Stress-related memories disrupt sociability and associated patterning of hippocampal activity: a role of hilar oxytocin receptor-positive interneurons

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.

The modulation of emotional and social behaviors by oxytocin signaling in limbic network

“…This increases OTR binding in networks like the lateral septum, where OT modulates the expression and extinction of socially derived threat responses in lactating females, which appears to be tempered by sex hormones ( Zoicas et al, 2014 ; Menon et al, 2018 ). In this brain area, OT signaling promotes rather exacerbated threat responses (freezing) and aggression responses to social threats ( Guzmán et al, 2013 ; Meyer et al, 2020 ), similarly, in the PVN of rodent females, increased OT release is correlated to high levels of maternal aggression ( Bosch et al, 2005 ). Excessive or uncontrollable socially induced stress is associated with OT signaling impairments, which are also correlated to high levels of anxiety-like behavior.…”

Neuromodulatory functions exerted by oxytocin on different populations of hippocampal neurons in rodents

“…In the dentate gyrus (DG), OTRs are present almost exclusively in the region of hilus, where they are expressed by the GABAergic interneurons (INs) and, to a lesser extent, by the excitatory mossy cells ( Lin et al, 2017 ; Raam et al, 2017 ; Lin and Hsu, 2018 ; Meyer et al, 2020 ; Bertoni et al, 2021 ). GABAergic INs of the hilus constitute a neurochemically ( Lin et al, 2017 ; Raam et al, 2017 ; Meyer et al, 2020 ) and electrophysiologically ( Meyer et al, 2020 ) heterogeneous population: immunohistochemical studies have shown OTR expression in somatostatin- (SST + ), parvalbumin- (PV + ), calretinin- (CR + ), neuronal nitric oxide synthase- (nNOS + ), and neuropeptide Y-positive (NPY + ) GABAergic INs ( Lin et al, 2017 ; Raam et al, 2017 ; Meyer et al, 2020 ), but there is evidence for OTR expression even in parvalbumin- (PV – ) and cholecystokinin-negative (CCK – ) INs ( Harden and Frazier, 2016 ). In CA2/CA3 regions of the hippocampus, OTRs have been identified in both glutamatergic pyramidal cells (PYRs) and INs ( Lin et al, 2017 , 2018 ; Raam et al, 2017 ; Lin and Hsu, 2018 ; Tirko et al, 2018 ; Bertoni et al, 2021 ).…”

“…The dentate gyrus (DG) represents the main entry point of information into the hippocampus via perforant pathway as it is the first station of the hippocampal tri-synaptic circuit. The OTRs are mainly expressed in the GABAergic INs and the excitatory mossy cells in the hilum of the DG, whereas there has been no reported expression in the granular layer ( Lin et al, 2017 , 2018 ; Raam et al, 2017 ; Lin and Hsu, 2018 ; Meyer et al, 2020 ). Nevertheless, the electrophysiological effects of the OT on the neurons of this area remain poorly understood.…”

“…In turn, the activating action of TGOT on the hilar GABAergic INs was reflected in an indirect effect on the mossy cells that receive en passant somatodendritic synapses from the former: these cells responded to TGOT administration with an increase in the frequency and amplitude of GABAergic spontaneous inhibitory post-synaptic currents (sIPSCs) ( Figures 1A, C ). It is worth noting that a small subpopulation of OTR-expressing mossy cells exists ( Raam et al, 2017 ; Meyer et al, 2020 ), but the direct action of OT on this neuronal type is still unknown.…”

“…The action of OT in the hippocampus relies on a precise, finely tuned, and timely modulation of specific neurons in each hippocampal subregion. The expression of oxytocin receptors (OTRs) is indeed restricted to specific classes of hippocampal neurons that have been determined in multiple studies ( Campbell et al, 2009 ; Mitre et al, 2016 ; Lin et al, 2017 , 2018 ; Raam et al, 2017 ; Lin and Hsu, 2018 ; Tirko et al, 2018 ; Cilz et al, 2019 ; Meyer et al, 2020 ; Bertoni et al, 2021 ). Moreover, the effects of the OT on individual OTR-expressing neurons, as well as the intracellular signaling pathways that are activated, are highly heterogeneous due to a promiscuous G protein coupling of the OTR ( Gravati et al, 2010 ).…”