Prefrontal control of fear: more than just extinction

“com In addition to diverse inputs, mPFC also has divergent outputs capable of coordinating different and sometimes competing brain systems [48,49 ].”

“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.”

“However, unlike neurons in lateral amygdala whose conditioned responses last only a few hundred milliseconds [32], PL neurons show sustained increases in activity that mirror the time course of freezing responses, lasting tens of seconds [31 ].”

“Another key input is the ventral hippocampus (Hipp), which unlike the dorsal hippocampus, projects monosynaptically to PL, IL, and BA [44].”

“Focal inactivation of BA prevented not only renewal of fear after extinction, but also expression of extinction, depending on the time point of inactivation [38 ].”

“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].”

“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].”

“During renewal of fear, the excitatory drive emanating from mPFC would converge with amygdala projections to the periaqueductal grey, to produce defensive responses, while at the same time suppressing approach behaviors, via the midbrain dopaminergic system [50].”

“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].”

“It is well established that N-methylD-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 [12–14].”

“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].”

“Accordingly, histone acetylation of the BDNF gene promoter in IL was found to be correlated with extinction [18], and mice exhibiting a deficient BDNF gene showed impaired extinction and reduced IL volume [19,20].”

“What might constitute a physiological signature of extinction learning in IL? The degree of extinction success is correlated with high-frequency bursting in IL neurons immediately after extinction training [12].”

“Capitalizing on a unique distribution of receptor subtypes, however, it was recently observed that lesions or activation of ITCs impaired or facilitated extinction, respectively [36 ,37 ].”

“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].”

“The role of IL in extinction consolidation is further supported by recent findings using post-extinction infusions into IL of the inactivating agent muscimol [15], a cannabinoid antagonist [16], or dopamine (D1) antagonist [17].”

“It is well established that N-methylD-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 [12–14].”

“Furthermore, mice with deficient 5-HT transporter activity showed poor extinction and shrunken IL dendrites [21], and similar behavioral findings were obtained for cAMP-responsive element-binding protein-mediated gene expression in IL [22].”

“In support of the latter possibility, it was recently shown that conditioning and extinction decreased and increased, respectively, the intrinsic excitability of IL neurons [23 ].”

“Consistent with such a role, PL neurons are activated by conditioned stimuli [24 ,31 ].”

“In support of this, studies using the activity marker c-Fos show that IL activity was increased in rodents that successfully retrieved extinction [24 ], but not in strains that are extinction-deficient [25 ,26].”

“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].”

“It is well established that N-methylD-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 [12–14].”

“In adolescent rats, where extinction does not require NMDAr, IL was not necessary for extinction, nor was IL activated by extinction [27 ].”

“Current Opinion in Neurobiology 2010, 20:231–235 agents that reduce fear expression, such as propranolol [33] and cannabidiol [34].”

“It is well established that N-methylD-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 [12–14].”

“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].”

“In support of this, studies using the activity marker c-Fos show that IL activity was increased in rodents that successfully retrieved extinction [24 ], but not in strains that are extinction-deficient [25 ,26].”

“The role of IL in extinction consolidation is further supported by recent findings using post-extinction infusions into IL of the inactivating agent muscimol [15], a cannabinoid antagonist [16], or dopamine (D1) antagonist [17].”

“Current Opinion in Neurobiology 2010, 20:231–235 agents that reduce fear expression, such as propranolol [33] and cannabidiol [34].”

“The role of IL in extinction consolidation is further supported by recent findings using post-extinction infusions into IL of the inactivating agent muscimol [15], a cannabinoid antagonist [16], or dopamine (D1) antagonist [17].”

“Also, nonamygdala outputs of PL and IL, such as the nucleus accumbens for appetitive behavior [39] and raphe nucleus for ‘controlability’ [40] are emerging as important for emotional regulation.”

“Weakening this pathway with low-frequency stimulation or stress impairs extinction [45,46].”

“This suggests that the amygdala may recruit IL and PL [41–43], which in turn regulate amygdala output.”

“Later, the prefrontal cortex (PFC) emerged as a critical regulator of aversive conditioning [3,4].”

“In addition, PL excitatory and IL inhibitory networks could interact via reciprocal inhibitory connections [47].”

“Also, nonamygdala outputs of PL and IL, such as the nucleus accumbens for appetitive behavior [39] and raphe nucleus for ‘controlability’ [40] are emerging as important for emotional regulation.”

“Later, the prefrontal cortex (PFC) emerged as a critical regulator of aversive conditioning [3,4].”

“, 2005) and that exerts an inhibitory influence on emotional esponsiveness as observed during extinction of conditioned fear, arrants further investigation (Sotres-Bayon and Quirk, 2010).”

“Thus, the prefrontal cortex is not simply an inhibitor, but is able to exert dual control over fear expression via separate modules, each with access to separate sets of inputs and outputs (Sotres-Bayon & Quirk 2010).”