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
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A classic review that covers the seminal work on the role of the amygdala in fear conditioning.
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A comprehensive review of classic research on the key role of the amygdala in anxiety.
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An instructive collection of classic experimental approaches, behavioural paradigms and influential concepts in fear and anxiety.
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An elegant study using modern circuit-based approaches to investigate positive and negative valence coding in the VTA.
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A seminal work demonstrating that amygdala neurons undergo plastic changes as a result of aversive conditioning.
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- Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995).
A classic in vivo study showing that fear conditioning induces plasticity in LA neurons.
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- Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron 19, 613–624 (1997).
A paper demonstrating that different neuronal populations in the amygdala encode different aspects of the fear memory.
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A multidimensional study on the cortical circuit basis for auditory fear conditioning.
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A classic study showing distinct roles for different brain areas in fear conditioning.
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- NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J. Neurosci. 22, 5239–5249 (2002). , &
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- N-methyl-d-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning. Behav. Neurosci. 105, 126–133 (1991). , , &
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- Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).
An early demonstration that AMPA receptor trafficking mediates fear memory formation.
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A report that establishes the existence of distinct neuronal subpopulations that are devoted to the encoding of fear and fear extinction.
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- Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012). et al.
- CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nature Neurosci. 12, 1438–1443 (2009). et al.
- Assignment of model amygdala neurons to the fear memory trace depends on competitive synaptic interactions. J. Neurosci. 33, 14354–14358 (2013). , &
- Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice. Eur. J. Neurosci. 25, 1205–1211 (2007). , &
- Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition. Nature Neurosci. 9, 1028–1035 (2006). et al.
- Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nature Neurosci. 6, 587–592 (2003). , &
- Similar inhibitory processes dominate the responses of cat lateral amygdaloid projection neurons to their various afferents. J. Neurophysiol. 77, 341–352 (1997). &
- GABAA and GABAB receptors differentially regulate synaptic transmission in the auditory thalamo-amygdala pathway: an in vivo microiontophoretic study and a model. Synapse 24, 115–124 (1996). , &
- Norepinephrine enables the induction of associative long-term potentiation at thalamo-amygdala synapses. Proc. Natl Acad. Sci. USA 104, 14146–14150 (2007). , , &
- An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J. Neurosci. 19, 10575–10583 (1999).
Important work that demonstrates the role of ITC cell masses in gating information flow in the amygdala.
- A specific class of interneuron mediates inhibitory plasticity in the lateral amygdala. J. Neurosci. 30, 14619–14629 (2010). , , &
- Amygdala interneuron subtypes control fear learning through disinhibition. Nature 509, 453–458 (2014).
A recent study taking advantage of the cellular specificity and temporal precision of optogenetics to characterize amygdala interneuron function.
- Cell-type-specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo. Neuron 74, 1059–1074 (2012). , , , &
- Pyramidal cells of the rat basolateral amygdala: synaptology and innervation by parvalbumin-immunoreactive interneurons. J. Comp. Neurol. 494, 635–650 (2006). , &
- Postsynaptic targets of somatostatin-containing interneurons in the rat basolateral amygdala. J. Comp. Neurol. 500, 513–529 (2007). , &
- Oxytocin selectively gates fear responses through distinct outputs from the central amygdala. Science 333, 104–107 (2011). et al.
- Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308, 245–248 (2005). , &
- Serotonin-immunoreactive axon terminals innervate pyramidal cells and interneurons in the rat basolateral amygdala. J. Comp. Neurol. 505, 314–335 (2007). , &
- Cholinergic innervation of pyramidal cells and parvalbumin-immunoreactive interneurons in the rat basolateral amygdala. J. Comp. Neurol. 519, 790–805 (2011). , &
- Dopaminergic innervation of interneurons in the rat basolateral amygdala. Neuroscience 157, 850–863 (2008). , , &
- Dendritic inhibition in the hippocampus supports fear learning. Science 343, 857–863 (2014). et al.
- Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression. Nature 505, 92–96 (2014).
An elegant study that identifies a prefrontal microcircuit that is crucial for fear responses.
- Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013). et al.
- A synaptic memory trace for cortical receptive field plasticity. Nature 450, 425–429 (2007). , &
- Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378, 75–78 (1995). , , , &
- Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition. Nature Neurosci. 15, 769–775 (2012). et al.
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- Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468, 277–282 (2010).
This investigation identifies a CEA microcircuit that is instrumental in fear learning.
- Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468, 270–276 (2010).
This study identifies distinct cell classes that constitute the CEA microcircuit important for fear.
- Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73, 553–566 (2012). et al.
- Experience-dependent modification of a central amygdala fear circuit. Nature Neurosci. 16, 332–339 (2013).
This paper identifies SOM+ neurons in the CEA as vital components in fear memory formation and expression.
- Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988). , , &
- Central amygdala activity during fear conditioning. J. Neurosci. 31, 289–294 (2011). , &
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- Topography of projections from amygdala to bed nuclei of the stria terminalis. Brain Res. Brain Res. Rev. 38, 192–246 (2001). , &
- Projections from the lateral part of the central amygdalar nucleus to the postulated fear conditioning circuit. Brain Res. 763, 247–254 (1997). &
- Fear conditioning potentiates synaptic transmission onto long-range projection neurons in the lateral subdivision of central amygdala. J. Neurosci. 34, 2432–2437 (2014). , &
- The medial geniculate, not the amygdala, as the root of auditory fear conditioning. Hear. Res. 274, 61–74 (2011).
- Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. J. Neurosci. 29, 8474–8482 (2009). , &
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- Activity in prelimbic cortex is necessary for the expression of learned, but not innate, fears. J. Neurosci. 27, 840–844 (2007). &
- Long-range connectivity defines behavioral specificity of amygdala neurons. Neuron 81, 428–437 (2014). et al.
- Gating of fear in prelimbic cortex by hippocampal and amygdala inputs. Neuron 76, 804–812 (2012). , , &
- Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nature Neurosci. 17, 106–113 (2014). , , , &
- Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval. Science 301, 846–850 (2003).
An important contribution that establishes a role for synchronized oscillations between brain regions in fear conditioning.
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- Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear. Front. Behav. Neurosci. 8, 129 (2014). et al.
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- Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala. Eur. J. Neurosci. 24, 261–269 (2006). , , , &
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A classic neuropharmacology paper that demonstrates the necessity for NMDAR activation in fear extinction.
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- Amygdala intercalated neurons are required for expression of fear extinction. Nature 454, 642–645 (2008). , , , &
- The intercalated cell masses project to the central and medial nuclei of the amygdala in cats. Neuroscience 57, 1077–1090 (1993). &
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- Fear extinction causes target-specific remodeling of perisomatic inhibitory synapses. Neuron 80, 1054–1065 (2013). , , &
- Localization of the CB1 type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons. Neuroscience 107, 641–652 (2001). &
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- Inactivation of the infralimbic but not the prelimbic cortex impairs consolidation and retrieval of fear extinction. Learn. Mem. 16, 520–529 (2009). &
- Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002).
A seminal study that shows the involvement of the mPFC in extinction.
- Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex. Neuron 53, 871–880 (2007). , , &
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A good example of the power of modern optogenetic studies to reveal circuits for specific aspects of an emotional state.
- Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013).
This study uses a combination of modern circuit-based techniques to show that the BNST mediates distinct aspects of anxiety behaviour.
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One of the first studies to apply modern approaches to study the circuit basis of anxiety.
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A powerful use of in vivo electrical recordings to gain a circuit perspective in anxiety research.
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A multimethod approach that refined the role of the septohippocampal system in stress-induced anxiety.
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- Midbrain dopaminergic neurons and striatal cholinergic interneurons encode the difference between reward and aversive events at different epochs of probabilistic classical conditioning trials. J. Neurosci. 28, 11673–11684 (2008). , , , &
- Dopamine is necessary for cue-dependent fear conditioning. J. Neurosci. 29, 11089–11097 (2009). , &
- Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature 459, 837–841 (2009). &
- Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nature Neurosci. 14, 620–626 (2011). et al.
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- Natural neural projection dynamics underlying social behavior. Cell 157, 1535–1551 (2014). et al.
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- Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J. Neurosci. 31, 11457–11471 (2011). , , , &
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- Aversive-bias and stage-selectivity in neurons of the primate amygdala during acquisition, extinction, and overnight retention. J. Neurosci. 32, 8598–8610 (2012). &
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- Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513, 426–430 (2014). et al.
- Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011). et al.