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In emotion research, anxiety and fear have always been interconnected, sharing overlapping brain structures and neural circuitry. Recent investigations, however, have unveiled parallel long-range projection pathways originating from the ventral hippocampus, shedding light on their distinct roles in anxiety and fear. Yet, the mechanisms governing the emergence of projection-specific activity patterns to mediate different negative emotions remain elusive. Here, we show a division of labor in local GABAergic inhibitory microcircuits of the ventral hippocampus, orchestrating the activity of subpopulations of pyramidal neurons to shape anxiety and fear behaviors in mice. These findings offer a comprehensive insight into how distinct inhibitory microcircuits are dynamically engaged to encode different emotional states. The mechanisms by which the brain processes the intertwined states of anxiety and fear remain unclear. Here, authors show that distinct inhibitory microcircuits in the ventral hippocampus differentially regulate anxiety and fear behaviors.

Fear extinction is an adaptive process whereby defensive responses are attenuated following repeated experience of prior fear-related stimuli without harm. The formation of extinction memories involves interactions between various corticolimbic structures, resulting in reduced central amygdala (CEA) output. Recent studies show, however, the CEA is not merely an output relay of fear responses but contains multiple neuronal subpopulations that interact to calibrate levels of fear responding. Here, by integrating behavioural, in vivo electrophysiological, anatomical and optogenetic approaches in mice we demonstrate that fear extinction produces reversible, stimulus- and context-specific changes in neuronal responses to conditioned stimuli in functionally and genetically defined cell types in the lateral (CEl) and medial (CEm) CEA. Moreover, we show these alterations are absent when extinction is deficient and that selective silencing of protein kinase C delta-expressing (PKCδ) CEl neurons impairs fear extinction. Our findings identify CEA inhibitory microcircuits that act as critical elements within the brain networks mediating fear extinction. The central amygdala inhibitory microcircuits mediate fear extinction by reversible, stimulus- and context-specific changes in neuronal responses. These alterations are absent when extinction is deficient and selective silencing of PKCδ neurons impairs fear extinction.

The ventral hippocampus (vH) plays a crucial role in anxiety-related behaviour and vH neurons increase their firing when animals explore anxiogenic environments. However, if and how such neuronal activity induces or restricts the exploration of an anxiogenic location remains unexplained. Here, we developed a novel behavioural paradigm to motivate rats to explore an anxiogenic area. Male rats ran along an elevated linear maze with protective sidewalls, which were subsequently removed in parts of the track to introduce an anxiogenic location. We recorded neuronal action potentials during task performance and found that vH neurons exhibited remapping of activity, overrepresenting anxiogenic locations. Direction-dependent firing was homogenised by the anxiogenic experience. We further showed that the activity of vH neurons predicted the extent of exploration of the anxiogenic location. Our data suggest that anxiety-related firing does not solely depend on the exploration of anxiogenic environments, but also on intentions to explore them.

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.

Mastering navigation in environments with limited visibility is crucial for survival. Although the hippocampus has been associated with goal-oriented navigation, its role in real-world behaviour remains unclear. To investigate this, we combined deep reinforcement learning (RL) modelling with behavioural and neural data analysis. First, we trained RL agents in partially observable environments using egocentric and allocentric tasks. We show that agents equipped with recurrent hippocampal circuitry, but not purely feedforward networks, learned the tasks in line with animal behaviour. Next, we used dimensionality reduction of the agents’ internal representations to extract components reflecting reward, strategy, and temporal representations, which we validated experimentally against hippocampal recordings from rats. Moreover, hippocampal RL agents predicted state-specific trajectories, mirroring empirical findings. In contrast, agents trained in fully observable environments failed to capture experimental observations. Finally, we show that hippocampal-like RL agents demonstrated improved generalisation across novel task conditions. In summary, our findings suggest an important role of hippocampal networks in facilitating reinforcement learning in naturalistic environments. Neural mechanisms underlying reinforcement learning in naturalistic environments are not fully understood. Here authors show that reinforcement learning (RL) agents with hippocampal-like recurrence, unlike feedforward networks, match animal behaviour and neural data in navigation tasks, revealing that hippocampal circuits support RL in naturalistic environments.

Coordinated shifts of neuronal activity in the prefrontal cortex are associated with strategy adaptations in behavioural tasks, when animals switch from following one rule to another. However, network dynamics related to multiple-rule changes are scarcely known. We show how firing rates of individual neurons in the prelimbic and cingulate cortex correlate with the performance of rats trained to change their navigation multiple times according to allocentric and egocentric strategies. The concerted population activity exhibits a stable firing during the performance of one rule but shifted to another neuronal firing state when a new rule is learnt. Interestingly, when the same rule is presented a second time within the same session, neuronal firing does not revert back to the original neuronal firing state, but a new activity-state is formed. Our data indicate that neuronal firing of prefrontal cortical neurons represents changes in strategy and task-performance rather than specific strategies or rules.

Pavlovian fear conditioning, a simple form of associative learning, is thought to involve the induction of associative, NMDA receptor–dependent long-term potentiation (LTP) in the lateral amygdala. Using a combined genetic and electrophysiological approach, we show here that lack of a specific GABA B receptor subtype, GABA B(1a,2) , unmasks a nonassociative, NMDA receptor–independent form of presynaptic LTP at cortico-amygdala afferents. Moreover, the level of presynaptic GABA B(1a,2) receptor activation, and hence the balance between associative and nonassociative forms of LTP, can be dynamically modulated by local inhibitory activity. At the behavioral level, genetic loss of GABA B(1a) results in a generalization of conditioned fear to nonconditioned stimuli. Our findings indicate that presynaptic inhibition through GABA B(1a,2) receptors serves as an activity-dependent constraint on the induction of homosynaptic plasticity, which may be important to prevent the generalization of conditioned fear.

Acquiring and exploiting memories of rewarding experiences is critical for survival. The spatial environment in which a rewarding stimulus is encountered regulates memory retrieval. The ventral hippocampus (vH) has been implicated in contextual memories involving rewarding stimuli such as food, social cues or drugs. Yet, the neuronal representations and circuits underlying contextual memories of socially rewarding stimuli are poorly understood. Here, using in vivo electrophysiological recordings, in vivo one-photon calcium imaging, and optogenetics during a social reward contextual conditioning paradigm in male mice, we show that vH neurons discriminate between contexts with neutral or acquired social reward value. The formation of context-discriminating vH neurons following learning was contingent upon the presence of unconditioned stimuli. Moreover, vH neurons showed distinct contextual representations during the retrieval of social reward compared to fear contextual memories. Finally, optogenetic inhibition of locus coeruleus (LC) projections in the vH selectively disrupted social reward contextual memory by impairing vH contextual representations. Collectively, our findings reveal that the vH integrates contextual and social reward information, with memory encoding of these representations supported by input from the LC. The neuronal mechanisms serving contextual memories of socially rewarding stimuli are unclear. Here the authors demonstrate that neurons in the ventral hippocampus of male mice discriminate between neutral and socially rewarding contexts, a process dependent on input from the locus coeruleus.

The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour. The neural circuitry of fear The central amygdala, composed mainly of GABAergic inhibitory neurons, is the part of the brain that processes Pavlovian conditioned fear. Two groups reporting in this issue of Nature use different yet complementary experimental approaches to arrive at similar conclusions about the functional architecture that underlies the conditioned fear response. They find that two microcircuits are involved, one required for fear acquisition and the other for conditioned fear responses. Haubensak et al . use genetically based functional manipulations to identify a subpopulation of GABAergic neurons that has a key role in gating learned fear. Ciocchi et al . use a combination of in vivo electrophysiological, optogenetic and pharmacological approaches in mice to identify three functionally distinct types of neurons that are embedded in a highly organized local disinhibitory network. The central amygdala relies on inhibitory circuitry to encode fear memories, but how this information is acquired and expressed in these connections is unknown. Two new papers use a combination of cutting-edge technologies to reveal two distinct microcircuits within the central amygdala, one required for fear acquisition and the other critical for conditioned fear responses. Understanding this architecture provides a strong link between activity in a specific circuit and particular behavioural consequences.

Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.