Dopaminergic circuits controlling threat and safety learning.

The ability to learn from experience that certain cues and situations are associated with threats or safety is crucial for survival and adaptive behavior. Understanding the neural substrates of threat and safety learning has high clinical significance because deficits in these forms of learning characterize anxiety disorders. Traditionally, dopamine neurons were thought to uniformly support reward learning by signaling reward prediction errors.

Functional architecture of dopamine neurons driving fear extinction learning.

The ability to extinguish fear responses to stimuli that no longer predict danger is critical for adaptive behavior and increases the likelihood of survival. During fear extinction, dopamine (DA) neurons signal the absence of the expected aversive outcome, and this extinction prediction error (EPE) signal is crucial for initiating and driving extinction learning. However, the neural circuits underlying the EPE signal have remained elusive.

Dopaminergic circuits underlying associative aversive learning.

Associative aversive learning enables animals to predict and avoid threats and thus is critical for survival and adaptive behavior. Anxiety disorders are characterized with deficits in normal aversive learning mechanisms and hence understanding the neural circuits underlying aversive learning and memory has high clinical relevance. Recent studies have revealed the dopamine system as one of the key modulators of aversive learning.

Prefrontal pyramidal neurons are critical for all phases of working memory.

The prefrontal cortex (PFC) is essential for working memory (WM) and has primarily been viewed as being responsible for maintaining information over a delay, but it is unclear whether it also plays a more general role during WM. Using task phase-specific optogenetic silencing of pyramidal neurons in the medial PFC (mPFC) of mice performing a spatial WM task, we find that the mPFC is required not only during the delay phase of the task but also during other phases requiring the encoding and retrieval of spatial information. Imaging of mPFC pyramidal neurons reveals that they are most strongly influenced by the animals' position and running direction, indicating a fundamental role in spatial navigation.

Dopamine in Fear Extinction.

The ability to extinguish fear memories when threats are no longer present is critical for adaptive behavior. Fear extinction represents a new learning process that eventually leads to the formation of extinction memories. Understanding the neural basis of fear extinction has considerable clinical significance as deficits in extinction learning are the hallmark of human anxiety disorders.

In vivo functional diversity of midbrain dopamine neurons within identified axonal projections.

Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain.

A Dopaminergic Basis for Fear Extinction.

It is a joyous relief when an event we dread fails to materialize. In fear extinction, the appetitive nature of an omitted aversive event is not a mere epiphenomenon but drives the reduction of fear responses and the formation of long-term extinction memories. Dopamine emerges as key neurobiological mediator of these related processes.

Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes.

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction.

Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression.

The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA).

Detecting joint pausiness in parallel spike trains.

Background: Transient periods with reduced neuronal discharge - called 'pauses' - have recently gained increasing attention. In dopamine neurons, pauses are considered important teaching signals, encoding negative reward prediction errors. Particularly simultaneous pauses are likely to have increased impact on information processing.

Hippocampal-Prefrontal Interactions in Cognition, Behavior and Psychiatric Disease.

The hippocampus and prefrontal cortex (PFC) have long been known to play a central role in various behavioral and cognitive functions. More recently, electrophysiological and functional imaging studies have begun to examine how interactions between the two structures contribute to behavior during various tasks. At the same time, it has become clear that hippocampal-prefrontal interactions are disrupted in psychiatric disease and may contribute to their pathophysiology.

Amygdala microcircuits controlling learned fear.

We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear.

Amygdala microcircuits mediating fear expression and extinction.

This review summarizes the latest developments in our understanding of amygdala networks that support classical fear conditioning, the experimental paradigm most commonly used to study learned fear in the laboratory. These recent advances have considerable translational significance as congruent findings from studies of fear learning in animals and humans indicate that anxiety disorders result from abnormalities in the mechanisms that normally regulate conditioned fear. Because of the introduction of new techniques and the continued use of traditional approaches, it is becoming clear that conditioned fear involves much more complex networks than initially believed, including coordinated interactions between multiple excitatory and inhibitory circuits within the amygdala.

The fear circuit revisited: contributions of the basal amygdala nuclei to conditioned fear.

The lateral nucleus (LA) is the input station of the amygdala for information about conditioned stimuli (CSs), whereas the medial sector of the central nucleus (CeM) is the output region that contributes most amygdala projections to brainstem fear effectors. However, there are no direct links between LA and CeM. As the main target of LA and with its strong projection to CeM, the basomedial amygdala (BM) constitutes a good candidate to bridge this gap.

Central amygdala activity during fear conditioning.

The central amygdala (Ce), particularly its medial sector (CeM), is the main output station of the amygdala for conditioned fear responses. However, there is uncertainty regarding the nature of CeM control over conditioned fear. The present study aimed to clarify this question using unit recordings in rats.

Impact of predatory threat on fear extinction in Lewis rats.

Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome.

Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep.

Brain activity in sleep plays a crucial role in memory consolidation, an offline process that determines the long-term strength of memory traces. Consolidation efficacy differs across individuals, but the brain activity dynamics underlying these differences remain unknown. Here, we studied how interindividual variability in fear memory consolidation relates to neural activity in brain structures that participate in Pavlovian fear learning.

The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear.

While learning to fear stimuli that predict danger promotes survival, the inability to inhibit fear to inappropriate cues leads to a pernicious cycle of avoidance behaviors. Previous studies have revealed large inter-individual variations in fear responding with clinically anxious humans exhibiting a tendency to generalize learned fear to safe stimuli or situations. To shed light on the origin of these inter-individual variations, we subjected rats to a differential auditory fear conditioning paradigm in which one conditioned auditory stimulus (CS+) was paired to footshocks whereas a second (CS-) was not.

De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala.

Memory consolidation is the process by which newly learned information is stabilized into long-term memory (LTM). Considerable evidence indicates that retrieval of a consolidated memory returns it to a labile state that requires it to be restabilized. Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of the amygdala (LA).

Glucocorticoids enhance the excitability of principal basolateral amygdala neurons.

A large body of pharmaco-behavioral data implicates the basolateral nucleus of the amygdala (BLA) in the facilitation of memory consolidation by emotions. Overall, this evidence suggests that stress hormones released during emotional arousal increase the activity of BLA neurons. In turn, this increased BLA activity would facilitate synaptic plasticity elsewhere in the brain, to which the BLA projects.

Extinction is not a sufficient condition to prevent fear memories from undergoing reconsolidation in the basolateral amygdala.

Consolidated memories when reactivated may return to a state that requires protein synthesis in order to be restabilized (reconsolidation). It has been shown in a variety of systems that if reactivation induces significant extinction then extinction is the protein synthesis dependent memory state, rather than reconsolidation. Thus, extinction consolidation may prevent the memory from undergoing reconsolidation.

Synaptic plasticity in the central nucleus of the amygdala.

In recent years, the amygdala has emerged as a critical site of plasticity for the acquisition of various forms of Pavlovian learning, either aversive or appetitive. In most of these models, the critical site of plasticity has been localized to the basolateral complex of the amygdala (BLA). In contrast, the central nucleus of the amygdala has emerged as a passive relay of potentiated BLA outputs toward downstream effectors.

Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning.

Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of amygdala (LA). Recently we have demonstrated that consolidated fear memories, when reactivated, return to a labile state which is sensitive to disruption by the protein synthesis inhibitor anisomycin. The specific molecular mechanisms that underlie this reconsolidation of fear memories are still largely unknown.

Characterization of fear memory reconsolidation.

Reactivation of consolidated memories returns them to a protein synthesis-dependent state. One interpretation of these findings is that the memory reconsolidates after use. Two alternative interpretations are that protein synthesis inhibition facilitates extinction and that postreactivation protein synthesis inhibition leads to an inability to retrieve the consolidated memory.