Abstract
In susceptible individuals, memories of stressful experiences can give rise to debilitating socio-affective symptoms. This occurs even when the ability to retrieve such memories is limited, as seen in patients suffering from traumatic amnesia. We therefore hypothesized that the encoding, rather than retrieval, mechanisms of stress-related memories underlie their impact on social and emotional behavior. To test this hypothesis, we used combinations of stress-enhanced and state-dependent fear conditioning, which engage different encoding mechanisms for the formation of stress-related memories. We found that the encoding of stress-enhanced state-dependent memories robustly and sex specifically impairs sociability in male mice and disrupts the asymmetry of dentate gyrus (DG)/CA3 activity accompanying social interactions. These deficits were restored by chemogenetic inactivation of oxytocin receptor-positive interneurons localized in the hilus (Oxtr-HI), and by inactivation of dorsohippocampal efferents to the caudal lateral septum. Together, our data suggest that disrupted patterning of dorsohippocampal DG/CA3 activity underlies stress-induced sociability deficits, and that Oxtr-HI can be a cellular target for improving these deficits.
Highlights
In susceptible individuals, autobiographical memories of intensely stressful experiences can have debilitating consequences on social and emotional behavior and lead to social dysfunction, anxiety, or depression[1,2,3]
Given that state-dependent fear conditioning (SDFC) is accompanied by increased activity in both the dentate gyrus (DG) and LS14, we investigated whether reducing activity in this pathway has the potential to ameliorate the stress-enhanced state-dependent fear conditioning (S-SDFC)-induced sociability deficits
The DG/CA3 activity and social interactions could be restored by inhibition of oxytocin receptor-positive interneurons localized in the hilus (Oxtr-HI), an effect that was more likely due to their anatomical and functional connectivity to the suprapyramidal blade, rather than to oxytocin and its receptor (Oxtr) signaling
Summary
Autobiographical (episodic) memories of intensely stressful experiences can have debilitating consequences on social and emotional behavior and lead to social dysfunction, anxiety, or depression[1,2,3] These symptoms are found both in patients suffering from post-traumatic stress disorder, who persistently retrieve such memories[4], and in patients suffering from dissociative amnesia, whose access to such memories is partially or completely blocked[5,6]. State-dependent memory is readily induced in mice trained on gaboxadol (GBX), an agonist of extrasynaptic GABAAR16 that enhances tonic inhibition in the DG17 Such memories are normally not accessible to retrieval, their presence can be demonstrated when mice are tested in the presence of the drug[14,15]. In this model, stress-related fear memories seem to be inhibited by cortical mechanisms and preferentially processed by hippocampal–lateral septal (LS) circuits[14]
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