The interhemispheric CA1 circuit governs rapid generalisation but not fear memory

Abstract

Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1–conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1–conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1–conCA1 circuit.

Anterior Cingulate Cortex and Ventral Hippocampal Inputs to the Basolateral Amygdala Selectively Control Generalized Fear

“…Here, we discovered that rapidly generalized memories do not require the vHPC, whereas remote generalized memories do, showing an opposite role of that of the dHPC. Thus, our data, in combination with recent findings (Lynch et al, 2017;Zhou et al, 2017), suggest that transformation of a specific fear memory into a generalized form may actually involve a shift in control over memory recall from the dHPC to the vHPC over time.…”

“…Although the ACC and HPC are implicated in anxiety disorders (see above citations) and generalized fear (Einarsson and Nader, 2012;Cullen et al, 2015;Zhou et al, 2017), little is known about the circuits through which they govern generalized fear responses. A single study found that circuits connecting the ACC and vHPC in the nucleus reunions are necessary for the learning of specific fear (Xu and Südhof, 2013), inactivating these circuits before training induces rapid fear generalization.…”

How could stress lead to major depressive disorder?

“…The encoding-retrieval exactly matched conditions lead to specific recall but these of partial matched ones result in generalization recall, according to the theoretical hypothesis “Toward a universal law of generalization for psychological science” ( Shepard, 1987 ). A recent report has demonstrated that rapid form of memory generalization is an active process to build up additional accesses to memory resources that allow fear to be transferred from one memory to another ( Zhou et al, 2017 ). Clinical study has suggested that MDD patients exhibit over generalization of negative memories ( Gotlib and Joormann, 2010 ).…”

“…Clinical study has suggested that MDD patients exhibit over generalization of negative memories ( Gotlib and Joormann, 2010 ). Therefore, according the rapid form of memory generalization, similar cues can retrieve negative emotion that links to old stress memories ( Zhou et al, 2017 ; Silva, 2017 ), possibly leading to automatically negative thinking ( Beck et al, 1961 ). Furthermore, psychological stress memories would have been accumulated to shape the cognitive appraisal pattern in individuals ( Bower, 1981 ; Folkman et al, 1986 ).…”

“…Monoaminergic systems-based drugs, which are still the drugs of choice for treating MDD, are possibly not the best choice for producing rapid-onset antidepressant action. We owe it to the patients to open our mind to consider other possibilities beyond the known antidepressants or the known mechanisms of antidepressant action, such as the active forgetting or rapid generalization mechanisms or the idea of updating old stress-related memories by novel positive memories ( Shuai et al, 2010 ; Ramirez et al, 2015 ; Zhou et al, 2017 ). Deeper understanding of the neural mechanisms of the formation of stress-related memories will contribute to shaping such novel approaches.…”