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”

“…prefrontal cortex plays a critical role in extinction of classical (fear) conditioning (Morgan and LeDoux, 1995; Morgan et al., 1993), while electrophysiological studies in animals have shown fear extinction ‘‘memory’’ responses in ventromedial prefrontal neurons (Milad and Quirk, 2002).”

“In humans and animals, extinction of a conditioned fear response depends on communication between the medial prefrontal cortex (mPFC) and the amygdala (1,2).”

“S5B), consistent with the role of the latter regions in the acquisition of conditioned fear in both rodents and humans (27, 28).”

“Growing evidence suggests an important role of medial PFC in encoding and consolidation of extinction memories (Laurent & Westbrook, 2009; Milad & Quirk, 2002).”

“For example, permanent and temporary lesions of the ventral mPFC impair long-term extinction (e.g., Morgan et al., 2003; Sierra-Mercado et al., 2006), and neural activity in this structure predicts the strength of extinction expression (Milad and Quirk, 2002).”

“The amygdala has direct structural and functional connections with the ventral PFC (Amaral, Price, Pitkanen, & Carmichael, 1992; Ghashghaei, Hilgetag, & Barbas, 2007; Milad & Quirk, 2002).”

“Extinction and exposure-based methods of impairing the expression of threat and traumarelevant memories rely on cortical processing and the strengthening of cortical circuits which can in turn inhibit the expression of the coexisting trauma memories (Milad and Quirk, 2002; Sotres-Bayon et al., 2004).”

“…similar regions highlighted in animal studies of extinction learning, with the caveat that there are difficulties in identifying homologies between human and rodent models (White & Davey 1989; Repa et al. 2001; Herry & Garcia 2002; Milad & Quirk 2002; Hobin et al. 2003; Quirk & Gehlert 2003).”

“Moreover, prefrontal cortical neurons exhibit extinction-related changes in spike firing, and pairing prefrontal cortical stimulation with auditory CSs yields behavioral extinction (Milad and Quirk 2002).”

“Moreover, medial prefrontal cortex neurons could also be shown to store long-term extinction memory (Milad and Quirk 2002).”

“…in the vmPFC, which has been shown to play a significant role in extinction of both CTA and conditioned fear responses (Morgan et al., 1993; Quirk et al., 2000; Milad and Quirk, 2002; Barrett et al., 2003; Santini et al., 2004; Mickley et al., 2005; Milad et al., 2005; Quirk and Mueller, 2008).”

“This is a striking observation, since the infralimbic cortex undergoes plastic changes during relearning/extinction training (Santini et al., 2008), which are thought to underlie its subsequent involvement in suppression of conditioned fear during extinction recall (Milad and Quirk, 2002).”

“Although it was reported long ago that amygdala lesions disrupt CER acquisition (for review, see Goddard, 1964), recent findings suggest that the retention of CER extinction is linked to prefrontal cortex (Milad and Quirk, 2002).”

“…reduces the response in the short term and is entirely non-invasive, extinction procedures do not typically modify the original memory trace and instead lead to the development of a new, separate memory that inhibits responding (Pavlov 1927; Bouton 1993; Quirk et al. 2000; Milad and Quirk 2002).”

“These studies, along with evidence that tDCS of the dorsolateral prefrontal cortex modulates consolidation of cued fear, underline the importance of mPFC in fear learning, which has been extensively studied in rodents (6,236,237).”

“…brain regions that interconnect with the AMYG, particularly the vmPFC, are important for consolidation and retrieval of extinction memories and consequent attenuation of conditioned fear responses perhaps via inhibiting AMYG output (Milad & Quirk, 2002; Phelps et al., 2004; Quirk & Mueller, 2008).”

“To determine further the impact of activity-dependent BDNF expression in perseveration, we examined the extinction of contextual fear memory (23, 24), a process requiring transcription and translation in the PFC and hippocampus (25, 26).”

“The mPFC, on the other hand, is involved in fear extinction learning, or the acquired down-regulation of threat-related responses after threats have passed (Milad and Quirk, 2002; Milad et al., 2006).”

“, 2007; Sharpe and Killcross, 2015; Xu and S€ udhof, 2013; Yoshida and Ishii, 2006), and it is critical for the regulation of emotional memory (Bukalo et al., 2015; Courtin et al., 2014; Dejean et al., 2016; Likhtik et al., 2014; Livneh and Paz, 2012; Milad and Quirk, 2002; Motzkin et al., 2015; Rozeske et al., 2015;…”

“…2006, 2011; Farrell et al., 2010; Santini and Porter, 2010); extinction recall is associated with increased burst firing in IL pyramidal neurons (Milad and Quirk, 2002; Rabinak et al., 2008; Santini et al., 2008; Santini and Porter, 2010); and enhanced PL excitability is associated with…”

“…the projection pathway from the IL to the BLA is known to mediate the recall of extinction following fear conditioning (Lebron et al., 2004; Morgan et al., 1993; Milad and Quirk, 2002), a task consistent with the mPFC's regulation of amygdala activity and suppression of inappropriate responses.”

“IL is a critical site of plasticity for extinction (18), and neurons in IL increase their tone responses and bursting after extinction (41, 42).”

“Although recent studies suggest that mPFC is not influential or active during acquisition[38,50], this should be explored further.”

“, 1993; Myers and Davis, 2007), as well as direct electrophysiological recordings (Milad and Quirk, 2002), indicate a key role for the mPFC in extinction.”

“Consistently, a region that plays an important function in the storage of extinction memory, the medial prefrontal cortex (PFC) ( Milad and Quirk 2002 ), is able to stimulate ICM neurons, e.g.”

“Previous animal studies have shown that successful extinction of fear reaction requires interaction between synaptic plasticity of the amygdala and the ACC (Milad and Quirk, 2002; Herry and Mons, 2004).”

“The first four trials were used for extinction recall because we wanted to minimize any confound introduced by additional extinction learning during this phase, and electrophysiological data from rodents indicates that the vmPFC only signals extinction recall during the beginning of extinction recall [42].”

“Whereas the prefrontal cortex involves excitatory glutamatergic-mediated mechanisms to form new extinction memories (Milad and Quirk, 2002), and the amygdala recruits learning mechanisms involving both excitatory and inhibitory neurotransmission to regulate expression of fear (Falls et al.”

“…includes the amygdala, prefrontal cortex, and hippocampus, and recent studies have implicated the medial prefrontal cortex as a potential site for the consolidation of extinction learning and subsequent retention of extinction memory (Milad & Quirk, 2002; Milad, Rauch, Pitman, & Quirk, 2006).”

“Tone responses in IL are orrelated with extinction retention (10), and electrical stimulation esigned to mimic tone responses in this region during extinction nhances extinction retention (10,37).”

“In rats, cells within the infralimbic cortex (IL), a homologous structure to the human vmPFC, display robust CS-elicited activity during extinction recall which is inversely correlated with spontaneous recovery of fear CRs (Milad and Quirk, 2002).”

“2001; Stevenson and Gratton 2004) and infralimbic prefrontal cortex (Quirk et al. 2000; Santini et al. 2001, 2004; Milad and Quirk 2002; Lebron et al. 2004) will be crucial to dissecting the synaptic, cellular, and circuit bases of the D2 antagonist facilitation of extinction.”

“Distinct role of ITC clusters in different fear states The recruitment of ITC neurons by BLA and infralimbic cortex (IL) was proposed to account for the inhibition of CEm neurons and hence of fear expression after extinction training (Milad and Quirk, 2002; Burgos-Robles et al., 2007; Jüngling et al., 2008; Sotres-Bay…”

“Biological processes Animal research implicates the amygdala during fear extinction, including the medial prefrontal cortex in rats (Milad & Quirk, 2002) and humans (Phelps, Delgado, Nearing, & LeDoux, 2004), and specifically the basolateral nucleus of the amygdale (Quirk, Repa, & LeDoux, 1995;…”

“…input to the basolateral nuclei of the amygdala and the intercalated cells, which inhibit amygdala activity by regulating inputs from the basolateral nuclei to the central nucleus (Akirav, Raizel, & Maroun, 2006; Harris & Westbrook, 1998; Milad & Quirk, 2002) (reviewed in Kim, et al., 2011).”

“…function components in trauma appears to refl ect the notion that medial prefrontal structures play a critical role in reducing conditioned fear (Milad & Quirk, 2002; Shin, Rauch, & Pitman, 2005), and that dorsolateral prefrontal structures are associated with the executive defi cits commonly…”

“Animal research supports this view, because fear extinction depends on the activity of medial prefrontal areas rather than on changing amygdala-dependent associations [64] [65] [66], and sustained fear extinction requires memory consolidation in prefrontal areas involving protein synthesis [67].”

“Furthermore, Milad and Quirk showed that response patterns of the IL were increased with tone presentations after extinction (95).”

“The capability to engage this active process is another measure of cognitive flexibility, and facilitates the management of stressful situations accumulated over a lifetime or encountered during more transient exposure to new experiences (Milad and Quirk 2002; Sotres-Bayon et al. 2012).”

“www.learnmem.org tinction behavior (Milad and Quirk 2002; Myers and Davis 2002; Lin et al. 2003b; Quirk et al. 2003).”

“To avoid ‘floor’ effects, the number of extinction trials on day 2 was kept intentionally relatively small (4 trials), similar to a previous study (11) in which subjects were given only 4 trials of extinction training.”

“Considering that the amygdala and mPFC are implicated in fear memory extinction (Akirav et al. 2006; Milad and Quirk 2002; Morgan et al. 1993; Sotres-Bayon et al. 2006), VH neurons projecting to both the amygdala and mPFC may play a crucial role in fear memory retrieval after extinction.”

“Successful fear extinction has been ascribed to inhibitory top-down modulation of the amygdala through medial prefrontal cortex inputs (34), and functional connectivity between the amygdala and ventromedial prefrontal cortex has been observed during fear extinction and emotion regulation in humans (35).”

“Interestingly, the frontal associative cortex showed increased spine elimination during initial classical conditioning to sound cues but an increase in spine formation during extinction training (10), paralleling earlier studies in which the specific role of higher-order cortical areas has been demonstrated in extinct…”

“…the medial PFC, which in both humans and rats is reciprocrally connected with they amygdala, is involved in the extinction of fear conditioning (Milad & Quirk, 2002; reviewed in Milad et al., 2006; Morgan et al., 1993), and may be deficient in PTSD patients (reviewed in Milad et al., 2006).”

“Stimulation of IL facilitates extinction [63] and causes inhibition of amygdala output neurons [64].”

“In contrast, IL activity is associated with fear inhibition (Milad and Quirk, 2002).”

“2003), and neurons in the mPFC exhibit enhanced firing to an extinguished CS (Milad and Quirk 2002).”

“In addition to local changes in the lateral amygdala that may encode extinction memories, there is also evidence that the medial prefrontal cortex is involved in the retrieval of extinction memories (Morgan et al. 1993; Morgan and LeDoux 1995; Milad and Quirk 2002; Lebron et al. 2004; Maren and Quirk 2004; Milad et al…”

“…accelerated extinction of a cue-reward behavior via selective stimulation of PrL FSIs is consistent with the hypothesized differential roles played by the PrL and IL subregions during the expression and extinction of cue-mediated behaviors (Milad and Quirk, 2002; Burgos-Robles et al., 2009).”

“The same group has also found that successful recall of fear extinction is associated with increased burst firing of mPFC neurons (Burgos-Robles, Vidal-Gonzalez, Santini, & Quirk, 2007), which may be required for extinction-related neuronal plasticity in the mPFC as observed with single-unit recordings ( Milad & Quirk…”

“Theoretical accounts of these findings suggest that the OFC mediates the acquisition of stimulus–reinforcement associations as well as the flexible adjustment of these associations when contingencies change to bias decision making in the context of goal-directed behavior (Pickens, Saddoris, Gallagher, & Holland, 2005;…”

“Following behavioral protocols for testing fear extinction (51, 52) on day 3, the mice were placed in a test chamber and received 10 trials of the CS at random intervals without a footshock.”

“reduces responsiveness of amygdala neurons and defensive freezing behavior to conditioned tones [10].”

“…2014b; Ramirez et al., 2015), as well as structures linked to conditioned fear and fear extinction such as basal amygdala (BA; Herry et al., 2006; Laurent et al., 2008; Sierra-Mercado et al., 2011), and IL (Milad and Quirk, 2002; Sierra-Mercado et al., 2011; Do-Monte et al., 2015a), respectively.”

“Conversely, mPFC activity in healthy rats increases dramatically during testing on the day after extinction (Milad & Quirk, 2002) and stimulation of the mPFC enhances extinction learning (Herry & Garcia, 2002; Milad & Quirk, 2002).”

“During extinction, the infralimbic medial prefrontal cortex (PFC) is recruited along with the hippocampal-amygdala circuit (Figure 1B), and exerts a key role in fear reduction by inhibiting the amygdala [9, 10].”

“Within the mPFC, the IL seems to be particularly important for extinction learning (Quirk et al., 2000; Milad & Quirk, 2002; Milad et al., 2004; Santini et al., 2004; Berretta et al., 2005).”

“Neural activity in mPFC increases during extinction learning (Milad and Quirk, 2002; Rosenkranz et al., 2003), direct electrical stimulation of mPFC facilitates extinction learning (Garcia, 2002), and vmPFC damage alters rats' capacity for extinction learning (Morgan et al., 1993, 2003; Morgan and…”

“This fear regulatory network has been well-characterized as playing a critical role in extinction learning and memory (54, 55).”

“…infralimbic output hence inhibit pain behaviors and mitigate pain-related cognitive deficits. with increased activity of infralimbic neurons (Milad and Quirk, 2002; Chang et al., 2010; Sepulveda-Orengo et al., 2013) through a mechanism that involves metabotropic glutamate receptor 5…”