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”

“This issue has, however, been directly investigated by previous studies (Quirk et al. 2000; Milad and Quirk 2002), the results of which suggest that the MPFC’s role in extinction is with multiple extinction sessions) between subsequent sessions.”

“While extinction in adult rats is dependent upon the infralimbic (IL) region of the PFC (Milad & Quirk, 2002), infant extinction is IL independent (Kim, Hamlin, & Richardson, 2009).”

“When infralimbic cortex microstimulation was paired with presentations of a previously fear conditioned cue in nonextinguished animals, freezing to those cues was attenuated, and this effect was also seen the next day when no stimulation was given.(47,48) Collectively, these findings indicate that mPFC plays a signifi…”

“There is evidence that the medial prefrontal cortex provides the mask that restricts expression of fear CRs after extinction because its stimulation mimics (Milad and Quirk, 2002) and its destruction impairs (Morgan et al.,”

“Indeed, both human (Fernandez et al. 2001) and animal (Herry and Garcia 2002, 2003; Milad and Quirk 2002 ) studies have revealed that extinction of conditioned traumatic responses can be characterized by an increase, a decrease, or no changes in neuronal activity in the mPFC.”

“Control from other brain regions comes from the infralimbic ventromedial prefrontal cortex (25) and the insula (26, 27).”

“Previous studies that measured neural activation through immediate-early gene expression (Zeidan et al, 2011), electrophysiological recordings (Milad and Quirk, 2002), or functional imaging (Phelps et al, 2004) indicate a relatively straightforward relationship between activity in IL (in rodents) or vmPFC (in humans)…”

“…the ventral mPFC (prelimbic and infralimbic cortices) modulates emotional and cognitive aspects of goal directed behavior (Vertes, 2006) and is critical in the extinction of fear (Morgan et al., 1993; Morgan and LeDoux, 1995; Milad and Quirk, 2002; Walker et al., 2002; Santini et al., 2004).”

“Repetitive transcranial magnetic stimulations to the mPFC enhance extinction memory (Milad and Quirk, 2002) and reduced conditioned fearful responses (Milad et al., 2004).”

“Based on the opposing roles of PL and IL in fear expression and extinction one would expect differences in amygdalar activation by these inputs (Milad and Quirk, 2002; Burgos-Robles et al., 2009; Sierra-Mercado et al., 2011).”

“Although the present finding and other electrophysiological data (Herry et al., 1999; Herry and Garcia, 2002; Milad and Quirk, 2002), together with studies using various other approaches (Barrett et al., 2003; Herry and Mons, 2004; Hugues et al., 2004; Santini et al., 2004), support the involvement…”

“Activity in the infralimbic (IL) subdivision of the mPFC is thought to regulate successful extinction learning (Milad and Quirk, 2002; Maren and Quirk, 2004; Giustino and Maren, 2015).”

“Converging evidence indicates that the medial prefrontal cortex (mPFC) and the intercalated cells within the amygdala play important roles in the extinction of fear memory (Milad and Quirk, 2002; Myers and Davis, 2002; Royer and Paré, 2002; Maren and Quirk, 2004; Sotres-Bayon, 2004).”

“Cannabinoid transmission through CB1 receptor in mPFC is known to modulate emotional processing, memory, and balance of morphine-related reward and aversion in rats (Ahmad et al., 2013; Milad and Quirk, 2002).”

“Moreover, plasticity in these regions is believed to mediate reversal of conditioned fear responses with extinction [103, 104].”

“Using a quite different approach, Quirk's group provided evidence for the medial frontal cortex as an important site of consolidation of memory for extinction of conditioned fear (Quirk et al. 2000; Milad and Quirk 2002).”

“In rodent models, the vmPFC has been implicated in extinction learning (Morgan and LeDoux, 1995; Milad and Quirk, 2002).”

“previously fear conditioned cue in nonextinguished animals, freezing to those cues is attenuated (Milad and Quirk, 2002; Milad et al., 2004), consistent with the putative role of this region in the expression of extinction.”

“Furthermore, electrical stimulation of IL facilitates extinction (Milad et al. 2002) and causes an inhibition of CeM responses to BL inputs (Quirk et al. 2003) even though IL has no direct projections to CeM (Cassell and Wright 1986; McDonald et al. 1996).”

“Particularly germane to treatment research, animal models demonstrate that ventral medial prefrontal cortex activation is critical in extinguishing fearful response [16].”

“During extinction recall trials, IL neurons display increased activity to CS cues, and may thus exert online top-down suppression of conditioned fear responses [10, 94].”

“fear is reduced) when the IL of the mPFC activates the inhibitory GABAergic interneurons and/or intercalated neurons in the amygdala, which then inhibit the output of the amygdala, thereby reducing the CR (Milad and Quirk, 2002; Likhtik et al., 2005; 2008; Milad et al., 2006; Quirk and Mueller, 2007; Peters et al., 20…”

“Infralimbic neurons, which are part of the medial prefrontal cortex, fire only when rats are recalling extinction—greater firing correlates with reduced fear behaviors (185).”

“More importantly, consolidation of fear extinction memory requires plasticity within the prefrontal cortex, hippocampus, and amygdala, which in turn depends on NMDA receptors, protein kinases, and protein synthesis (Milad and Quirk, 2002; Peters et al., 2010).”

“[17–20] In contrast, the more ventral region of the prefrontal cortex in the rat, the infralimbic cortex (IL), plays an important role in the acquisition and consolidation of extinction learning and recall.[15] Homologs of these regions in the human brain (at least at the functional level) have now been identified.”

“During anxiety and stress states, there is laterality in function of mPFC and amygdala (Andersen & Teicher, 1999; Sullivan & Gratton, 1999, 2002; Baker & Kim, 2004), and these regions regulate each other (Milad & Quirk, 2002; Quirk & Beer, 2006; Likhtik et al., 2008).”

“Excitatory connections from ventromedial PFC (VMPFC) synapse on GABA-mediated interneurons (intercalated cell masses) located between the basal and central nuclei of the amygdala (Milad & Quirk, 2002; Pare et al., 2004).”

“…for anxiety disorders has gained significant attention by discovering the roles of the basolateral amygdala (Lu et al., 2001; Walker et al., 2002) and prefrontal cortex (Morgan et al., 1993; Morgan & LeDoux, 1995; Milad & Quirk, 2002; Sotres-Bayon et al., 2006) in extinction of cue-dependent fear.”

“Neurons in the mPFC might be activated across re-extinction training in contrast to extinction training (Herry and Garcia 2002; Milad and Quirk 2002), thereby allowing the mPFC to re-exert its inhibitory influence on CeA efferent neurons when neuronal activity in the BLA is disrupted across brief or long re-extinction…”

“This outcome was not expected based on previously published work [26].”

“…the sgACC in overcoming fear is also in line with studies of experimental extinction of fear conditioning, which report a role for vmPFC in retrieval of the inhibitory association (Morgan et al., 1993; Milad and Quirk, 2002; Phelps et al., 2004; Milad et al., 2005, 2007a; Kalisch et al., 2006 ).”

“from fear expression to fear suppression during fear extinction learning and retention (Milad and Quirk, 2002; Paré et al., 2004; Santini et al., 2004).”

“IL activity is required for expression of fear extinction (Milad and Quirk, 2002; Sierra-Mercado et al., 2011; Vidal-Gonzalez et al., 2006), and stimulation of the medial prefrontal cortex inhibits BLA-driven activity of the CeL (Quirk et al.”

“Indeed, electrical stimulation in the IL-PFC (Milad and Quirk, 2002) and/or hippocampus (Farinelli et al., 2006) enhances the retention of extinction.”

“…(IL) was involved in this phenomenon, we stained this region for Fos and glutamate decarboxylase (GAD) 67, as IL has been proposed to be a key site for suppressing conditioned freezing (Milad & Quirk, 2002; Quirk et al., 2006) and thus is probably involved in the social buffering of freezing.”

“Ventral medial prefrontal cortex is also involved in the retention of extinction memories (Milad & Quirk, 2002).”

“These made standardized investigations methodologically possible and with the improvement of a neurophysiological and neurobiological understanding of anxiety disorders the idea of a neural anxiety network consolidated.”

“, 2006), whereas the infralimbic subregion (IL) is essential for fear extinction (Kim et al., 2009; Laurent and Westbrook, 2009; Milad and Quirk, 2002; Sierra-Mercado et al., 2011).”

“Extinction learning involves the ventromedial prefrontal cortex (PFC), amygdala, and hippocampus (Milad and Quirk, 2002; Phelps et al., 2004; Bouton et al., 2006).”

“Here the neuronal region of interest was the ventromedial prefrontal cortex (vmPFC; Milad and Quirk, 2002; Milad et al., 2007; Spoormaker et al., 2012).”

“Specifically, OFC neurons do not increase activity during the presentation of the NS or extinguished RS as neurons in infralimbic cortex do in fear-extinction studies (Milad and Quirk, 2002).”

“, 2014), whereas the IL cortex is critical for fear extinction (Milad and Quirk, 2002; Sierra-Mercado et al., 2006; Laurent and Westbrook, 2009; Chang and Maren, 2011; SierraMercado et al., 2011; Holmes et al., 2012; Do-Monte et al., 2015).”

“Specifically, the IL enhances extinction learning (Milad and Quirk, 2002; Milad et al., 2004; Mueller et al., 2008) whereas the PL increases conditioned fear expression (Vidal-Gonzalez et al.”

“This assumption has been based on animal studies demonstrating an inhibitory effect of medial PFC projections on output from the central nucleus of the amygdala (Milad and Quirk, 2002; Quirk et al., 2003).”

“The rationale for trial grouping was based on our previous human studies (9, 13, 25–28) and the animal literature (3), showing that ventromedial prefrontal cortex involvement in extinction recall is only evident during the early phase of extinction recall.”

“The generation of this type of activity increases spike firings, and the robust increment in spike firings in the infralimbic region of the mPFC reportedly occurs in response to reexposure of rats to the CS (Milad and Quirk, 2002).”

“Supporting a possible regulatory role in defensive responses, the BNST is proposed to be an important relay station linking important forebrain structures involved in conditioned emotional response to context such as the amygdala, hippocampus and medial prefrontal cortex (Dong et al., 2001a, 2001b; Davis et al., 1997a…”

“…memories correlates with an increase in CS-evoked activity in the IL and potentiation of mPFC-evoked field potentials (Herry and Garcia, 2002; Milad and Quirk, 2002; Burgos-Robles et al., Please cite this article in press as: Courtin J et al. Medial prefrontal cortex ne…”

“In addition, IL stimulation paired with the CS facilitated extinction memory (Milad and Quirk, 2002; Milad et al., 2004).”

“We chose the mFC (Additional file 1: Figure S1), because it extensively overlaps with regions referred to as the anterior cingulate cortex [24] and because it plays an important role in rodent emotional memory and behavior associated with limbic regions, such as the amygdala and hippocampus [25-27].”

“As key constituents of this circuit, the anterior cingulate cortex and amygdala mediate fear/threat responding and aversive conditioning [8,9], processes which are relevant to social anxiety and are posited to be mediated largely by glutamatergic neurotransmission based on preclinical studies [10].”

“IL neurons are activated by conditioned fear stimuli that have been extinguished [25–27], and Figure 3.”

“PCAF activity influences synaptic plasticity within the infralimbic prefrontal cortex Given that LTP is a putative mechanism for plasticity associated with memory formation (Bliss and Lomo, 1973) and that plasticity within the ILPFC is required for the formation of fear extinction memory (Milad and Quirk, 2002), we ne…”

“…infralimbic cortex reported in our study corresponds to the same infralimbic region (Bregma 3.2 mm), where there is strong coupling between neuronal electrical activity and retention of extinction (Milad and Quirk 2002) and where lesions impair the recovery of extinguished fear (Quirk et al. 2000).”

“More specifically, GABAergic intercalated cells (ITC) within the amygdala have been found to inhibit the central nucleus of the amygdala in the generation of fear responses, and the mPFC has excitatory connections to those ITC cells within the amgydala [40,48].”

“Activation in vmPFC has been associated with both extinction learning and recall (Milad & Quirk, 2002; Milad, Wright, & Orr, 2007), in particular, the association between vmPFC activation during extinction learning and anxiety reduction at follow-up parallels animal research showing that greater…”

“Both the animal and imaging literatures offer evidence that the vMPFC provides important regulatory input to the amygdala during emotional processing (eg, Goel & Dolan, 2003 ; Kim, Somerville, Johnstone, Alexander, & Whalen, 2003 ; Milad & Quirk, 2002 ; Bechara et al, 1999 ; Damasio, 1997 ; Morgan, Romanski, & LeDoux,…”