Neurons in medial prefrontal cortex signal memory for fear extinction

“ANOVA showed a highly significant main effect of group (F (2,29) 1⁄4 16.”

“Destruction of the ventral medial prefrontal cortex, which consists of infralimbic and prelimbic cortices, blocks recall of fear extinctio”

“, 1980; Carmichael and Price, 1995; Ghashghaei and Barbas, 2002) and the LC, regulates and updates learned negative associations via extinction learning or re-learning new safe/neutral associations (Delgado et al., 2008; Milad et al., 2005; Milad and Quirk, 2002).”

“…mPFC activity controls extinction learning: permanent lesions or reversible inactivation of ventral mPFC increase resistance to extinction, while electrical stimulation of ventral mPFC facilitates extinction responding (Milad and Quirk, 2002; Quirk and Mueller, 2008; Sierra-Mercado et al., 2006).”

“…cortex (IL) is necessary for the consolidation and retrieval of extinction memory in the rat (Herry et al., 2010; Lebron, Milad, & Quirk, 2004; Milad & Quirk, 2002, 2012; Milad, Rauch, Pitman, & Quirk, 2006; Milad, Vidal-Gonzalez, & Quirk, 2004; Quirk, Garcia, & Gonzalez-Lima, 2006; Quirk &…”

“…cells send a GABAergic projection to the main output station of the amygdala for conditioned fear responses (Paré and Smith, 1993a,b;Royer et al., 1999), and that behavioral studies implicate the infralimbic cortex in the extinction of these responses (Morgan et al., 1993;Milad and Quirk, 2002).”

“…storage of extinction, a conclusion further supported by the evidence that neurons in the mPFC (speciWcally the infralimbic cortex) Wre speciWcally when rats are recalling extinction memories and that electrical stimulation of mPFC reduces freezing to conditioned tones (Milad & Quirk, 2002).”

“Not only are there clear functional differences between pyramidal and GABAergic interneurons and their influence over cocaine-related behaviors (Miller and Marshall, 2004), but there are diverse subtypes of GABAergic and likely glutamatergic neurons in mPFC, each of which play different functions…”

“…is proposed that following extinction training, the mPFC, particularly the IL is critical for inhibiting amygdala responses to the CS, and thereby preventing conditioned responding (Milad et al, 2004, 2007; Milad and Quirk, 2002; Quirk et al, 2003; Rosenkranz et al, 2003; Quirk and Mueller, 2008).”

“These include the basolateral nucleus of the amygdala (Falls et al., 1992; Walker et al., 2002), the prefrontal cortex (Quirk et al., 2000; Milad and Quirk, 2002; Burgos-Robles et al., 2007) and the hippocampus (Sananbenesi et al., 2007). mGluR5 is expressed in all these structures, and therefore…”

“Human imaging studies implicate the vmPFC in recall of extinction (Milad et al, 2007; Kalisch et al, 2006; Phelps et al, 2004), and several anatomically selective neural stimulation, lesion, and inactivation studies in rodents provide compelling evidence that the infralimbic, but not prelimbic, subregion of the vmPFC…”

“Interestingly , these brain regions are known to play a pivotal role in extinction of conditioned fear ( Milad and Quirk , 2002 ; Quirk et al .”

“Finally, maintaining fear extinction depends on memory retrieval processes mediated by the VMPFC,[41] and this mechanism appears to be dysfunctional in some anxiety disorders (e.”

“Later work has suggested that mPFC is particularly important for the consolidation and recall of extinction learning [124,125].”

“Although it is established that the infralimbic cortex (IL) region of the mPFC is required for fear extinction (9, 11, 14), the role of the prelimbic cortex (PL) in the regulation of fear learning and extinction are yet to be fully understood.”

“Thus, stimulating the infralimbic cortex in ratsVhomologous to the VMPFC (BA 11) and subgenual anterior cingulate cortex (BA 25) in humansVdiminishes fear responding to fear cues (69), and greater VMPFC activity is associated with reduced fear responding (skin conductance responses) in humans (46,51).”

“To test this account, Milad and Quirk (2002) made electrophysiological recordings from the IL cortex.”

“The fear-conditioning paradigm is a widely used animal model to study learning and memory function, as well as extinction of acquired fear memories (LeDoux, 2000; Milad and Quirk, 2012; Maren et al., 2013).”

“Using a similar protocol as the present study, infralimbic neurons showed robust potentiation of toneevoked responses 24 h after extinction training, when rats were recalling extinction (Milad and Quirk 2002).”

“Animal studies: current state of the field Numerous studies have focused on PFC individual neuronal representations of fear and anxiety (Morgan and LeDoux, 1995; Baeg et al., 2001; Milad and Quirk, 2002; Davis, 2006; Quirk and Beer, 2006; Burgos-Robles et al., 2009).”

“While the prefrontal cortex has been recently implicated for its involvement in the extinction of fear memory [45-47], it has not been shown that ACC inputs to the amygdala may contribute to the formation of fear memory.”

“Moreover, this cortical area plays a key role in fear extinction processes (Morgan et al. 1993; Milad and Quirk 2002).”

“Conversely, stimulation of infralimbic prefrontal cortex neurons results in low levels of conditioned behaviour in animals (Milad & Quirk 2002).”

“…of extinction is associated with a potentiation of synaptic efficacy, an increase in glucose metabolism, and in the expression of the immediate-early gene (IEG) c-fos in the medial prefrontal cortex (mPFC; Herry & Garcia, 2002; Milad & Quirk, 2002; Barrett et al., 2003; Herry &Mons, 2004).”

“Such an inhibiting effect is also supported by findings demonstrating that experimental lesions in the medial PFC of rodents block the extinction of conditioned fear ( Milad & Quirk, 2002 ), and that an insufficient level of potentiation in the medial PFC during the extinction of learned fear leads to persistent fear…”

“Importantly, extinction consolidation can be strengthened by either electrical stimulation of infralimbic cortex (Milad and Quirk, 2002; Vidal-Gonzalez et al., 2006) or potentiation of AMPA glutamate receptors within this region (Zushida et al., 2007).”

“…with experiments in which single-unit recordings in the IL of fear-conditioned rats revealed sensitivity to “extinguished” CSs only following successful extinction 68 , and a general model in which extinction-induced IL plasticity is essential for the retention of extinction memory 36 .”

“…of Neuroscience, 20, 781–790 & Crepel, 1991, 1992), and (iii) activation of NMDA receptors in the mPFC and ⁄ or the amygdala as well as prefrontal LTP is required for consolidation processes leading to long-term extinction memory (Santini et al., 2001; Herry & Garcia, 2002; Milad & Quirk, 2002).”

“Descending inhibitory inputs from the medial prefrontal cortex (mPFC) can regulate the transmission of excitatory neurotransmission from theBLA to the CeAand is thought to playa key role in the extinction of conditioned fear responses (Milad and Quirk, 2002; Likhtik et al., 2005, 2008; Peters et al., 2009).”

“, 1999 ) , and specifically within the infralimbic cortex ( Milad and Quirk , 2002 ; Milad et al .”

“…to be particularly important in the extinction of conditioned fear measured as freezing behavior to a tone previously paired with shock (e.g. Morgan et al., 1993, 2003; Morgan and LeDoux, 1995; Herry et al., 1999; Herry and Garcia, 2002; Milad and Quirk, 2002, although see Gerwitz et al., 1997).”

“For example, there is some striking recent evidence that the prefrontal cortex (PFC) is involved in extinction (Milad and Quirk 2002), but others have failed to find evidence that the PFC is involved in extinction (e.g., Gewirtz et al. 1997).”

“OMPFC, particularly the IL, is involved in fear reduction and extinction of learned fear (Garcia et al., 1999; Herry and Garcia, 2002; Milad and Quirk, 2002 ).”

“Previous studies support a model in which central amygdala neurons are inhibited by intercalated interneurons, which become more active as a result of infralimbic prefrontal cortex activation during extinction (Amano et al., 2010; Likhtik et al., 2008; Milad and Quirk, 2002).”

“However,”

“Areas in the PFC have an inhibitory effect on the amygdala (Phelps et al., 2004; Baumann and Turpin, 2010), and the modulation of emotional responsiveness by the PFC through inhibition of the amygdala is supported by lesion studies (Morgan and Ledoux, 1999; Milad and Quirk, 2002).”

“In the IL, a structure necessary for consolidation of extinction memories (SotresBayon and Quirk, 2010), increased firing to the CS is observed during extinction recall (Milad and Quirk, 2002).”

“For example, rodent studies have found that lesions to the infra-limbic cortex, a possible rodent homologue of the subgenual anterior cingulate cortex, interfere with extinction (7, 34).”

“These data , as well as electrophysiological data show - ing that electrical stimulation of infralimbic cortex simulates ex - tinction memory ( Milad and Quirk , 2002 ) , suggest that infralim - bic cortex may be a locus of consolidation or storage of extinction memories .”

“The current results revealed increased mutual influences between the medial orbitofrontal gyrus (mOFG) and amygdala in SAD patients. It has been demonstrated that these two regions are reciprocally connected with each other both functionally and anatomically”

“For example, damage to rhinal cortex can cause reversal impairments in monkeys (Murray et al., 1998), and damage to prelimbic and infralimbic prefrontal regions can cause impairments in flexible behavior in a variety of settings in rats (Birrell and Brown, 2000; Chudasama and Robbins, 2003; Milad and Quirk, 2002; Rago…”

“During an extinction session for tone fear conditioning, electrical stimulation of the IL paired with presentation of the previously conditioned tones reduces freezing in rats (Milad and Quirk 2002).”

“The VMPFC plays a central role in human social and affective functioning (Mitchell, 2011) with much of its functions accomplished automatically as for example during extinction of previously conditioned behaviors (Milad and Quirk, 2002; Morgan et al., 2003) (see Phillips et al., 2008 for review).”

“Neural activity in the vmPFC is increased during recall of extinction memory (Milad and Quirk, 2002), and HFS of the IL following retrieval of a conditioned fear memory enhances subsequent fear extinction learning (Maroun et al.”

“Single units within IL fire selectively to presentations of a previously fear conditioned cue during an extinction retention test 24 h after extinction training but not during the extinction training session itself (Milad and Quirk, 2002).”

“Our data are in line with animal data and human neuroimaging studies providing evidence that the mPFC regulates the expression of fear and anxiety by inhibiting the amygdala (Milad & Quirk, 2002; Maren & Quirk, 2004; Sotres-Bayon et al., 2004; Milad et al., 2006).”

“These effects are mediated by IL-enhanced inhibition of amygdala circuits (Milad and Quirk, 2002; Quirk et al., 2003).”

“The negative correlation between cuerelated anxiety levels and CBF in the infralimbic cortex is consistent with studies in rats (Milad and Quirk, 2002) demonstrating that pairing conditioned threat cues with brief infralimbic stimulation reduced fear.”

“Amygdala neurons in the fear circuit are under the inhibitory control of local GABAergic interneurons (Ehrlich et al., 2009), the medial intercalated neurons (Amano et al., 2010), and the infralimbic ventromedial prefrontal cortex (vmPFC, Milad & Quirk, 2002).”

“…recall additionally involves the vmPFC, which has projections to the inhibitory GABAergic intercalated cells in the amygdala, among others, which inhibit the fear response in the centromedial nucleus of the amygdala (Milad Quirk, 2002; Milad Quirk, 2012; Milad et al., 2007; Pitman et al., 2012).”

“The mPFC, particularly the infralimbic cortex, is involved in fear extinction, and increased CS-related unit activity and induction of synaptic plasticity following extinction training were observed in the infralimbic cortex (Maren and Quirk, 2004; Milad and Quirk, 2002).”

“Research supporting this concept has come from animal studies 53 54 that have reported involvement of the medial prefrontal cortex (mPFC) in the learning of new inhibitory associations, which has direct projections onto the amygdala.”

“The evidence suggests that there are reciprocal connections between the mPFC and BLA (Pérez-Jaranay and Vives, 1991; Rosenkranz and Grace, 2002; Likhtik et al., 2005) that regulate affect and memory (Garcia et al., 1999; Milad and Quirk, 2002; Laviolette et al., 2005; Laviolette and Grace, 2006).”

“The mPFC is also involved in the expression of anxiety, mainly through its modulatory impact on the amygdala (Milad and Quirk, 2002; Grace and Rosenkranz, 2002; Rosenkranz and Grace, 2001; Rangel et al, 2003).”

“Critically, activity in prefrontal cortex and anterior cingulate might be involved in the suppression of amygdala response (Hariri et al., 2003), and was found to mediate extinction in conditioning paradigms in both animals and humans (Milad and Quirk, 2002; Phelps et al., 2004).”

“Studies show that neurons of the medial prefrontal cortex play an active role in inhibition of fear responses that are mediated by the amygdala [39,40].”

“Lesions of this area block the extinction of fear conditioning in animal studies ( 5 ), and in humans the area is thought to be important in the evaluation of the consequences of social behavior (2).”

“This was not a finding that we hypothesized but is interesting given that PTSD is associated with difficulties in regulating arousal (48,49) and impairments in fear extinction (6,50), processes that are mediated by both neurons within the vACC (infralimbic cortex in rodents) and their connections with the amygdala (3,…”

“Given the role of the vmPFC in integrating cognitive and emotional information (Bechara et al., 1999) and in modulating amygdalar activity (Milad & Quirk, 2002), and the empirical findings summarized above, we propose that higher levels of adaptive emotional behavior, as reflected in greater PWB in…”

“Recent studies have suggested that the top-down regulation of the amygdala by the IL-mPFC regulates fear extinction (Morgan and LeDoux, 1995; Bremner et al., 1999; Quirk et al., 2000, 2006; Milad and Quirk, 2002; Phelps et al., 2004; Santini et al., 2004, 2008; Amano et al., 2010).”

“…(IL) activity is critical for inhibiting conditioned fear responses and facilitating extinction memory (Burgos-Robles, Vidal-Gonzalez, Santini, & Quirk, 2007; Chang & Maren, 2011; Milad & Quirk, 2002; Milad, Vidal-Gonzalez, & Quirk, 2004; Vidal-Gonzalez, Vidal-Gonzalez, Rauch, & Quirk, 2006).”