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”

“These brain regions are involved in a variety of domains, including the processing of emotional information and the retention of information about safety signals (Bush, Luu, & Posner, 2000; Milad & Quirk, 2002; Quirk, Russo, Barron, & Lebron, 2000; Vogt, Finch, & Olson, 1992).”

“Milad and Quirk (2002) used animal models to show the role of mPFC in storing long-term memories for fear of extinction [89].”

“…amygdala and medial prefrontal cortex (Liberzon and Sripada, 2007; Shalev et al., 2008), the latter responsible for executive control and emotional regulation of fear and stress (Elliott et al., 2000; Malhi and Lago-poulos, 2008; Milad and Quirk, 2002; Phan et al., 2002; Rauch et al., 2006).”

“Consistent with this, previous studies have shown that brief electrical stimulation in IL during extinction facilitates extinction recall 24 h later only when the stimulation is given 0.1 s after tone onset (Milad and Quirk, 2002; Milad et al., 2004).”

“Inhibitory effects of the medial prefrontal cortex on learned fear behavior have been demonstrated in adult rats (Milad and Quirk, 2002).”

“…(Li and Kirouac, 2012) while other groups have reported that this area of the prefrontal cortex is involved in the expression of learned fear (Quirk et al., 2000; Milad and Quirk, 2002; Vidal-Gonzalez et al., 2006; Corcoran and Quirk, 2007; BurgosRobles et al., 2009; Sierra-Mercado et al., 2011).”

“The mPFC provides top-down control over processing of aversive and appetitive stimuli and has a well-established role in the regulation of mood (Covington et al., 2010; Milad and Quirk, 2002; Peters et al., 2009; Warden et al., 2012).”

“In contrast, the elevated pMAPK expression in the mPFC during extinction recall in MS infants is reminiscent of findings in adult animals (e.g., Knapska and Maren, 2009; Milad and Quirk, 2002).”

“2002; Milad and Quirk 2002), decreases (Herry and Garcia 2002), or no change (Milad and Quirk 2002) in neuronal activity in the”

“The ventromedial prefrontal cortex (vmPFC), in particular, has been shown to be important for making the switch from fear expression to fear suppression during fear extinction learning and retention (Milad and Quirk, 2002; Pare et al., 2004; Santini et al., 2004).”

“neurons in infralimbic cortex showed an increase in firing in response to the CS during extinction retrieval [46].”

“2a in Milad & Quirk, 2002).”

“…play a crucial role in regulating amygdala responses (Diekhof, Geier, Falkai, & Gruber, 2011; Johnstone, van Reekum, Urry, Kalin, & Davidson, 2007; Milad & Quirk, 2002; Ochsner et al., 2004; Quirk & Beer, 2006; Urry et al., 2006) and a recent effective connectivity study shows disrupted…”

“…with significant activation of the mPFC region (Barrett, Shumake, Jones, & Gonzalez-Lima, 2003; Milad & Quirk, 2002; Milad, Vidal-Gonzalez, & Quirk, 2004) and that stimulation of the mPFC enhances extinction retention in rodents (Herry & Garcia, 2002; Milad & Quirk, 2002; Milad et al., 2004).”

“Lesion and single-cell recording studies have found the vmPFC to impact recall of fear extinction without impacting acquisition or within-session extinction [23,24], suggesting that its role is specific to the retrieval of extinction memory.”

“Ventral ACC/PFC projections onto the BLA are deemed particularly critical in dampening the acquisition and expression of fear, as they compete with the BLA-to-CMA fear circuit (Milad and Quirk, 2002; Peters, et al., 2009; Vidal-Gonzalez, et al., 2006).”

“These latter effects, however, have only been reported when brief trains of current were coupled with conditioned stimuli (Milad and Quirk, 2002; Vidal-Gonzalez et al, 2006) or when more sustained stimulation (eg, 10 min) was administered immediately after the retrieval of a fear memory (Maroun et…”

“Activity in the infralimbic subregion of the medial prefrontal cortex is a key mediator of the inhibitory memory that underlies extinction (Laurent and Westbrook, 2009; Milad and Quirk, 2002; Quirk et al, 2000, 2006).”

“The vmPFC is critical in learning about fear and safety cues, and lesions in this region produce impairment in extinction retention (Milad and Quirk,2002; Phelps et al., 2004).”

“This interpretation is consistent with the idea that the mPFC plays a critical role in the inhibition of CRs by suppressing the output of the amygdala (Milad and Quirk, 2002; Maren and Quirk, 2004).”

“The ventromedial PFC is important for an individual’s ability to shift from fear expression to fear suppression (Milad & Quirk 2002; Milad et al. 2007; Santini et al. 2004).”

“and processing of stress, fear, and emotions (George et al., 1995; Hariri et al., 2003; Kim et al., 2003; Milad and Quirk, 2002).”

“…enhancement involves the forebrain structures, such as the auditory cortex, amygdala, and prefrontal cortex (Falls et al., 1992; Quirk et al., 1997; Milad and Quirk, 2002), and the extinction of top-down PPI enhancements in rats also becomes useful for studying posttraumatic stress disorder (PTSD)…”

“Several studies have indicated the existence of large individual differences in the response to non-reinforced CS presentations during retrieval despite similar extinction learning rates (Burgos-Robles et al., 2007; Herry and Mons, 2004; Milad and Quirk, 2002).”

“Single-unit recording studies have shown that, when vmPFC neurons are responsive to the fear tone during extinction training, animals show better extinction recall later (Milad and Quirk, 2002).”

“…the expression of learned fear is reduced both by PL inactivation or IL stimulation, while the extinction of conditioned freezing response is prevented both by IL inactivation or PL stimulation (Milad and Quirk, 2002; Morgan and LeDoux, 1995; Quirk et al., 2000; Vidal-Gonzalez et al., 2006).”

“In seminal work, reviewed in Milad and Quirk [155], recordings from IL neurons during acquisition, extinction and extinction recall phases revealed that IL neurons fired only when recalling a CS/noUS association on extinction recall days.”

“Although we were not able to obtain reliable extinction when CS-alone trials were delivered within 6 h of conditioning, it should be noted that in both rats (Quirk et al. 2000; Milad and Quirk 2002; Myers et al. 2006) and humans (Phelps et al.”

“En hancing the neural and neurochemical substrates of inhibitory fear learning could solve this challenge and improve PTSD treatment outcomes (Graham and Milad, 2011; Jovanovic and Res sler, 2010; Milad and Quirk, 2012).”

“For the medial prefrontal cortex, a role specifically for monitoring social evaluation has been shown in SAD patients(51,52) and this region is also implicated in fear extinction.(54,55) Dopaminergic transmission in the hippocampus has shown to be involved in memory function in animal research as well as in molecular…”

“Lesions of medial prefrontal cortex (mPFC) impair extinction learning (Morgan and LeDoux, 1995; Quirk et al., 2000); in addition, electrophysiological data have demonstrated that firing patterns of neurons in ventral mPFC are correlated with memory for fear extinction ( Milad and Quirk, 2002; Burgos-Robles et al., 200…”

“Stimulation of the infralimbic portion of mPFC reduces freezing to tones that have come to predict shock [25], and inclusive lesions of mPFC impair extinction learning [26].”

“The neural circuit involved in fear extinction included the amygdala, hippocampus (Hip), ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulated cortex (dACC) (Morgan and LeDoux, 1995; Milad and Quirk, 2002; Quirk, 2002).”

“…circuit has been shown to play a critical role in the processing and integration of emotionally salient sensory information and learning (Milad and Quirk, 2002), however, a mechanism by which cannabinoid signaling within this circuit could influence emotional associative learning at…”

“Omitting the presentation of the UCS allows the investigation of extinction processes (Milad and Quirk, 2002).”

“2003a,b,c) and prefrontal cortex (Morgan et al. 1993; Quirk et al. 2000; Herry and Garcia 2002; Milad and Quirk 2002; Santini et al. 2004; Shah et al. 2004) participate in the learning and retention of fear extinction.”

“Several studies indicated that stimulation of the vmPFC led to a suppression of conditioned fear expression in rats (Milad and Quirk, 2002; Vidal-Gonzalez et al., 2006).”

“During the recall of extinction memory, these changes would allow IL neurons to respond more robustly to the conditioned stimulus (Milad and Quirk, 2002) and inhibit fear expression via increased activation of inhibitory networks in the amygdala (Quirk et al., 2003; Ehrlich et al., 2009; Amano et…”

“However, the contributions of the closely related infralimbic/prelimbic prefrontal cortex (I/P PFC) are better understood and previous reports state that lesions to this region do not prevent short-term extinction learning, but do impair recall of extinction after a delay (Milad and Quirk 2002; Morgan and LeDoux 1999).”

“Non-human animal research has consistently demonstrated this top-down inhibition of the amygdala by the vmPFC during fear extinction (Morgan et al., 1993; Milad and Quirk, 2002; Quirk et al., 2003; Rosenkranz et al., 2003; Delgado et al., 2008).”

“Milad and Quirk found that stimulation of the medial prefrontal cortex decreases the responsiveness of central amygdala neurons that regularly fire to the CS only when animals are recalling extinction of a fear task learned using that CS (Milad and Quirk, 2002).”

“Moreover, they corroborate previous data suggesting that IL activity during extinction training is probably necessary for later retrieval (Milad and Quirk, 2002; Milad and Quirk, 2012), an effect that may be due to the development of plasticity within the IL and downstream structures (eg, ITC and BLA; Amano et al, 201…”

“Since the CeA mediates the expression of the conditioned fear response through its projections to brainstem and hypothalamic sites (LeDoux et al. 1988), stimulation of the IL may be expected to inhibit fear responses, and this appears to be the case (Milad and Quirk 2002).”

“Fear extinction is associated with activation in the medial prefrontal cortex in rats [36] and humans [37] and also the basolateral nucleus of the amygdala [38,39].”

“Ventromedial prefrontal cortex (vmPFC) is implicated in fear extinction in animal [30–32] and human [18,33].”

“Prefrontal Cortex Cognitive control of stress/threat responses through top-down modulation of subcortical areas, to initiate behavior and decision-making (Milad and Quirk, 2002; Gruene et al., 2015; Capuzzo and Floresco, 2020; Diehl et al., 2020; Scheggia et al., 2020) OT reduces stress/threat responses (freezing) thr…”

“neurons in the IL, but not the PL, fire in response to the CS that is no longer paired with the US (Chang et al., 2010; Milad and Quirk, 2002).”

“We concentrated on the IL-PFC as previous studies suggested the IL as involved in the enhancement of extinction learning (Milad and Quirk, 2002; Mueller et al, 2008).”

“Estrogen receptors are expressed in the vmPFC [35], which is known to be critical for inhibiting fear responses during fear extinction [36, 37].”

“Other signaling pathways mobilize intracellular calcium ions and lipid mediators that have profound effects on neuronal functions, influencing the mechanisms underlying the extinction of fear memory [160,161].”

“Whereas the role of mPFC in regulating fear responding is well established (Milad and Quirk, 2002; Quirk et al., 2006; Vidal-Gonzalez et al., 2006), little causal evidence implicates dmPFC as a component of the fear prediction error circuitry.”

“For example, there is evidence from animal models that top-down inhibition from mPFC is involved in extinction of conditioned fear responses (Milad and Quirk, 2002; Quirk et al., 2000).”

“It was previously shown that the neuronal activity in the prefrontal cortex is increased during extinction (Milad and Quirk, 2002), which in turn leads to a reduced amygdalar activity (Quirk et al., 2003) and thus to lower fear reactivity (Milad et al., 2004).”

“This model of prefrontal–limbic interaction is based on strong evidence from animal models [54,114], and is being validated in humans through increasingly sophisticated functional imaging studies demonstrating that frontal regions control and modulate limbic activity and that inadequate modulation is associated with p…”

“The ventromedial prefrontal cortex (vmPFC) has been suggested to play a significant role in the extinction of conditioned fear responses (Milad and Quirk 2002; Akirav et al. 2006).”

“…reactivity and the storage of fear memories, while the vmPFC appears critical for the consolidation and expression of extinction memory (Quirk et al., 2000; Sotres-Bayon et al., 2006), and the suppression of fear after extinction (Milad and Quirk, 2002; Quirk et al., 2006; Zbukvic et al., 2016).”

“…the infralimbic (IL) subdivision of the mPFC, incontrasttotheprelimbic(PL)subdivision,isparticularlyimpor-tant for extinction (Morgan et al. 1993; Milad and Quirk 2002; Sierra-Mercado et al. 2006; Kim et al. 2009) while other studies have reported similar results for the IL and PL (Santini et…”