Anagnostaras SG, Gale GD, Fanselow MS. Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus 11: 8-17

Department of Psychology and Brain Research Institute, University of California, Los Angeles 90095-1563, USA.
Hippocampus (Impact Factor: 4.16). 01/2001; 11(1):8-17. DOI: 10.1002/1098-1063(2001)11:1<8::AID-HIPO1015>3.0.CO;2-7
Source: PubMed


Dorsal hippocampal (DH) lesions produce a severe deficit in recently, but not remotely, acquired contextual fear without impairing memory of discrete training stimuli, i.e., DH lesions produce an anterograde and time-limited retrograde amnesia specific to contextual memory. These data are consistent with the standard model which posits temporary involvement of the hippocampus in recent memory maintenance. However, three recent controversies apparently weaken the case for a selective mnemonic role for the hippocampus in contextual fear. First, although retrograde amnesia (from posttraining lesions) is severe, anterograde amnesia (from pretraining lesions) may be mild or nonexistent. Second, a performance, rather than mnemonic, account of contextual freezing deficits in hippocampal-lesioned animals has been offered. Third, damage to the entire hippocampus, including the ventral hippocampus, can produce a dramatic and temporally stable disruption of context and tone fear. These data are reviewed and explanations are offered as to why they do not necessarily challenge the standard model of hippocampal memory function in contextual fear. Finally, a more complete description of the hippocampus' proposed role in contextual fear is offered, along with new data supporting this view. In summary, the data support a specific mnemonic role for the DH in the acquisition and consolidation of contextual representations.

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    • "The hippocampus, in addition, contains high levels of NMDARs and plays a pivotal role in fear extinction retention processes (Fredrikson et al. 1976; Quirk and Mueller 2008) and processing of emotional behaviour (Kjelstrup et al. 2002; Bannerman et al. 2004; McHugh et al. 2004). The hippocampus is also implicated in encoding contextual information (Maren and Holt 2000) and data suggests that the dorsal region has a selective role in fear conditioning to contextual stimuli (Young et al. 1994; Kim and Fanselow 1992), especially the acquisition and consolidation of contextual representations (Anagnostaras et al. 2001), making this brain region an interesting target to investigate in the context of DCS-induced fear extinction following contextual fear conditioning. This study aimed to identify the molecular mechanisms of intrahippocampally-administered DCS in facilitating fear extinction in a contextual fear conditioning protocol by investigating gene expression profiles in the left dorsal hippocampus (LDH) of male Sprague Dawley rats. "
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    ABSTRACT: D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.
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    • "Trace destabilization was also shown to depend on NMDA receptors containing the GluN2B subunit (Ben Mamou et al., 2006; Milton et al., 2013; Haubrich et al., 2015), particularly in the hippocampus, a brain structure involved in contextual fear memory reconsolidation (Anagnostaras et al., 2001; Rudy, et al., 2004; Winocur et al., 2009). Thus, we infused the selective GluN2B antagonist ifenprodil bilaterally into the CA1 hippocampal area 15 min prior to reactivation session aiming to prevent memory destabilization, and, thus, gather support for the reconsolidation hypothesis (Fig. 4 "
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    ABSTRACT: Memories can be destabilized by the reexposure to the training context, and may reconsolidate into a modified engram. Reconsolidation relies on some particular molecular mechanisms involving LVGCCs and GluN2B-containing NMDARs. In this study we investigate the interference caused by the presence of a distractor - a brief, unanticipated stimulus that impair a fear memory expression - during the reactivation session, and tested the hypothesis that this disruptive effect relies on a reconsolidation process. Rats previously trained in the contextual fear conditioning (CFC) were reactivated in the presence or absence of a distractor stimulus. In the test, groups reactivated in the original context with distractor displayed a reduction of the freezing response lasting up to 20 days. To check for the involvement of destabilization / reconsolidation mechanisms, we studied the effect of systemic nimodipine (a L-VGCC blocker) or intra-CA1 ifenprodil (a selective GluN2B/NMDAR antagonist) infused right before the reactivation session. Both treatments were able to prevent the disruptive effect of distraction. Ifenprodil results also bolstered the case for hippocampus as the putative brain structure hosting this phenomenon. Our results provide some evidence in support of a behavioral, non-invasive procedure that was able to disrupt an aversive memory in a long-lasting way.
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    • "Our study is in line with groups that have found, though with different TBI models that were more severe than that used in our model, that impairments in passive avoidance testing can be observed as early as the 5th day following surgery (Hogg et al., 1998) and last between 25 and 30 days after injury (Milman et al., 2005; Zhao et al., 2012). The animals may not be able to retrieve this memory because mechanisms associated with the consolidation of the memory may be impaired (Anagnostaras et al., 2001; Brun Fig. 7 "
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    ABSTRACT: Patients that suffer mild traumatic brain injuries (mTBI) often develop cognitive impairments, including memory and learning deficits. The hippocampus shows a high susceptibility to mTBI-induced damage due to its anatomical localization and has been implicated in cognitive and neurological impairments after mTBI. However, it remains unknown whether mTBI cognitive impairments are a result of morphological and pathophysiological alterations occurring in the CA1 hippocampal region. We investigated whether mTBI induces morphological and pathophysiological alterations in the CA1 using the controlled cortical impact (CCI) model. Seven days after CCI, animals subjected to mTBI showed cognitive impairment in the passive avoidance test and deficits to long-term potentiation (LTP) of synaptic transmission. Deficiencies in inducing or maintaining LTP were likely due to an observed reduction in the activation of NMDA but not AMPA receptors. Significant reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents (IPSCs) were also observed 7days after CCI. Design-based stereology revealed that although the total number of neurons was unaltered, the number of GABAergic interneurons is significantly reduced in the CA1 region 7days after CCI. Additionally, the surface expression of α1, ß2/3, and γ2 subunits of the GABAA receptor were reduced, contributing to a reduced mIPSC frequency and amplitude, respectively. Together, these results suggest that mTBI causes a significant reduction in GABAergic inhibitory transmission and deficits to NMDA receptor mediated currents in the CA1, which may contribute to changes in hippocampal excitability and subsequent cognitive impairments after mTBI. Copyright © 2015. Published by Elsevier Inc.
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