While fear research has largely focused on the amygdala, recent findings highlight cortical control of the amygdala in the service of fear regulation. In rodent models, it is becoming well established that the infralimbic prefrontal cortex (IL) plays a key role in extinction learning, and recent findings are uncovering molecular mechanisms involved in extinction-related plasticity. Furthermore, mounting evidence implicates the prelimbic prefrontal cortex (PL) in the production of fear responses. Both IL and PL integrate inputs from the amygdala, as well as other structures to gate the expression of fear via projections to inhibitory or excitatory circuits within the amygdala. We suggest that dual control of the amygdala by separate prefrontal modules increases the flexibility of an organism's response to danger cues.Keywords infralimbic cortex; prelimbic cortex; amygdala; plasticity; emotion Back to cortical control of fearOver a century ago, the prevalent notion was that evolutionary recent cortical areas exert control over evolutionary older subcortical areas [1,2]. Later, the prefrontal cortex (PFC) emerged as a critical regulator of aversive conditioning [3,4]. More recently, focus shifted to the amygdala as a hub of emotions [5,6], when it was reported that interfering with activity in the PFC or other cortical areas did not prevent fear learning. A wealth of data supports the role of the amygdala in fear learning. Nonetheless, interest in the role of PFC in emotion re-emerged with the discovery that the medial PFC (mPFC) was necessary for extinction of conditioned fear [7,8]. In the last few years, it has become clear that mPFC contains different subregions, playing unique roles in fear learning and extinction. In particular, it was shown that the infralimbic region (IL) of the mPFC is a critical site of plasticity for inhibition of fear responses after extinction, and new findings are uncovering the mechanisms involved. In contrast, mounting evidence implicates the prelimbic (PL) region of the mPFC in the production of fear responses. Both IL and PL are thought to exert their influences via the amygdala, suggesting that the amygdala must work with mPFC to orchestrate fear responses. Here, we review these recent findings, and consider the possible significance of this dual cortical control of the amygdalabased fear responses.Correspondence should be addressed to: Gregory J. Quirk, Ph.D., Department of Psychiatry, University of Puerto Rico School of Medicine, PO Box 365067, San Juan 00936-5067, Puerto Rico, Tel/Fax: 1 787 999 3057, gjquirk@yahoo.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclai...

Summary The prefrontal cortex (PFC) regulates emotional responses, but it is unclear how PFC integrates diverse inputs to select the appropriate response. We therefore evaluated the contribution of basolateral amygdala (BLA) and ventral hippocampus (vHPC) inputs to fear signaling in the prelimbic (PL) cortex, a PFC region critical for the expression of conditioned fear. In conditioned rats trained to press for food, BLA inactivation decreased the activity of projection cells in PL, and reduced PL conditioned tone responses. In contrast, vHPC inactivation decreased activity of interneurons in PL, and increased PL conditioned tone responses. Consistent with hippocampal gating of fear after extinction, vHPC inactivation increased fear and PL pyramidal activity in extinguished, but not in conditioned, rats. These results suggest a prefrontal circuit whereby hippocampus gates amygdala-based fear. Thus, deficient hippocampal inhibition of PFC may underlie emotional disorders, especially in light of reduced hippocampal volume observed in depression and PTSD.

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Fear extinction refers to the ability to adapt as situations change by learning to suppress a previously learned fear. This process involves a gradual reduction in the capacity of a fear-conditioned stimulus to elicit fear by presenting the conditioned stimulus repeatedly on its own. Fear extinction is context-dependent and is generally considered to involve the establishment of inhibitory control of the prefrontal cortex over amygdala-based fear processes. In this paper, we review research progress on the neural basis of fear extinction with a focus on the role of the amygdala and the prefrontal cortex. We evaluate two competing hypotheses for how the medial prefrontal cortex inhibits amygdala output. In addition, we present new findings showing that lesions of the basal amygdala do not affect fear extinction. Based on this result, we propose an updated model for integrating hippocampal-based contextual information with prefrontal-amygdala circuitry.

Individuals use both passive and active defensive responses to environmental threats. Much is known about the neural circuits of passive defensive responses (e.g., freezing), but less is known about the substrates of active defensive responses (e.g., avoidance). We developed an active avoidance task in which rats learn to avoid a tone-signaled footshock by stepping onto a nearby platform. An advantage of this task is that freezing, which can interfere with avoidance, is reduced, thereby facilitating comparison of the effects of manipulations on avoidance versus freezing. After 10 d of avoidance training, rats were infused with muscimol to pharmacologically inactivate the prelimbic cortex (PL), infralimbic cortex (IL), ventral striatum (VS), or basolateral amygdala (BLA). Inactivating PL, VS, or BLA all impaired avoidance expression, but these areas differed with respect to freezing. Inactivating BLA decreased freezing consistent with loss of the toneshock association, whereas inactivation of VS increased freezing consistent with loss of avoidance memory. Inactivation of PL had no effect on freezing. Inactivation of IL did not impair avoidance expression but did impair avoidance extinction. Our findings suggest that active avoidance is mediated by prefrontal-striatal circuits, which may be overactive in individuals suffering from trauma-related disorders.