Newly developed technologies enable us to gain novel insights into how the brain generates fear and anxiety states, based on the identification and manipulation of neuronal circuits within and among individual brain regions.
Fear is mediated by a brain-wide distributed network involving long-range projection pathways and local connectivity. The disinhibitory microcircuit is a common motif in the basolateral amygdala (BLA), central amygdala and the prelimbic region of the medial prefrontal cortex, and is instrumental in fear acquisition and expression.
Encoding of fear extinction involves many of the same brain areas that are involved in fear acquisition and expression; however, different circuits within the amygdala and prefrontal cortex are involved. Indeed, fear extinction circuits may in fact inhibit fear circuits to dampen fearful responding.
As with fear and fear extinction, a brain-wide neuronal network underlies anxiety, with identified local microcircuits within the bed nucleus of the stria terminalis, the lateral septum, the ventral tegmental area (VTA) and the BLA. Importantly, there is potential overlap between fear and anxiety circuits.
There is overlap of neuronal circuits that mediate negative and positive valence in areas such as the VTA. Understanding the interplay between these circuits is of vital importance for understanding adaptive behavioural states.
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.
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The authors thank J. Letzkus for providing constructive criticism of the initial manuscript. Work on this article was supported by the Novartis Research Foundation, the Swiss National Science Foundation (grants to A.L.), and the Brain & Behaviour Research Foundation, which awarded NARSAD Young Investigator grants to P.T. and J.P.F.
The authors declare no competing financial interests.
In the psychological or behavioural context, valence is used to describe the emotional value — positive or negative — that is associated with a distinct or situational stimulus.
In contrast to long-range projection pathways between distinct brain regions, microcircuits consist of interconnected neurons within a specific brain region and often involve inhibitory interneurons.
- Neuronal substrates
Used as an umbrella term to encompass multiple aspects of brain function, neuronal substrates include anatomical and cellular neuroarchitecture, electrical and neurochemical processes, and circuit mechanisms.
Often used to describe changes specifically in synaptic transmission, plasticity can also refer to different experience- or learning-induced changes within neuronal circuits — such as alteration of connectivity, morphology, and cellular and molecular composition — or to observed changes in stimulus- or context-driven neuronal activity patterns.
- Projection neurons
(Also known as principal neurons). An excitatory glutamatergic or inhibitory GABAergic projection neuron projects to a brain area outside the region in which its cell body is located.
Mainly comprising inhibitory GABAergic cells, locally connected interneurons exhibit specific morphology, electrophysiological properties, molecular composition, projection targets and cellular functions to control activity of projection neurons or other interneurons.
- Defensive behaviours
Expressed in response to threatening stimuli or situations, defensive behaviours serve to avoid or reduce harm and are highly conserved across mammals.
- Fear memory trace
Often used to emphasize its physical location inside the brain, a fear memory trace refers to the neuronal substrates that underlie the formation, storage and recall of the internal representation of a fearful event.
Describing a neuronal mechanism prevalent in fear learning, disinhibition results in enhanced activity of a postsynaptic neuron by way of inhibiting an inhibitory presynaptic input.
- Theta rhythms
A specific type of oscillatory neuronal activity in the 4–10 Hz range. Theta rhythms have been strongly implicated in fear learning and expression.
- Intercalated cell masses
(ITC cell masses). As specialized clusters of mostly inhibitory neurons nestled in the fibre bundles surrounding the amygdala, ITC cell masses are thought to gate information flow in the amygdala.
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Tovote, P., Fadok, J. & Lüthi, A. Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16, 317–331 (2015). https://doi.org/10.1038/nrn3945
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