Abstract
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 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.
Anxiety plays a key role in guiding behavior in response to potential threats. Anxiety is mediated by the activation of pyramidal neurons in the ventral hippocampus (vH), whose activity is controlled ...by GABAergic inhibitory interneurons. However, how different vH interneurons might contribute to anxiety-related processes is unclear. Here, we investigate the role of vH parvalbumin (PV)-expressing interneurons while mice transition from safe to more anxiogenic compartments of the elevated plus maze (EPM). We find that vH PV interneurons increase their activity in anxiogenic EPM compartments concomitant with dynamic changes in inhibitory interactions between PV interneurons and pyramidal neurons. By optogenetically inhibiting PV interneurons, we induce an increase in the activity of vH pyramidal neurons and persistent anxiety. Collectively, our results suggest that vH inhibitory microcircuits may act as a trigger for enduring anxiety states.
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•vH PV interneurons are activated in anxiogenic compartments of the EPM•vH PV interneurons show state-dependent interactions with pyramidal neurons•vH PV interneurons disinhibit pyramidal neurons in anxiogenic EPM compartments•Optogenetic inhibition of vH PV interneurons induces persistent anxiety
Volitaki et al. find that inhibitory vH PV interneurons increase their activity in the anxiety-inducing compartments of the elevated plus maze. Optogenetic inhibition of PV interneuron activity in the anxiogenic compartments disinhibits pyramidal neurons and leads to persistent anxiety, suggesting that vH PV interneurons are potential targets for anxiety disorders.
Anxiety is an aversive mood reflecting the anticipation of potential threats. The ventral hippocampus (vH) is a key brain region involved in the genesis of anxiety responses. Recent studies have ...shown that anxiety is mediated by the activation of vH pyramidal neurons targeting various limbic structures. Throughout the cortex, the activity of pyramidal neurons is controlled by GABA–releasing inhibitory interneurons and the GABAergic system represents an important target of anxiolytic drugs. However, how the activity of vH inhibitory interneurons is related to different anxiety behaviours has not been investigated so far. Here, we integrated in vivo electrophysiology with behavioural phenotyping of distinct anxiety exploration behaviours in rats. We showed that pyramidal neurons and interneurons of the vH are selectively active when animals explore specific compartments of the elevated-plus-maze (EPM), an anxiety task for rodents. Moreover, rats with prior goal-related experience exhibited low-anxiety exploratory behaviour and showed a larger trajectory-related activity of vH interneurons during EPM exploration compared to high anxiety rats. Finally, in low anxiety rats, trajectory-related vH interneurons exhibited opposite activity to pyramidal neurons specifically in the open arms (i.e. more anxiogenic) of the EPM. Our results suggest that vH inhibitory micro-circuits could act as critical elements underlying different anxiety states.
•Interneurons of the vH are activated in specific compartments of the EPM, an anxiety task for rodents.•Rats trained on a goal-related task exhibit lower anxiety expressed by an increased exploration of the open arms of the EPM.•Rats with lower anxiety show stronger trajectory-related activity of vH interneurons on the EPM compared to anxious rats.•In low anxiety rats, trajectory-related vH interneurons show inhibitory interactions with pyramidal neurons in open arms.
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.
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.
Extinction memory retrieval is influenced by spatial contextual information that determines responding to conditioned stimuli (CS). However, it is poorly understood whether contextual representations ...are imbued with emotional values to support memory selection. Here, we performed activity-dependent engram tagging and in vivo single-unit electrophysiological recordings from the ventral hippocampus (vH) while optogenetically manipulating basolateral amygdala (BLA) inputs during the formation of cued fear extinction memory. During fear extinction when CS acquire safety properties, we found that CS-related activity in the vH reactivated during sleep consolidation and was strengthened upon memory retrieval. Moreover, fear extinction memory was facilitated when the extinction context exhibited precise coding of its affective zones. Last, these activity patterns along with the retrieval of the fear extinction memory were dependent on glutamatergic transmission from the BLA during extinction learning. Thus, fear extinction memory relies on the formation of contextual and stimulus safety representations in the vH instructed by the BLA.
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.
Classical fear conditioning is a powerful behavioral paradigm that is widely used to study the neuronal substrates of learning and memory. Previous studies have clearly identified the amygdala as a ...key brain structure for acquisition and storage of fear memory traces. Whereas the majority of this work has focused on principal cells and glutamatergic transmission and its plasticity, recent studies have started to shed light on the intricate roles of local inhibitory circuits. Here, we review current understanding and emerging concepts of how local inhibitory circuits in the amygdala control the acquisition, expression, and extinction of conditioned fear at different levels.
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.
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