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].”

“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].”

“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].”

“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].”

“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).”

“Recent studies implicate the prelimbic cortex in fear expression as well, possibly by way of its connections to B and, from there, to CE (Sotres-Bayon and Quirk, 2010).”

“Whereas PL supports fear expression (see above), IL is implicated in extinction (Sotres-Bayon and Quirk, 2010).”

“…fear and extinction, a dichotomy of function has been proposed within the mPFC in which the prelimbic (PL) and infralimbic (IL) cortices regulate the expression and suppression of fear, respectively (Quirk and Mueller, 2008; Sotres-Bayon and Quirk, 2010;Milad andQuirk, 2012;Maren et al., 2013).”

“…areas, including the hippocampus and prefrontal cortex, are thought to play a critical role in both learning safety signals and using those signals to functionally down-regulate the amygdala and reduce the fear response (Myers and Davis, 2007; Quirk and Beer, 2006; Sotres-Bayon and Quirk, 2010).”

“The same corticostriatal network has been implicated in evaluation of reward, emotion, and aversiveness in other domains as well (Bar, 2009; Blood et al., 1999; Breiter et al., 2001; Kable and Glimcher, 2009; Ressler and Mayberg, 2007; Sotres-Bayon and Quirk, 2010).”

“The net result of fear extinction is reduced inhibitory output from the CeAM to brainstem effector regions, an effect caused by more inhibitory ITC input onto CeAM neurons, less inhibitory ITC input onto CeAL GABA neurons that project to CeAM, or both (40,103).”

“Here, we studied the mechanisms underlying how the PFC integrates information using the well-characterized circuit of auditory fear conditioning (LeDoux, 2000; Maren and Quirk, 2004; Sotres-Bayon and Quirk, 2010), by evaluating the contribution of different inputs toPFC inbehaving rats.”

“In the last decade, a multitude of research on fear extinction has demonstrated that the interaction between the amygdala and PFC is critical for extinction processes (Milad and Quirk, 2012; Sotres-Bayon and Quirk, 2010).”

“And how does learning-related plasticity in turn alter the function of the local circuit (i.e., which aspects of stimulus encoding are changed to mediate memory expression), and how does previous experience affect the circuit’s plasticity state?”

“…target of excitatory projections from the infralimbic mPFC (McDonald 1998;Busti et al. 2011;Amir et al. 2011;Pinard et al. 2012) and are activated during behavioral extinction of negative emotional responses (Orsini and Maren 2012;Herry et al. 2010;Pape and Pare 2010;Sotres-Bayon and Quirk 2010).”

“Such a signal may reflect the convergence of inputs to IL signaling auditory, contextual, and internal state information (Sotres-Bayon and Quirk, 2010).”

“In recent years, fear extinction research has taught us much about the neural correlates of learning not to fear(1, 2).”

“…studies of the mPFC have established that this region is involved in both fear conditioning and its extinction (Burgos-Robles et al. 2007; Corcoran & Quirk, 2007; Laurent & Westbrook, 2008; Sotres-Bayon & Quirk, 2010), with the ILPFC and PLPFC having distinct roles (Burgos-Robles et al. 2007).”

“, repeated presentations of a conditioned stimulus without the aversive outcome) show that extinction learning and recall are mediated via the infralimbic (IL) region of the medial PFC and its connections with the amygdala; IL projections activate inhibitory cells within the amygdala that block the generation of the d…”

“Thus, in addition to its role in fear acquisition [23], the amygdala appears to also play a critical role in fear extinction [24,25].”

“Cortical control of amygdala function has been identified as a critical mechanism of fear extinction (Herry et al., 2010; Likhtik et al., 2005; Marek et al., 2013; Orsini and Maren, 2012; Pape and Pare, 2010; Sotres-Bayon and Quirk, 2010).”

“Not surprisingly, considerable work now implicates these brain areas in the regulation of fear expression after extinction (Maren and Quirk, 2004; Quirk et al., 2000, 2006; Quirk and Mueller, 2008; Sotres-Bayon et al., 2006; Sotres-Bayon and Quirk, 2010).”

“…that PV INmediated feedforward inhibition in dACC controls the temporal integration window of PNs, akin to the thalamically recruited inhibition in sensory cortices (Daw et al., 2007; Hull and Scanziani, 2007; Chittajallu and Isaac, 2010; Sotres-Bayon and Quirk, 2010; Isaacson and Scanziani, 2011).”

“Intercalated cell islands (ITC) of the amygdala, positioned between the basolateral amygdala complex (BLA) and the central amygdala nucleus and intercalated within the medial portion of the external capsule surrounding the BLA, were counted in sections between 1.22 and 1.94 from bregma.”

“Expression of amygdala-dependent fear memories is regulated by prelimbic (PL) and infralimbic (IL) prefrontal cortices, which increase and decrease freezing, respectively, through projections to the amygdala (Vidal-Gonzalez et al., 2006; Sotres-Bayon and Quirk, 2010; Amir et al., 2011; Cho et al., 2013).”

“In extinction, the hippocampus and medial PFC (mPFC), especially the infralimbic (IL) area, are involved besides the amygdala (Herry et al., 2010; Pape and Pare, 2010; Sotres-Bayon and Quirk, 2010; Lin et al., 2010).”

“The hippocampus in particular is integral in encoding contextual representations of where an event occurred [40], and the mPFC has key roles in learning, maintaining and updating associations between a CS and events [42].”

“…periods to L1 of PFC may contribute to the celebrated propensity of this cortical area to process high-frequency (e.g., gamma) oscillations and persistent activity associated with attention and memory (Miller and Cohen, 2001; Lewis et al., 2005; Curtis and Lee, 2010; Sotres-Bayon and Quirk, 2010).”

“A previous report from our laboratory demonstrates a role for infralimbic prefrontal cortex (ilPFC; Moscarello and LeDoux, 2013), which can exert feedforward inhibition on CeA and negatively regulate the expression of innate defensive behaviors, such as freezing (Sotres-Bayon and Quirk, 2010).”

“It is part of a larger neural circuitry that is implicated in the control of emotion, most notably including the prefrontal cortex (PFC; Quirk and Beer, 2006; Sotres-Bayon and Quirk, 2010).”

“Interactions between the PFC and basolateral amygdala (BLA) are particularly important for the control of emotion (Sotres-Bayon and Quirk, 2010).”

“Regions of the brain important for higher-level cognition, such s the hippocampus and prefrontal cortex, play an important ole in regulating the stress response (Leuner and Gould, 2010; oozendaal et al., 2009; Sotres-Bayon and Quirk, 2010), and prexisting differences in the structural make-up of these regions ight the…”

“Plasticity in the amygdala and IL underlie acquisition and consolidation of fear extinction memories (Duvarci and Pare, 2014; Maren et al., 2013; Pape and Pare, 2010; Sotres-Bayon and Quirk, 2010; Tovote et al., 2015).”

“Sotres-Bayon and Quirk (2010) propose the existence of a BA-centered network that is capable of switching between states of high and low threat reactivity.”

“Through connections with subcortical nuclei such as the amygdala, the nucleus accumbens, the ventral striatum and the dorsal raphe nucleus, the medial, ventral and lateral portions of the prefrontal cortex (PFC) play a key role in both negative and positive emotional regulation [9,10,11].”

“Moreover, activating the BLA may enable sustained firing of mPFC neurons during fear conditioning (Sotres-Bayon and Quirk, 2010; Sotres-Bayon et al., 2012).”

“In terms of connectivity, in rats NaccSh targets the AIC, the PL and the IL. IL plays a role in inhibiting instrumental behaviors and in the extinction of Pavlovian processes (Quirk et al., 2000; Coutureau and Killcross, 2003; Rhodes and Killcross, 2004; Sotres-Bayon and Quirk, 2010).”

“The ASST is a test of PFC function, a brain region that is critical for normal executive function and may be necessary for extinguishing CS-US associations (Kim and Jung, 2006; Quirk and Mueller, 2008; Sotres-Bayon and Quirk, 2010; Kesner and Churchwell, 2011; Khan and Muly, 2011).”

“We chose to separately examine IL and PL contributions to DH compensation because these regions have been shown to play opposing roles in modulating fear expression (13, 26).”

“Specifically, it is proposed that this region integrates input from other brain structures to enhance the expression of fear conditioning via excitatory projections to the amygdala (Corcoran & Quirk, 2007; Sierra-Mercado, Padilla-Coreano, & Quirk, 2011; Sotres-Bayon & Quirk, 2010).”

“…Ishikawa et al., 2008b, a) whereas other studies emphasize the mPFC in the representation of aversive stimuli and contexts as in fear conditioning (Morgan and LeDoux, 1995; Maren and Quirk, 2004; Peters et al., 2009; Sotres-Bayon and Quirk, 2010; Quirk and Mueller, 2008; Orsini et al., 2011).”

“In fear conditioning experiments, the PL promoted fear behavior and its inhibition reduced expression of fear to contextual stimuli (Corcoran and Quirk, 2007; Peters et al., 2009; Sotres-Bayon and Quirk, 2010).”

“In adults, the hippocampus works in concert with the amygdala and PFC to contextualize cues during aversive learning, facilitate escape behavior from aversive stimuli, and attenuate fear expression during extinction (Sotres-Bayon and Quirk, 2010; Sotres-Bayon et al., 2012).”

“The PFC is a major input to the BLA, where it exerts powerful top-down control of learning and expression of emotional behavior (Sotres-Bayon and Quirk, 2010).”

“tinction learning (18), as well as the OFC, a region implicated in OCD (35).”

“However, a negative correlation between vmPFC activation and SCRs would have been expected regarding the literature (Quirk and Mueller, 2008; Hartley and Phelps, 2010; Sotres-Bayon and Quirk, 2010).”

“…to the vmPFC, including the infralimbic (IL) and prelimbic (PrL) cortices; which both integrate information about aversive stimuli, in order to coordinate the proper emotional response through projections to the amygdala (Sotres-Bayon and Quirk, 2010; Sylvester et al., 2012; Varela et al., 2012).”

“In the frontal lobe, the mPFC has been implicated in fear expression and extinction (Sotres-Bayon and Quirk, 2010; Milad and Quirk, 2012).”

“…and instinctive behaviour (LeDoux, 1992), has complex anatomical and functional connections with the prefrontal cortices (Salzman and Fusi, 2010; Sotres-Bayon and Quirk, 2010) with the insular regions (Augustine, 1996) and the temporal pole, which has been implicated in cognitive processes…”

“The infralimbic region of the mPFC inhibits amygdala output to suppress (“extinguish”) aversive behaviors [10,13-18].”

“…a conceptual framework emerged positing the PL may be part of a “go” circuit that initiates goal-directed action, whereas IL-related circuits may subserve a “stop” function, regulating behavioral suppression (Peters et al., 2008; Sotres-Bayon and Quirk, 2010; Gass and Chandler, 2013).”

“The mPFC has been identified as a critical circuit node involved in modulating the expression and extinction of cue-mediated behaviors (Kalivas et al., 2006; Quirk and Mueller, 2008; Peters et al., 2009; Sotres-Bayon and Quirk, 2010; Van den Oever et al., 2010).”

“The prefrontal cortex (PFC) is required for executive control of behavior (Ridderinkhof et al., 2004; McGuire and Botvinick, 2010) and for effective coping with stress (Amat et al., 2005; Sotres-Bayon and Quirk, 2010; Warden et al., 2012).”

“…Learning and Memory xxx (2016) xxx–xxx 5 and that the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) crucially regulate fear and its extinction (Giustino & Maren, 2015; Milad & Quirk, 2012; Quirk & Beer, 2006; Riga et al., 2014; Sotres-Bayon & Quirk, 2010).”

“…the infralimbic cortex in certain aspects of behavioral extinction through inhibition of amygdala output (Maren and Quirk, 2004; Likhtik et al., 2005; Akirav and Maroun, 2007; Sah and Westbrook, 2008; Herry et al., 2010; Kim and Richardson, 2010; Pape and Pare, 2010; Sotres-Bayon and Quirk, 2010).”

“PFC subregions also differentially influence fear learning, with IL primarily responsible for extinction (Burgos-Robles et al., 2007; Sotres-Bayon and Quirk, 2010; DoMonte et al., 2015), and PL enabling fear expression (BurgosRobles et al.”

“; both cortical areas can be defined as subregions of the mPFC and are known to be involved in fear extinctio”

“We present cross-species studies relating fear learning to anxiety across development and discuss how clinical treatments can be optimized for individuals and targeted to the biological states of the developing brain.”