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In this Review, Lüscher and Lüthi draw some parallels between anxiety and addiction disorders as diseases of the brain's emotional valence system. The authors present an update on the anatomy and heterogeneity of the fear and reward circuitries, analyze our understanding of the synaptic and cellular mechanisms thought to underlie the two conditions and discuss recent studies causally linking the resulting circuit dysfunctions and alterations in behavior. Current models of addiction and anxiety stem from the idea that aberrant function and remodeling of neural circuits cause the pathological behaviors. According to this hypothesis, a disease-defining experience (for example, drug reward or stress) would trigger specific forms of synaptic plasticity, which in susceptible subjects would become persistent and lead to the disease. While the notion of synaptic diseases has received much attention, no candidate disorder has been sufficiently investigated to yield new, rational therapies that could be tested in the clinic. Here we review the arguments in favor of abnormal neuronal plasticity underlying addiction and anxiety disorders, with a focus on the functional diversity of neurons that make up the circuits involved. We argue that future research must strive to obtain a comprehensive description of the relevant functional anatomy. This will allow identification of molecular mechanisms that govern the induction and expression of disease-relevant plasticity in identified neurons. To establish causality, one will have to test whether normalization of function can reverse pathological behavior. With these elements in hand, it will be possible to propose blueprints for manipulations to be tested in translational studies. The challenge is daunting, but new techniques, above all optogenetics, may enable decisive advances.

Key Points 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. Recent methodological progress has greatly facilitated the determination of the connectivity and functional characterization of complex neural circuits. In this Review, Tovote, Fadok and Lüthi examine studies that have adopted circuit-based approaches to gain insight into how the brain governs fear and anxiety. 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.

In adult animals, fear conditioning induces a permanent memory that is resilient to erasure by extinction. In contrast, during early postnatal development, extinction of conditioned fear leads to memory erasure, suggesting that fear memories are actively protected in adults. We show here that this protection is conferred by extracellular matrix chondroitin sulfate proteoglycans (CSPGs) in the amygdala. The organization of CSPGs into perineuronal nets (PNNs) coincided with the developmental switch in fear memory resilience. In adults, degradation of PNNs by xnondroitinase ABC specifically rendered subsequently acquired fear memories susceptible to erasure. This result indicates that intact PNNs mediate the formation of erasure-resistant fear memories and identifies a molecular mechanism closing a postnatal critical period during which traumatic memories can be erased by extinction.

Competitive circuits in the amygdala of mice drive either freezing or flight behaviour in response to threat, and involve distinct neuronal subtypes. Freeze or flee — choosing the best response to danger The appropriate selection of either a passive or an active fear response when faced with a threat is critical to an animal's survival, but how that decision is made remains poorly understood. Here, Andreas Lüthi and colleagues describe competitive circuits in the amygdala that involve distinct neuronal subtypes and drive either the freezing or the flight behaviour. When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses 1 , 2 , 3 . Freezing is an evolutionarily conserved passive fear response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents 4 . However, rodents also exhibit active responses such as flight under natural conditions 2 . The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established 1 , 5 , 6 , 7 . Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF + ) mediate conditioned flight, and activation of somatostatin-positive (SOM + ) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF + and SOM + neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.

How is it that groups of neurons dispersed through the brain interact to generate complex behaviors? Three papers in this issue present brain-scale studies of neuronal activity and dynamics (see the Perspective by Huk and Hart). Allen et al. found that in thirsty mice, there is widespread neural activity related to stimuli that elicit licking and drinking. Individual neurons encoded task-specific responses, but every brain area contained neurons with different types of response. Optogenetic stimulation of thirst-sensing neurons in one area of the brain reinstated drinking and neuronal activity across the brain that previously signaled thirst. Gründemann et al. investigated the activity of mouse basal amygdala neurons in relation to behavior during different tasks. Two ensembles of neurons showed orthogonal activity during exploratory and nonexploratory behaviors, possibly reflecting different levels of anxiety experienced in these areas. Stringer et al. analyzed spontaneous neuronal firing, finding that neurons in the primary visual cortex encoded both visual information and motor activity related to facial movements. The variability of neuronal responses to visual stimuli in the primary visual area is mainly related to arousal and reflects the encoding of latent behavioral states. Science , this issue p. eaav3932 , p. eaav8736 , p. eaav7893 ; see also p. 236 Longitudinal large-scale imaging of amygdala activity reveals dynamic encoding of behavioral states by two distinct neural ensembles. Internal states, including affective or homeostatic states, are important behavioral motivators. The amygdala regulates motivated behaviors, yet how distinct states are represented in amygdala circuits is unknown. By longitudinally imaging neural calcium dynamics in freely moving mice across different environments, we identified opponent changes in activity levels of two major, nonoverlapping populations of basal amygdala principal neurons. This population signature does not report global anxiety but predicts switches between exploratory and nonexploratory, defensive states. Moreover, the amygdala separately processes external stimuli and internal states and broadcasts state information via several output pathways to larger brain networks. Our findings extend the concept of thalamocortical “brain-state” coding to include affective and exploratory states and provide an entry point into the state dependency of brain function and behavior in defined circuits.

Learning drives behavioral adaptations necessary for survival. While plasticity of excitatory projection neurons during associative learning has been extensively studied, little is known about the contributions of local interneurons. Using fear conditioning as a model for associative learning, we found that behaviorally relevant, salient stimuli cause learning by tapping into a local microcircuit consisting of precisely connected subtypes of inhibitory interneurons. By employing deep-brain calcium imaging and optogenetics, we demonstrate that vasoactive intestinal peptide (VIP)-expressing interneurons in the basolateral amygdala are activated by aversive events and provide a mandatory disinhibitory signal for associative learning. Notably, VIP interneuron responses during learning are strongly modulated by expectations. Our findings indicate that VIP interneurons are a central component of a dynamic circuit motif that mediates adaptive disinhibitory gating to specifically learn about unexpected, salient events, thereby ensuring appropriate behavioral adaptations.

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits. Stimulus convergence and concomitant auditory cortex disinhibition are essential for fear learning. Sounds like fear It is generally recognized that learned behavioural responses, such as those associated with sound, involve changes within specific neural circuits. However, we are only beginning to understand how those changes are implemented and what interactions between different types of neurons within the circuits contribute to the learning process. Using classical sound-based fear-conditioning in mice as a model system, Andreas Lüthi and colleagues identify a distinct disinhibition-based circuit that is critical to learning. The neural circuit involved is not specific to auditory cortex, and may represent a general mechanism through which cholinergic neuromodulation gates cortical activity.

Switching between exploratory and defensive behaviour is fundamental to survival of many animals, but how this transition is achieved by specific neuronal circuits is not known. Here, using the converse behavioural states of fear extinction and its context-dependent renewal as a model in mice, we show that bi-directional transitions between states of high and low fear are triggered by a rapid switch in the balance of activity between two distinct populations of basal amygdala neurons. These two populations are integrated into discrete neuronal circuits differentially connected with the hippocampus and the medial prefrontal cortex. Targeted and reversible neuronal inactivation of the basal amygdala prevents behavioural changes without affecting memory or expression of behaviour. Our findings indicate that switching between distinct behavioural states can be triggered by selective activation of specific neuronal circuits integrating sensory and contextual information. These observations provide a new framework for understanding context-dependent changes of fear behaviour. Tripping the 'fear switch' For many animals, an ability to switch from a 'normal' bold or exploratory approach to a situation to a more defensive approach when prudent is an important survival aid. Much is known about the role of entire brain areas in such processes, but what happens at the level of neuronal circuits is less well understood. 'Fear extinction' and 'renewal', two processes in which learned fearful responses to stimuli associated with unpleasant consequences are unlearned, then renewed, are effective models for probing mechanisms associated with changes in behavioural state. Herry et al . show that changes in the balance of activity of two distinct neuronal populations in the basolateral amygdala can trigger transitions between states of high and low fear in mice. Likhtik et al . report another mechanism for 'unlearning' fearful memories, this time in rats. Amygdala cells known as intercalated neurons, which receive information from the basolateral amygdala, appear to be responsible in this case. This work suggests possible new avenues for the treatment of anxiety disorders. Changes in the balance of activity of two distinct neuronal populations in the basolateral amygdala trigger transitions between states of high and low fear in mice. The two populations of neurons tend to participate in different anatomical circuits, suggesting that even within a single brain area, selective activation of specific neuronal circuits can trigger large changes in behavioral state.

The behaviour of an animal is determined by metabolic, emotional and social factors 1 , 2 . Depending on its state, an animal will focus on avoiding threats, foraging for food or on social interactions, and will display the appropriate behavioural repertoire 3 . Moreover, survival and reproduction depend on the ability of an animal to adapt to changes in the environment by prioritizing the appropriate state 4 . Although these states are thought to be associated with particular functional configurations of large-brain systems 5 , 6 , the underlying principles are poorly understood. Here we use deep-brain calcium imaging of mice engaged in spatial or social exploration to investigate how these processes are represented at the neuronal population level in the basolateral amygdala, which is a region of the brain that integrates emotional, social and metabolic information. We demonstrate that the basolateral amygdala encodes engagement in exploratory behaviour by means of two large, functionally anticorrelated ensembles that exhibit slow dynamics. We found that spatial and social exploration were encoded by orthogonal pairs of ensembles with stable and hierarchical allocation of neurons according to the saliency of the stimulus. These findings reveal that the basolateral amygdala acts as a low-dimensional, but context-dependent, hierarchical classifier that encodes state-dependent behavioural repertoires. This computational function may have a fundamental role in the regulation of internal states in health and disease. Deep-brain calcium imaging of mice engaged in social or spatial exploration reveals that these state-dependent behaviours are encoded by distinct neuronal ensembles of the basolateral amygdala.

Animals make decisions based on the value of potential outcomes. This perceived value is not fixed; it changes depending on internal needs, such as hunger or thirst, and past experiences. The basolateral amygdala (BLA) is known to be crucial for updating predicted reward values. However, it has been unclear how the BLA represents the specific value of different rewards. Two-photon calcium imaging in male mice showed that population response magnitude scaled with subjective value, and different rewards recruited distinct neuronal subpopulations. Value representations quickly re-scaled when a novel, higher-value reward appeared, and internal state shaped them: thirst selectively boosted responses to water, whereas aversive experience dampened sucrose responses. Thus, BLA circuits carry flexible, stimulus-specific value signals that integrate relative value and current affective or homeostatic conditions, providing a neural basis for adaptive decision making and learning. Our findings reveal that the BLA maintains adaptable, reward-specific value signals, essential for guiding choices according to current needs and changing circumstances. How basolateral amygdala represents the specific value of rewards remains unclear. Here the authors find that basolateral amygdala neurons assign stimulus-specific values to different rewards and rapidly re-scale these signals with changing reward context, thirst or stress, illuminating how the brain guides flexible, state-dependent choices.