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Amygdala–prefrontal interactions in (mal)adaptive learning

Profile image of Ekaterina LikhtikEkaterina Likhtik

2015, Trends in Neurosciences

https://doi.org/10.1016/J.TINS.2014.12.007
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20 pages

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Abstract

The study of neurobiological mechanisms underlying anxiety disorders has been shaped by learning models that frame anxiety as maladaptive learning. Pavlovian conditioning and extinction are particularly influential in defining learning stages that can account for symptoms of anxiety disorders. Recently, dynamic and task related communication between the basolateral complex of the amygdala (BLA) and the medial prefrontal cortex (mPFC) has emerged as a crucial aspect of successful evaluation of threat and safety. Ongoing patterns of neural signaling within the mPFCBLA circuit during encoding, expression and extinction of adaptive learning are reviewed. The mechanisms whereby deficient mPFC-BLA interactions can lead to generalized fear are discussed in learned and innate anxiety. Findings with crossspecies validity are emphasized.

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Nature Neuroscience, 2013

Successfully differentiating safety from danger is an essential skill for survival. While decreased activity in the medial prefrontal cortex (mPFC) is associated with fear generalization in animals and humans, the circuit level mechanisms used by the mPFC to discern safety are not clear. To answer this question, we recorded activity in the mPFC, basolateral amygdala (BLA), and dorsal (dHPC) and ventral hippocampus (vHPC) in mice during exposure to learned (differential fear conditioning) and innate (open field) anxiety. We found increased synchrony between the mPFC and BLA in the theta frequency range (4-12 Hz) only in animals that differentiate between averseness and safety. Moreover, during recognized safety across learned and innate paradigms, BLA firing becomes entrained to theta input from the mPFC. These data suggest that selective tuning of BLA firing to mPFC input provides a safety-signaling mechanism whereby the mPFC taps into the microcircuitry of the amygdala to diminish fear.

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The structural and functional connectivity of the amygdala: From normal emotion to pathological anxiety
M. Justin Kim

Behavioural Brain Research, 2011

The dynamic interactions between the amygdala and the medial prefrontal cortex (mPFC) are usefully conceptualized as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as well as regulate these reactions when the situation calls for it. In this review, we will begin by discussing the role of this amygdala-mPFC circuitry in the conditioning and extinction of aversive learning in animals. We will then relate these data to emotional regulation paradigms in humans. Finally, we will consider how these processes are compromised in normal and pathological anxiety. We conclude that the capacity for efficient crosstalk between the amygdala and the mPFC, which is represented as the strength of the amygdala-mPFC circuitry, is crucial to beneficial outcomes in terms of reported anxiety.

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Prefrontal-Amygdala Circuits Regulating Fear and Safety
Joseph Stujenske

2016

Switching between a state of fear and safety is a critical aspect of adaptive behavior. Aversive and non-aversive associations must be formed quickly and reliably but remain malleable as these associations change dynamically. When these associations become biased towards aversive associations by traumatic and stressful circumstances, as in PTSD, fear generalization and impaired fear extinction arise. These changes are associated with reduced activity in the medial prefrontal cortex (mPFC) and enhanced activity in the basolateral amygdala (BLA). It has been hypothesized that the mPFC mediates top-down control of the BLA to signal safety. It has previously been demonstrated that synchronous activity within the mPFC-BLA circuit is strongly engaged during fear conditioning, but it is unknown how activity in this circuit changes to mediate aversive discrimination. We investigated how the mPFC and BLA cooperate to mediate successful discrimination between aversive and non-aversive stimuli both for learned and innately-valent associations. Extracellular elecrophysiological recordings were obtained simultaneously form the mPFC and BLA in mice during innate anxiety, fear discrimination, and fear extinction. Local field potentials were recorded in both structures along with single unit recordings from the BLA. We discovered that fear was associated with enhanced theta-frequency synchrony and theta-gamma coupling within the mPFC-BLA circuit. On the other hand, safety was associated with predominant mPFC-to-BLA directionality of synchronous information flow and enhanced fast gamma frequency activity in both structures. Interestingly, gamma oscillations in the BLA were strongly coupled to theta frequency activity arising in the mPFC. This data is consistent with entrainment of inhibitory circuits in the BLA by mPFC input to mediate safety. We used to optogenetic techniques to test this hypothesis. Silencing mPFC-to-BLA input induced fear generalization, while activating mPFC-to-BLA input enhanced discrimination. We provide evidence that the mPFC directly projects to both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Silencing SOM+ but not PV+ interneurons also induced fear generalization. Likewise, silencing SOM+ interneurons impaired fear extinction. This data is consistent with downstream activation of SOM+ interneurons by prefrontal inputs to mediate successful discrimination between aversive and non-aversive stimuli. Future experiments for confirming this hypothesis are proposed.

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The amygdala and medial prefrontal cortex: partners in the fear circuit
Roger Marek

The Journal of Physiology, 2013

Fear conditioning and fear extinction are Pavlovian conditioning paradigms extensively used to study the mechanisms that underlie learning and memory formation. The neural circuits that mediate this learning are evolutionarily conserved, and seen in virtually all species from flies to humans. In mammals, the amygdala and medial prefrontal cortex are two structures that play a key role in the acquisition, consolidation and retrieval of fear memory, as well extinction of fear. These two regions have extensive bidirectional connections, and in recent years, the neural circuits that mediate fear learning and fear extinction are beginning to be elucidated. In this review, we provide an overview of our current understanding of the neural architecture within the amygdala and medial prefrontal cortex. We describe how sensory information is processed in these two structures and the neural circuits between them thought to mediate different aspects of fear learning. Finally, we discuss how changes in circuits within these structures may mediate fear responses following fear conditioning and extinction.

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Experimental Neurology, 2016

Individuals exhibiting an anxiety disorder are believed to possess an innate vulnerability that makes them susceptible to the disorder. Anxiety disorders are also associated with abnormalities in the interconnected brain regions of the amygdala and prefrontal cortex (PFC). However, the link between anxiety vulnerability and amygdala-PFC dysfunction is currently unclear. Accordingly, the present study sought to determine if innate dysfunction within the amygdala to PFC projection underlies the susceptibility to develop anxiety-like behavior, using an anxiety vulnerable rodent model. The inbred Wistar Kyoto (WKY) rat was used to model vulnerability, as this strain naturally expresses extinction-resistant avoidance; a behavior that models the symptom of avoidance present in anxiety disorders. Synaptic plasticity was assessed within the projection from the basolateral nucleus of the amygdala (BLA) to the prelimbic cortical subdivision of the PFC in WKY and Sprague Dawley (SD) rats. While WKY rats exhibited normal paired-pulse plasticity, they did not maintain long-term potentiation (LTP) as SD rats. Thus, impaired plasticity *

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    Frontiers in Behavioral Neuroscience

    Recent findings have shown that the auditory cortex, and specifically the higher order Te2 area, is necessary for the consolidation of long-term fearful memories and that it interacts with the amygdala during the retrieval of long-term fearful memories. Here, we tested whether the reversible blockade of Te2 during memory consolidation may affect the activity changes occurring in the amygdala during the retrieval of fearful memories. To address this issue, we blocked Te2 in a reversible manner during memory consolidation processes. After 4 weeks, we assessed the activity of Te2 and individual nuclei of the amygdala during the retrieval of long-term memories. Rats in which Te2 was inactivated upon memory encoding showed a decreased freezing and failed to show Te2-to-basolateral amygdala (BLA) synchrony during memory retrieval. In addition, the expression of the immediate early gene zif268 in the lateral, basal and central amygdala nuclei did not show memory-related enhancement. As all sites were intact upon memory retrieval, we propose that the auditory cortex represents a key node in the consolidation of fear memories and it is essential for amygdala nuclei to support memory retrieval process.

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    Scientific reports, 2017

    Resilience has been conceptualized in part as a dynamic process that includes the ability to adapt to stressful conditions. As such it encompasses the extent to which neural plasticity may be promoted. The current study examined metaplasticity by referring to the "plasticity of synaptic plasticity" in a neural circuit composed of the basolateral amygdala (BLA) and the nucleus accumbens (NAcc), using behavioural stress controllability with or without preceding stimulation of the dorsal periaqueductal gray (i.e. dPAG priming). A tendency for increased plasticity in the controllable versus the uncontrollable group was found in both the BLA and NAcc. dPAG priming suppressed NAcc LTP in all groups, but it suppressed BLA LTP only in the uncontrollable group, demonstrating dissociation between either controllable and uncontrollable groups or the NAcc and BLA. Thus, metaplasticity in the dPAG-BLA-NAcc circuit regulated differentially by controllable or uncontrollable stress may un...

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    Effects of electroacupuncture on stress and anxiety-related responses in rats
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    Anais da Academia Brasileira de Ciências, 2017

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