Prefrontal control of fear: more than just extinction

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Although 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 (IL) prefrontal cortex 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 (PL) prefrontal cortex 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.

Section snippets

Back to cortical control of fear

Over 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

IL-mediated inhibition of fear after extinction

Although previous recording and lesion studies have implicated IL in extinction [9], recent findings have identified specific molecular cascades in IL involved in extinction learning. It is well established that N-methyl-d-aspartate receptors (NMDAr) within the amygdala are necessary for extinction [10, 11], but more recent reports implicate IL NMDAr in extinction, especially in the period immediately following extinction [12, 13, 14]. The role of IL in extinction consolidation is further

PL-mediated excitation of fear expression

Although earlier studies suggested a role of PL in excitation of fear [28, 29], new studies using a variety of techniques have confirmed and extended that role [51]. Inactivation restricted to PL reduced expression of conditioned fear to contextual and auditory stimuli, but had no effect on the expression of innate fears, or the development of plasticity related to conditioning or extinction [15, 30]. In other words, PL activity is necessary for fear expression, but not for fear plasticity (in

Outputs and inputs of IL and PL

The opposite effects of IL and PL on fear expression are thought to be mediated by outputs to different targets within the amygdala [29, 35]. IL projects to the intercalated cell masses (ITC) and lateral division of the central nucleus (CeL) both of which consist of GABAergic neurons that inhibit amygdala output neurons of the medial division of the central nucleus (CeM). In contrast, PL targets the BA. This suggests that ITC cells should be critical for extinction, whereas BA should be

Why does the amygdala ‘need’ the prefrontal cortex for fear?

Given that auditory fear conditioning can occur in the absence of cortical areas, one might be tempted to think that the amygdala, together with its subcortical connections, is sufficient for normal fear learning and expression. However, as reviewed above, PL and IL are required for fear expression and extinction, under normal circumstances. This suggests that the mPFC has access to information that the amygdala does not, which enables emotional regulation, such as the emotional history of a

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Denis Paré and Anthony Burgos-Robles for providing comments on this manuscript.

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