; LA, lateral amygdala.

  2. Using optogenetics in auditory fear conditioning.
    Figure 2: Using optogenetics in auditory fear conditioning.

    a | Cre-conditional viruses (such as modified adeno-associated virus (AAV)) that express light-sensitive opsins (such as channelrhodopsin 2 (ChR2) or archaerhodopsin (Arch)) can be injected locally into the brain of mutant mouse lines in which Cre recombinase expression is controlled by the promoter of a specific genetic marker, such as parvalbumin (PV). Only the infected cells of defined genetic identity will then develop light sensitivity and can be optically activated or inhibited. In addition, individual neurons of a specific neuronal subtype can be identified using combined optical stimulation and extracellular recordings in freely moving mice. b | Stimulus-specific activity patterns of optically identified cells can be measured during auditory fear conditioning. For example, PV-expressing (PV+) cells in the basolateral amygdala (BLA) are inhibited by the footshock (the unconditioned stimulus (US)) but are excited by the tone (the conditioned stimulus (CS)). Such physiological activity profiles can instruct precisely timed optogenetic interventions during stimulus presentations. c | Fast and temporally precise optogenetic manipulation of neuronal activity presents a powerful tool with which to dissect the circuits underlying conditioned fear. Activity of defined neuronal subpopulations (such as PV+ cells) can be differentially manipulated during CS or US presentations, thus revealing timing-specific and stimulus-specific roles of individual circuit elements in the acquisition of conditioned fear. Specific effects of optical manipulations can be controlled for by a within-subject experimental design: several CS–US pairings with concomitant light exposure are compared with CS–US pairings without light exposure using a tone of a different frequency (in the top panels, differences in frequency are denoted by the different shades of green). Optogenetic augmentation of the natural activity profile of BLA PV+ cells enhances fear learning. That is, when BLA PV+ cells are inhibited during US application in the training session, fear responses to the CS, expressed as freezing behaviour during the cued fear test, are enhanced (lower left panel). Vice versa, activation of BLA PV+ cells during US impairs fear learning and results in diminished fear responses during the cued fear test. By contrast, optogenetic training manipulations during CS exposure result in the opposite effects (lower right panel). Figure is from Ref. 77, Nature Publishing Group.

  3. Disinhibitory microcircuits in fear learning.
    Figure 3: Disinhibitory microcircuits in fear learning.

    a | Projection neurons in the basolateral amygdala (BLA) are under inhibitory control by parvalbumin-expressing (PV+) interneurons77, which target the cell body, and by dendrite-targeting, somatostatin-expressing (SOM+) interneurons, which in turn are under the inhibitory control of PV+ interneurons. During exposure to the conditioned stimulus (CS), increased inhibition of PV+ interneurons onto SOM+ cells results in disinhibition of projection neuron dendrites, thus increasing CS-evoked projection neuron activity (left panel) and enhancing acquisition of fear memory. Application of the unconditioned stimulus (US) causes disinhibition of projection neurons along the entire somatodendritic axis, thus promoting fear learning (right panel). b | In the auditory cortex (AuD), a footshock (the US) excites layer 1 inhibitory cells that project onto layer 2/3 PV+ interneurons, thereby disinhibiting output cells and promoting fear learning43. c | In the medial prefrontal cortex (mPFC), output cells are under inhibitory control of PV+ cells, which themselves become inhibited by CS-induced excitation of presynaptic inhibitory neurons. CS-mediated disinhibition of output cells plays a major part in fear learning87. d | CS-induced excitation of inhibitory ON cells in the lateral central amygdala (CEl) increases inhibition onto inhibitory OFF cells expressing protein kinase Cδ (PKCδ) that project to the medial central amygdala (CEm) output neurons. Disinhibition of these output cells by the CS results in enhanced fear expression. CEA, central amygdala.

  4. The anxiety network.
    Figure 4: The anxiety network.

    a | Anxiety states are mediated by local and long-range connections between multiple brain areas. b | Some regions that have major roles in anxiety, such as the basolateral amydala (BLA) and the anterodorsal bed nucleus of the stria terminalis (adBNST), mediate both anxiogenic and anxiolytic behavioural effects. This indicates the presence of distinct neuronal circuits in anxiety, the functions of which are determined by their target-specific and/or cell-specific connections. For example, activation of the BLA-to-ventral hippocampus (vHC) pathway is anxiogenic152, whereas activation of the BLA-to-central amygdala (CEA) projection is anxiolytic151. By contrast, two parallel ventral BNST (vBNST)-to-ventral tegmental area (VTA) pathways mediate either anxiogenic or anxiolytic behavioural outcomes147. Large parts of the anxiety network remain to be characterized in terms of cellular identity and functions as well as precise local and long-range connectivity using modern circuit-based approaches. HYP, hypothalamus; LC, locus coeruleus; LS, lateral septum; mPFC, medial prefrontal cortex; ovBNST, oval BNST; PAG, periaqueductal grey; PB, parabrachial nucleus; RN, raphe nuclei.

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Author information

  1. These authors contributed equally to this work.

    • Philip Tovote &
    • Jonathan Paul Fadok

Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

    • Philip Tovote,
    • Jonathan Paul Fadok &
    • Andreas Lüthi

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The authors declare no competing interests.

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Author details

  • Philip Tovote

    Philip Tovote received his Ph.D. from the University of Göttingen, Germany, for work done at the Max Planck Institute for Experimental Medicine on the regulation of neuroautonomic fear responses. He worked on neuropeptidergic modulation of fear and anxiety at the University of Hawaii, Honolulu, USA, and is currently a senior postdoctoral fellow and NARSAD Young Investigator at the Friedrich Miescher Institute in Basel, Switzerland. He is using modern optogenetic, in vivo electrophysiological and tracing techniques to investigate the forebrain and brainstem circuits underlying specific aspects of defensiveness. Philip Tovote's homepage.

  • Jonathan Paul Fadok

    Jonathan Paul Fadok completed his B.A. in anthropology at the University of Arizona, Tucson, USA, and his Ph.D. in neurobiology and behaviour with Richard Palmiter at the University of Washington, Seattle, USA. His Ph.D. work focused on studying the role of the mesocorticolimbic dopaminergic system in fear and anxiety states. He is currently a postdoctoral fellow with Andreas Lüthi at the Friedrich Miescher Institute in Basel, Switzerland. His work focuses on using modern, circuit-based approaches to dissect the complex interplay of neuronal populations within and between brain areas that are important for adaptive behavioural states. Jonathan Paul Fadok's homepage.

  • Andreas Lüthi

    Andreas Lüthi received his Ph.D. from the University of Basel, Switzerland, working on the synaptic mechanisms of hippocampal long-term potentiation. After postdoctoral fellowships with Graham L. Collingridge at the University of Bristol, UK, and Beat H. Gähwiler at the University of Zurich, Switzerland, he established his own group, which was first located at the University of Basel, Switzerland, and then at the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. His research focuses on the cellular and circuit mechanisms underlying associative learning using a multidisciplinary approach to study classical conditioning paradigms in mice. Andreas Lüthi's homepage.

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