Hippocampal Inactivation Disrupts Contextual Retrieval of Fear Memory after Extinction

“…behavior as evidenced by impairments in context-dependent extinction of fear conditioning that results from inactivation of this brain region (Corcoran and Maren, 2001; Corcoran et al., 2005; Ji and Maren, 2005) and cellular substrate inhibition (Szapiro et al., 2003; Vianna et al., 2003;…”

“Direct evidence for this suggestion is provided by Maren and colleagues ( Corcoran & Maren, 2001, 2004; Ji & Maren, 2005), who have shown that reversible inactivation of the dorsal hippocampus alleviated the renewal effect.”

“The memory for the context in which extinction is acquired primes extinction retrieval, and if extinction is tested in a context that is inconsistent with the extinction context, fear renewal occurs (Corcoran and Maren, 2001, 2004; Bouton et al., 2006).”

“These results suggest that the hippocampus uses contextual cues to help determine whether to recall fear or extinction during testing.(13) The spontaneous recovery of fear indicates that extinction recall is subject to temporal factors in much the same way that it is subject to contextual factors.”

“In the case of renewal, it is important to note that the extinction of a fear response is context-specific (Bouton, 2002; 2004; Corcoran and Maren, 2001; Huff, Hernandez, Blanding, and LaBar, 2009) and a mere change of context can revoke the extinguished CR, whereas the acquisition of a fear…”

“Maren and his colleagues have documented a role for the dorsal hippocampus in ‘‘ABA’’ and ‘‘ABC’’ fear renewal (e.g., Corcoran & Maren, 2001, 2004; Ji & Maren, 2005, 2007; Maren & Hobin, 2007).”

“The extinction trials were performed on groups of rats trained and tested as described above and subsequently tested again, with the same procedure, every other day during a 10-days interval (Corcoran and Maren, 2001; Fischer et al, 2004).”

“Indeed, previous studies provide substantial evidence that the hippocampus plays a critical role in contextual fear conditioning [1,7,13,19,20].”

“…and/or retrieval of fear memories for contexts (Saulskaya & Marsden, 1995; Maren, 1999; ã 2002 Federation of European Neuroscience Societies, European Journal of Neuroscience, 16, 1789±1796 Corcoran & Maren, 2001; Pezze et al., 2001; Levita et al., 2002; but see Haralambous & Westbrook, 1999).”

“Under some circumstances, the hippocampus mediates contextdependent fear renewal (Corcoran & Maren, 2001; Ji & Maren, 2005, 2007), likely through interactions with the amygdala and ventromedial prefrontal cortex (Hobin, Goosens, & Maren, 2003; Kalisch et al., 2006; Maren & Quirk, 2004;…”

“US association (Berman & Dudai, 2001; Corcoran & Maren, 2001; Rescorla, 2001; Vianna, Szapiro, McGaugh, Medina, & Izquierdo, 2001).”

“…rats were impaired in using spatial context to guide their conditioned approach responses, consistent with the notion that the HPC is critical in context-dependent memory retrieval (Hirsh, 1974; Good & Honey, 1991; Davidson & Jarrard, 1993; Corcoran & Maren, 2001; Kennedy & Shapiro, 2004).”

“Data during the first four 1 min blocks of tone presentation served as a reliable measure of tone freezing that was not confounded by within-session habituation (Corcoran and Maren, 2001).”

“Like original learning, extinction involves acquisition of new information (Corcoran and Maren, 2001), which superimposes, but does not destroy, the original learned association (Rescorla, 2001).”

“Finally, according to Bouton (e.g., Bouton, 1991), and the available empirical evidence, rats tested in any context other than the extinction context should show renewal (e.g., Corcoran & Maren, 2001 ).”

“Potentiation of synaptic efficacy sions do not alter retention of fear extinction (Garcia et al. 2006), while inactivation of the dorsal HPC impairs fear extinction (Corcoran and Maren, 2001, 2004; Corcoran et al. 2005).”

“…Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience, 25, 2498–2503 contextual learning (for a review, see Holland & Bouton, 1999), and more specifically in renewal (Corcoran & Maren, 2001) and reinstatement (Wilson et al., 1995).”

“The amygdala is involved in processing threat-related stimuli (Davis and Whalen, 2001; Morris et al., 1998; Whalen et al., 1998, 2001) and is necessary for fear conditioning (Davis and Whalen, 2001; LeDoux, 2000; Shin et al., 2006).”

“Numerous studies suggest that several brain structures are also involved in the extinction of conditioned fear that includes the BLA (Maren, 2001; Davis and Whalen, 2001; LeDoux, 2002), medial prefrontal cortex (mPFC) (Quirk et al, 2000; Grace and Rosenkranz, 2002; Barrett et al, 2003; Quirk and Milad, 2002) and dorsa…”

“While not required for the processing of associative components of fear conditioning (mostly done in the amygdala), the hippocampus appears to be selectively involved in consolidation and retrieval of the contextual components ( Corcoran & Maren, 2001, 2004; Bast et al., 2003; Malin & McGaugh, 2006).”

“…with these findings, others have shown that suppression of dorsal hippocampal activity disrupts the expression of preference for a cocaine-conditioned context (Meyers et al., 2006) or the expression of conditioned fear to a context previously associated with footshock (Corcoran & Maren, 2001).”

“Previous studies have suggested that contextual memory is, at least in part, dependent on the hippocampal activity as destruction of the hippocampus impairs this form of memory (Maren et al., 1997; Corcoran & Maren, 2001; Mattus-Amat et al., 2004).”

“The contextual fear component appears to require an intact hippocampus, as shown in lesion and pharmacological studies (Phillips and LeDoux 1992; Chen et al. 1996; Logue et al. 1997; Holland and Bouton 1999; Young et al. 2000; Anagnostaras et al. 2001; Corcoran and Maren 2001; Wallenstein and Vago 2001).”

“Whether or not reconsolidation occurs, the main consequence of retrieval is the initiation of extinction (20,23,57,59, 60 ,65).”

“Further, rats fear-conditioned in one environment and extinguished in a different environment show robust reinstatement of freezing to the tone conditioned stimulus when returned to the training context, and this effect is blocked by pre-test inactivation of the hippocampus [97, 98].”

“For example, pharmacological inactivation of the hippocampus impairs the renewal of fear indexed both behaviorally and neurally (Corcoran and Maren, 2001; Corcoran and Maren, 2004; Hobin, Ji, and Maren, 2006; Ji and Maren, 2008).”

“(Corcoran and Maren 2001; Corcoran et al. 2005; Bouton et al. 2006), whereas the mPFC and amygdala are involved in the acquisition, consolidation, and recall of extinction memories (Falls et al.”

“The SPS procedure has been found to enhance contextual fear conditioning, and the freezing behavior may serve as a good assessment for the severity of anxiety due to hippocampal dysfunction [36, 37].”

“The hippocampus is also important in extinction learning and extinction retrieval where contextual associations may be more important compared to cue acquisition (Corcoran and Maren, 2001; Kalisch et al., 2006), and in contingency awareness (e.g., Cacciaglia et al., 2014).”

“Thus, whereas CR responses in animals are easily reinstated by an unsignaled UCS (Bouton, 1993; Corcoran and Maren, 2001), here we demonstrate that presentation of threatrelated cues alone were able to reinstate the CR. Propranolol had no discernable effect on any phase of the cued differential…”

“Although a number of studies (e.g., Corcoran & Maren, 2001; Holt & Maren, 1999) have supported the idea that the hippocampus is necessary for contextual aspects of extinction learning and recall, it is also important to note the presence of evidence that suggests otherwise.”

“Thus, an important role of the hippocampus is to inhibit unnecessary associations and allow for the formation of meaningful or predictive associations (Corcoran and Maren 2001).”

“Considering that the hippocampus is apparently the key brain area responsible for retrieval (Eldridge et al., 2000; Corcoran and Maren, 2001; Izquierdo et al., 2000),”

“On the other hand, manipulations of the hippocampal formation have been shown to disrupt renewal (Corcoran and Maren, 2001, 2004; Corcoran et al., 2005; Hobin et al., 2006; Ji and Maren, 2005, 2008a,b).”

“For example, extinction of context-evoked freezing appears to depend, at least in part, on the hippocampus (e.g., Corcoran & Maren, 2001; Lattal, Barrett, & Wood, 2007; Power, Berlau, McGaugh, & Steward, 2006) and NMDA and GABA receptors may be critical for certain aspects of extinction (e.g.,…”

“…with evidence that both tone and contextual fear extinction involve plasticity not only in brain regions thought to control associative value but also within hippocampal circuits believed to generate context memory representations (Corcoran and Maren 2001; Tronson et al. 2009; Wang et al. 2015).”

“The dorsal hippocampus (dHipp) is critical for contextual modulation of extinction retention (Westbrook et al. 2000; Corcoran and Maren 2001, 2004; Bouton et al. 2006; Orsini et al. 2011).”

“6 Corcoran et al. (2005), See text 7 Corcoran and Maren (2001).”

“For instance, pharmacological inactivation of the hippocampus (Corcoran and Maren, 2001) and the ventromedial prefrontal cortex (vmPFC; Sierra-Mercado et al., 2006) disrupts the contextspecific expression of extinction.”

“Animal studies on fear extinction that used permanent lesions (Good and Honey, 1991) or temporary inactivations of hippocampus (Corcoran and Maren, 2001; Corcoran et al., 2005; Hobin et al., 2006; Holt and Maren, 1999) demonstrated that hippocampal inactivation disrupts contextual retrieval of fear conditioning.”

“Fear responses evoked by environmental contexts previously paired with noxious stimuli, as well as the extinction of these responses, are mediated by the hippocampus [63, 64].”

“e hippocampus comes into play when contextual fear is triggered and helps the PFC in the formation of the CS-US memory [12, 13].”

“Trauma and PTSD are closely associated with hippocampal impairment (Schacter, 1997; Eichenbaum, 2000; Corcoran and Maren, 2001; Mcgaugh, 2004; Shin et al., 2006; Schoenfeld et al., 2019).”

“dHipp inactivation or lesions disrupt context-dependent fear memory expression (Kim and Fanselow, 1992; Corcoran and Maren, 2001) and disrupt cocaine-induced CPP expression (Meyers et al, 2003, 2006).”

“…or “renewal” of extinguished fear depends on the HPC. Early studies showed that pharmacological inactivation of the dHPC prevents fear renewal (Corcoran and Maren, 2001; Hobin et al., 2006) and dampens the relapse-associated increases in the lateral amygdala activity that accompany renewal…”

“Corcoran and Maren, 2001) and reduced connectivity to the mygdala (Dolcos et al., 2004; McGaugh, 2004) may underie impairments in contextual memory processing and the bility to inhibit intrusive memories (Shin et al., 2004a), lthough findings have been mixed (Hughes and Shin, 2011). recent…”

“Given that the HPC has also been shown to encode contextual extinction memories 71,72 , it is also conceivable that this circuit is involved in arbitrating the competition between fear and extinction memories for expression in behavior.”

“However, unlike the present findings, contextual fear retrieval has also been shown to be dependent on the integrity of the dorsal HPC (Corcoran & Maren 2001; Matus-Amat et al., 2004), suggesting that the neural substrates underlying fear context and reward context processing may be different.”

“Additionally, the hippocampus appears to be involved in the contextual modulation of extinction through its projections to the mPFC (52, 53).”

“Experimental and clinical findings of fear renewal and relapse demonstrate that extinction learning does not readily generalize to other contexts in rodents and humans (e.g., Mineka et al., 1999; Corcoran and Maren, 2001; Bouton, 2002, 2004; Schiller et al., 2008; Huff et al., 2009).”

“The hippocampus has been shown to play a role in contextual fear conditioning, and context modulation of extinction retention (Corcoran and Maren, 2001), and it is crucially involved in the encoding, consolidation and retrieval of declarative memories (Bekes, 2010).”

“…-amino butyric acid (GABA)A agonist muscimol into the dorsal hippocampus also causes impairment on a variety of hippocampus-dependent tasks, including place learning (Mao and Robinson 1998; Moser and Moser 1998a; Vianna et al. 2000; Corcoran and Maren 2001; Maruki et al 2001; Rossato et al. 2004).”

“Even then, it is not known if structural memory circuits may still be available for recall during inactivation by various agents (e.g., Corcoran and Maren, 2001).”

“First, our findings are in line with animal work that demonstrated the persistence of conditioning and extinction memory traces over a time delay [13,51,52] as we observe discriminative responding at a one-week delayed recall test (Test 1) in all measurement modalities (subjective fear ratings, FPS, SCRs) to both cont…”

“This dose of muscimol has also been shown to disrupt the context-specific expression of both latent inhibition of cued fear conditioning and extinction of cued fear conditioning (Holt and Maren, 1999; Corcoran and Maren, 2001).”

“, 2011), while the hippocampus is required for both fear expression and extinction memory, serving to disambiguate conflicting CS memories and determine performance (Holt and Maren, 1999; Corcoran and Maren, 2001; Corcoran et al., 2005; Sierra-Mercado et al., 2011).”

“Intrahippocampal administering of a high dose of muscimol impaired whereas the GABAergic antagonist picrotoxin enhanced extinction of fear conditioning when administered after an extinction session (McGaugh et al, 1990; Corcoran and Maren, 2001).”

“As one of the inhibitory neurotransmitters of the CNS, GABA plays an essential role in regulating the stress response, emotion, and registration and encoding of fear memory (Corcoran and Maren, 2001).”

“…(Penn et al., 1997), whereas others suggest that presence of highly disorganised thoughts, language and behaviour, higher severity of symptomatology and higher severity of negative symptoms (Corcoran and Maren, 2001) are associated with poor performance on ToM tasks (Andreasen et al., 1986).”

“…on the necessary role of the hippocampus in memory formation, research has also demonstrated an involvement of the rodent (Riedel et al., 1999; Corcoran and Maren, 2001; Jezek et al., 2002; Szapiro et al., 2002; Micheau et al., 2004; Sutherland et al., 2010) and human (Dolan and Fletcher,…”

“…shown increases, decreases, no change, or have not reported locomotor activity after DH inactivation or lesion (Chee, Menard, & Dringenberg, 2015; Corcoran & Maren, 2001; Douglas, 1967; Fujiwara et al., 2012; Meyers et al., 2003, 2006; Rezayof, Razavi, Haeri-Rohani, Rassouli, & Zarrindast, 2007).”

“…CS in the extinction context (Experiment 2), presenting an extinguished CS in a familiar context in which it has never been encountered (AAB or ABC renewal) (Corcoran, 2004; Corcoran & Maren, 2001), or even presenting the extinguished CS in the original conditioning context (Ji & Maren, 2005).”

“…by the intra-hippocampal injection of ifenprodil not only is in full agreement with the previous studies that have implicated the hippocampus (Corcoran & Maren, 2001; Corcoran & Quirk, 2007; Ji & Maren, 2007) and NR2B-containing NMDA receptors (Sotres-Bayon et al., 2007) in fear memory…”

“…hippocampal formation, including the dorsal CA1, impaired contextdependent renewal (ABA, or ABC) of conditioned fear responses in some studies (Corcoran & Maren, 2001; Ji & Maren, 2005) while in another study lesions impaired reinstatement induced by exposure to the US, but not…”