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”

“…neural plasticity in the infralimbic cortex (IL), basolateral amygdala (BLA), and ventral hippocampus (vHipp) are critical for extinction retention (Milad and Quirk 2002; Santini et al. 2004; Sierra-Mercado et al. 2006, 2011; Vidal-Gonzalez et al. 2006; Burgos-Robles et al. 2007; Corcoran and…”

“…molecular cascades in IL. Physiological correlates of extinction have been observed in IL (Burgos-Robles et al., 2007; Herry & Garcia, 2002; Hugues & Garcia, 2007; Milad & Quirk, 2002) and electrical stimulation of IL enhances extinction (Milad & Quirk, 2002; Milad, VidalGonzalez, & Quirk, 2004).”

“It is worth mentioning to this respect that the degree of IL neuronal activity has been positively correlated with extinction retrieval (Herry and Garcia, 2002; Milad and Quirk, 2002) indicating as”

“The vmPFC is thought to generally exert inhibitory control over the amygdala and is important for acquiring and recalling fear extinction [58,82-84].”

“Although the PFC has been implicated in the extinction of conditioned fear (Milad and Quirk 2002; Santini et al. 2004), these authors reported that expression of conditioned fear during extinction is associated with elevations of endocannabinoid content in the amygdala, but not the PFC (Marsicano…”

“Thus, IL mPFC projections to the amygdala inhibit conditioned fear and it is postulated that the learning of fear extinction in rats involves both increased neuronal activity in the IL mPFC (Milad & Quirk, 2002) and protein synthesis in the mPFC (Santini, Ge, Ren, Pena de Ortiz, & Quirk, 2004).”

“Well known inhibitory mechanisms involving the prefrontal cortex (Milad and Quirk, 2002; Rosenkranz et al., 2003; Likhtik et al., 2005; Sotres-Bayon et al., 2006; Quirk and Mueller, 2008) and amygdala intercalated neurons (Chhatwal et al., 2005; Likhtik et al., 2008; Ehrlich et al., 2009) may…”

“Although some previous studies in awake rats did not report excitatory responses to conditioned stimuli (Garcia et al. 1999; Milad and Quirk 2002), others have found a subset of mPFC neurons that were excited by conditioned cues (Baeg et al. 2001; Gilmartin and McEchron 2005).”

“In support, artificial electrical stimulation of IL neuons coincident with CS presentation during extinction raining enhanced the memory/recall of extinction measured he following day (Milad and Quirk, 2002; Milad et al., 004).”

“Extinction of a fear memory also appears to be dose-dependent, with a single extinction session promoting fear inhibition through enhanced inhibitory tone in LA neurons, enhanced CS-evoked activity in the medial prefrontal cortex (mPFC), and enhanced synaptic efficacy at amygdala intercalated neurons (An et al., 2017;…”

“It has also been found that pre-frontal neurons can recruit inhibitory activity within amygdala (Milad and Quirk, 2002), and that various drugs thought to affect learning or consolidation prevent or retard the stabilization of extinction when applied to PFC (Santini et al.”

“For instance, activation of a subregion of mPFC, the infralimbic cortex (IL), inhibits fear through its projections to the amygdala, a critical hub for fear (86, 87).”

“…terminalis serves to not only detect threat but also mediate anxiety, encode memories, extinguish fear, and coordinate physiological responses to perceived threat (Bishop, 2007; Davis et al., 2009; Davis and Whalen, 2001; Milad and Quirk, 2002; Milad et al., 2006; Phelps, 2004; Shin et al., 2006).”

“In contrast, the ventral ACC and adjacent ventromedial PFC connect directly and reciprocally to affective brain regions such as the BLA and hippocampus, and are mainly involved in automatic regulation and extinction of fear [Chiba et al., 2001; Etkin et al., 2006, 2011; Milad and Quirk, 2002; Myers-Schulz and Koenigs,…”

“As exposurebased CBT builds upon basic learning principles [44], animal [45] and preclinical [46] human studies show that amygdalar activity is down-regulated by infralimbic cortex/ventromedial PFC activity following extinction.”

“The mPFC has been implicated in the extinction of conditioned fear, possibly through its connections with the CeA (Morgan et al., 1993; Morgan & LeDoux, 1999; Milad & Quirk, 2002; Herry & Garcia, 2002; Quirk et al., 2006).”

“Extinction depends on coordinated activity and plasticity in multiple brain regions including the amygdala [56], periaqueductal gray [57], prefrontal cortex [58], and hippocampus [59].”

“In addition, firing of neurons in IL is correlated with memory for fear extinction (Milad & Quirk, 2002) and consolidation of extinction is impaired by either blockade of protein synthesis (Santini, Ge, Ren, de Ortiz, & Quirk, 2004) or NMDA receptors (Burgos-Robles, Vidal-Gonzalez, Santini, &…”

“, 2003), plays an important role in fear extinction (Morgan and LeDoux, 1995; Milad and Quirk, 2002).”

“D1 receptors are typically Gs-coupled receptors and when activated they are expected to function in an excitatory fashion (Missale et al., 1998).”

“…activated when an extinguished CS is presented (e.g., Herry & Garcia, 2002), lesions of the mPFC impair long-term retention of extinction learning (e.g., Quirk, Russo, Barron, & Lebron, 2000), and stimulation of the mPFC facilitates the development of fear extinction (e.g., Milad & Quirk, 2002).”

“In particular, brief stimulation of the infralimbic cortex (a subregion of the vmPFC) was found to reduce fear memory and strengthened extinction (12, 49).”

“…amygdala (Davis, Walker, & Myers, 2003; Izquierdo, Cammarota, Vianna, & Bevilaqua, 2004; Myers & Davis, 2002; Walker, Ressler, Lu, & Davis, 2002), central amygdala (Bahar, Dorfman, & Dudai, 2003), medial prefrontal cortex (Milad & Quirk, 2002), and the insular cortex (Berman & Dudai, 2001).”

“The fact that this occurred, despite the absence of behavioral arousal, is consistent with the view that these cues maintain incentive value, but the extinction procedure resulted in other behavioral responses being adopted (Nader, 2003; Milad and Quirk, 2002).”

“It is well established that inhibition of IL impairs fear extinction (Burgos-Robles et al, 2007; Laurent and Westbrook, 2009; Quirk et al, 2000; SierraMercado et al, 2011), whereas stimulation of IL enhances extinction (Kim et al, 2010; Maroun et al, 2012; Milad and Quirk, 2002; Milad et al, 2004).”

“Increasing evidence supports a primary role of the infralimbic subdivision (IL) of the medial prefrontal cortex [mPFC; ventromedial PFC (vmPFC in humans)] in fear extinction and retrieval (Milad and Quirk, 2002).”

“Despite previous studies about the role of the mPFC in reward (Tzschentke, 2000) or aversion (Milad & Quirk, 2002), we are only starting to comprehend some of the processes that will get us closer to an answer.”

“IL , conversely, drives fear inhibition during extinction acquisition by interacting with the inhibitory cells in the BLA (Milad and Quirk, 2002; Vertes, 2004; Sierra-Mercado et al., 2011), primarily through intercalated cell masses (ITC)s (Likhtik et al., 2008; Sotres-Bayon and Quirk, 2010) (…”

“The hippocampus works synergistically with the cortex and amygdala to control the processing of emotional memories (Richardson et al. 2004) and reduction of fear (Milad and Quirk 2002).”

“Intracranial neuronal recordings and microstimulation/microinjection studies in rodents, as well as brain imaging studies in humans, have revealed that prefrontal cortex (PFC), hippocampus, and amygdala are involved in the extinction of conditioned fear [17, 55-61].”

“Given the known role of the medial prefrontal cortex (mPFC) in the consolidation and long-term retention of extinction memories (Milad and Quirk, 2002; DoMonte et al., 2015), these results indicate a detrimental effect of stress on this brain region (Radley et al.”

“By contrast, IL plays a specific role in storing memories related to threats especially during extinction [51].”

“Owing to the abundant expression of D4 receptors within the medial prefrontal cortex [12] and the specific role suggested for the infralimbic cortex in extinction memory [5,9], our hypothesis was that they might be involved in one of the processes underlying extinction of conditioned fear.”

“…test within the ventromedial prefrontal cortex (vmPFC), a region that is important for the consolidation and also involved in the retrieval and/or expression of extinction memories (Do-Monte et al., 2015; Kalisch et al., 2006; Milad et al., 2007; Milad and Quirk, 2012, 2002; Phelps et al., 2004).”

“Memory extinction is a new form of learning and the IrL has been shown to play an important role in the extinction of conditioned emotional response (Milad and Quirk, 2002; Barrett et al., 2003; Miller, 2004).”

“Medial prefrontal cortex The mPFC has been proposed to be necessary for the normal expression and extinction of CF (Morgan and LeDoux, 1995;Vouimba et al., 2000;Milad and Quirk, 2002;Pezze et al., 2003).”

“Inactivation of the mPFC increases reactivity to fear (Morgan & LeDoux, 1995) and amygdala stimulation (Jackson & Moghaddam, 2001), consistent with findings that mPFC neurons may encode fear extinction memories ( Milad & Quirk, 2002 ).”

“[24] Milad MR, Quirk GJ.”

“The mPFC is lso implicated in extinction of fear, as manipulations of the ILPFC result in impairments in fear extinction, mainly in the recall f extinction memory (Milad and Quirk, 2002).”

“…activity in the medial PFC in response to the threat cue is in line with previous studies demonstrating its role in fear learning (Gramsch et al., 2014; Fullana et al., 2016), fear memory and fear expression in humans and animals (Milad and Quirk, 2002; Maren and Quirk, 2004; Etkin et al., 2011).”

“(B) Rostral NTS (NTSr): CTA+EXT rats express more c-Fos-labeled neurons in rostral NTS (the gustatory portion of the NTS) [15,24,37,42] than do controls.”

“For example, ILC lesions prevent extinction of fear responses (Quirk et al. 2000; Chang and Maren 2010), fear extinction enhances ILC neuronal activity (Milad and Quirk 2002), and activation of the ILC in a fear context accelerates fear extinction (Thompson et al. 2010).”

“In contrast, a second region of rodent medial prefrontal cortex (mPFC), the infralimbic region, has been implicated in the retention or recall of Pavlovian extinction learning (Milad and Quirk, 2002; Phelps et al., 2004; Quirk et al., 2000).”

“Interestingly, IL has been linked to extinction of both appetitive and aversive associations (Bravo-Rivera et al., 2014; Capuzzo and Floresco, 2020; Laque et al., 2019; Milad and Quirk, 2002; Peters et al., 2008; Rhodes and Killcross, 2004; Riaz et al., 2019; Sierra-Mercado et al., 2011), suggesting a more generalized…”

“Likewise, successful retrieval of extinction memory is associated with increases in IL activity (Milad and Quirk, 2002; Chang et al., 2010; Wilber et al., 2011; Giustino et al., 2019).”

“for long-term fear extinction, which also requires gene expression in this brain region [24, 39, 42–44].”

“Thus, extinction requires associative learning, consolidation and formation of new memory (Milad and Quirk, 2002; Santini et al., 2001).”

“Studies of fear extinction have repeatedly found an important role for infralimbic prefrontal cortex (ilPFC) in the storage of fear memories (Milad & Quirk, 2002; Sierra-Mercado et al., 2011).”

“…evidence implicates the infralimbic (IL) region of the rat medial prefrontal cortex (MPFC) in expression of extinction (Quirk et al., 2000; Milad & Quirk, 2002; Rhodes & Killcross, 2004), a process generally considered to be mediated by the formation of inhibitory associations that…”

“Ventral prefrontal regions have been shown to be important for modifying previously learned associations via extinction learning [20].”

“Seed regions were then placed within these areas for subsequent functional connectivity psycho--physiological interaction (PPI) analyses on the primary data set (Friston et al. 1997; Mattfeld and Stark 2011).”

“The amygdala is a key brain region that in conjunction with the hippocampus and the prefrontal cortex supports fear memory formation and extinction (McGaugh, 2004; Milad and Quirk, 2002; Pape and Pare, 2010).”

“, the tone) are critically involved in the extinction learning (Milad and Quirk, 2002).”

“…conflicts, and that it exhibits changes that correlate with the transition to chronic pain (Baliki et al., 2012; Jensen et al., 2003a; Milad and Quirk, 2002; Mobbs et al., 2007; Ploghaus et al., 1999; Ren et al., 2016; Schiller et al., 2008; Schlund et al., 2016; Schwartz et al.,…”

“The elevated neuronal firing rate in the infralimbic mPFC has been correlated with spontaneous recovery of freezing after the fear extinction, and short-term electric stimuli in infralimbic mPFC has shown to facilitate fear extinction memory in rats [19].”

“The mPFC is thought to play a role in the extinction of behavioral responses (Milad & Quirk, 2002; Phelps, Delgado, Nearing, & LeDoux, 2004) and the top-down regulation of emotion in PTSD (Lanius et al., 2006; Rozeske, Valerio, Chaudun, & Herry, 2014; Shin & Handwerger, 2009).”

“In contrast, the infralimbic (IL) component of the mPFC appears to have an opposite function, with its requisite involvement in the inhibition of learned fear behavior (Milad and Quirk, 2002; Nieuwenhuis and Takashima, 2011; Quirk et al., 2000).”

“…evaluated, pharmacological, electrophysiological or genetic manipulations of the PL and IL can produce either similar or, more frequently, opposite behavioral effects (Milad and Quirk, 2002; Resstel et al., 2006; Lisboa et al., 2010; Sierra-Mercado et al., 2011; Arruda-Carvalho and Clem, 2014).”

“…is mediated by increased neuronal activity within the infralimbic region of the rodent mPFC (Burgos-Robles, VidalGonzalez, Santini, & Quirk, 2007; Milad & Quirk, 2002; Quirk & Mueller, 2008), and age-related decreases in the excitability of these neurons have been linked to flexibility…”