Amnesia for context fear is caused by widespread disruption of hippocampal activity.
Ontology highlight
ABSTRACT:
SUBMITTER: Krueger JN
PROVIDER: S-EPMC8562570 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The hippocampus contains one of the few neurogenic niches within the adult brain-the subgranular zone of the dentate gyrus. The functional significance of adult-born neurons in this region has been characterized using context fear conditioning, a Pavlovian paradigm in which animals learn to associate a location with danger. Ablation or silencing of adult-born neurons impairs both acquisition and recall of contextual fear conditioning, suggesting that these neurons contribute importantly to hippocampal memory. Lesion studies indicate that CFC depends on neural activity in both the dorsal and ventral hippocampus, subregions with unique extrahippocampal connectivity and behavioral functions. Because most studies of adult neurogenesis have relied on methods that permanently ablate neurogenesis throughout the entire hippocampus, little is known about how the function of adult-born neurons varies along the dorsal-ventral axis. Using a Nestin-CreERT2 mouse line to target the optogenetic silencer Archaerhodopsin to adult-born neurons, we compared the contribution of dorsal and ventral adult-born neurons to acquisition, recall, and generalization of CFC. Acquisition of CFC was impaired when either dorsal or ventral adult-born neurons were silenced during training. Silencing dorsal or ventral adult-born neurons during test sessions decreased context-evoked freezing but did not impair freezing in a hippocampus-independent tone-shock freezing paradigm. Silencing adult-born neurons modestly reduced generalization of fear. Our data indicate that adult-born neurons in the dorsal and ventral hippocampus contribute to both memory acquisition and recall. The comparatively large behavioral effects of silencing a small number of adult-born neurons suggest that these neurons make a unique and powerful contribution to hippocampal function.
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Project description:Return of fear is a serious problem in exposure-based treatments of anxiety disorders. Renewal of the fear response may occur when re-encountering the conditioned stimulus within a novel context. Findings in rodents underpin the hippocampus' role in conditioned fear renewal in novel contexts, but it has yet to be investigated in humans. Forty-six healthy men took part in a 2-day, context-dependent, cued fear conditioning paradigm with fear acquisition, extinction learning (day 1) and extinction recall in the acquisition, extinction and a novel context one day later. Conditioned evaluative, skin conductance responses (SCRs) and blood-oxygen-level-dependent responses served as dependent variables. Context-dependent fear renewal was reflected in stronger conditioned SCRs. In the acquisition context, individuals with a higher renewal of conditioned SCRs showed stronger activation of the fear circuit. Hippocampal activation distinguished conditioned responding in the novel compared with the extinction context. Individuals with a stronger renewal of conditioned SCRs in the novel context showed increased effective connectivity of hippocampal activation foci with structures in the fear and extinction network. These results outline the pivotal role of the hippocampus and its connectivity in conditioned fear renewal in a novel context in humans and might have important implications for exposure therapy in anxiety disorders.
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Project description:Patients with hippocampal amnesia play a central role in memory neuroscience but the neural underpinnings of amnesia are hotly debated. We hypothesized that focal hippocampal damage is associated with changes across the extended hippocampal system and that these, rather than hippocampal atrophy per se, would explain variability in memory between patients. We assessed this hypothesis in a uniquely large cohort of patients (n = 38) after autoimmune limbic encephalitis, a syndrome associated with focal structural hippocampal pathology. These patients showed impaired recall, recognition and maintenance of new information, and remote autobiographical amnesia. Besides hippocampal atrophy, we observed correlatively reduced thalamic and entorhinal cortical volume, resting-state inter-hippocampal connectivity and activity in posteromedial cortex. Associations of hippocampal volume with recall, recognition, and remote memory were fully mediated by wider network abnormalities, and were only direct in forgetting. Network abnormalities may explain the variability across studies of amnesia and speak to debates in memory neuroscience.
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Project description:Research on memory reconsolidation has been booming in the last two decades, with numerous high-impact publications reporting promising amnestic interventions in rodents and humans. However, our own recently-published failed replication attempts of reactivation-dependent amnesia for fear memories in rats suggest that such amnestic effects are not always readily found and that they depend on subtle and possibly uncontrollable parameters. The discrepancy between our observations and published studies in rodents suggests that the literature in this field might be biased. The aim of the current study was to gauge the presence of publication bias in a well-delineated part of the reconsolidation literature. To this end, we performed a systematic review of the literature on reactivation-dependent amnesia for contextual fear memories in rodents, followed by a statistical assessment of publication bias in this sample. In addition, relevant researchers were contacted for unpublished results, which were included in the current analyses. The obtained results support the presence of publication bias, suggesting that the literature provides an overly optimistic overall estimate of the size and reproducibility of amnestic effects. Reactivation-dependent amnesia for contextual fear memories in rodents is thus less robust than what is projected by the literature. The moderate success of clinical studies may be in line with this conclusion, rather than reflecting translational issues. For the field to evolve, replication and non-biased publication of obtained results are essential. A set of tools that can create opportunities to increase transparency, reproducibility and credibility of research findings is provided.
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