A dentate gyrus-CA3 inhibitory circuit promotes evolution of hippocampal-cortical ensembles during memory consolidation

Abstract

Memories encoded in the dentate gyrus (DG) - CA3 circuit of the hippocampus are routed from CA1 to anterior cingulate cortex (ACC) for consolidation. Although CA1 parvalbumin inhibitory neurons (PV INs) orchestrate hippocampal-cortical communication, we know less about CA3 PV INs or DG - CA3 principal neuron - IN circuit mechanisms that contribute to evolution of hippocampal-cortical ensembles during memory consolidation. Using viral genetics to selectively mimic and boost an endogenous learning-dependent circuit mechanism, DG cell recruitment of CA3 PV INs and feed-forward inhibition (FFI) in CA3, in combination with longitudinal in vivo calcium imaging, we demonstrate that FFI facilitates formation and maintenance of context-associated neuronal ensembles in CA1. Increasing FFI in DG - CA3 promoted context specificity of neuronal ensembles in ACC over time and enhanced long-term contextual fear memory. In vivo LFP recordings in mice with increased FFI in DG - CA3 identified enhanced CA1 sharp-wave ripple - ACC spindle coupling as a potential network mechanism facilitating memory consolidation. Our findings illuminate how FFI in DG - CA3 dictates evolution of ensemble properties in CA1 and ACC during memory consolidation and suggest a teacher-like function for hippocampal CA1 in stabilization and re-organization of cortical representations.

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

“…PV mediated perisomatic inhibitory synaptic transmission in downstream principal neurons (CA3/CA2) may facilitate encoding, routing and consolidation of experiential information in distinct neuronal ensembles by imposing a sparse activity regimen (Mori et al, 2007;Neubrandt et al, 2017;Pelkey et al, 2017;Torborg et al, 2010), synchronizing activity of principal cells and generation of network oscillations (Amilhon et al, 2015;Buzsaki, 2015;Cardin et al, 2009;Csicsvari et al, 2000;de la Prida et al, 2006;Gan et al, 2016;Hu et al, 2014;Klausberger et al, 2003;Ognjanovski et al, 2017;Sohal et al, 2009). Consistently, we recently demonstrated that increasing feed-forward inhibition (FFI) in DG-CA3 resulted in enhanced stability and precision of context-associated neuronal ensembles and hippocampal-cortical synchrony (Twarkowski et al, 2022). Whether DGC recruitment of PV IN mediated inhibition of CA3 and CA2 is necessary for encoding social experiences is not known.…”

“…Learning increases mossy fiber excitatory drive onto PV INs (Caroni, 2015; Guo et al, 2018; Ruediger et al, 2012; Ruediger et al, 2011; Twarkowski et al, 2022) and enhances PV IN perisomatic contacts (“PV IN plasticity”) in CA3 (Guo et al, 2018; Twarkowski et al, 2022). To determine if social experience also increases FFI connectivity and PV IN plasticity in CA3/CA2, lentiviruses expressing GFP (CaMKIIα-GFP) were injected into the DG of 2-months old Dyrk1a +/+ mice two weeks prior to habituation to a context over 7 days.…”

“…Based on these findings, we tested whether viral downregulation of Ablim3 in DGCs is sufficient to rescue inhibitory circuitry impairments associated with Dyrk1a LOF in DGCs in adult mice. Viral injection of a construct co-expressing Cre and GFP under the ubiquitin (Ubi) promoter and an extensively validated shRNA targeting Ablim3 in DGCs of adult Dyrk1a +/+, f/+ or f/f mice (Guo et al, 2018;Twarkowski et al, 2022) We next assessed whether viral Ablim3 downregulation in DGCs also prevents the social recognition impairment seen following loss of Dyrk1a in DGCs. Behavioral analysis of adult mice expressing non-target shRNA (shNT) or Ablim3 shRNA (shRNA) in DGCs in which one or both Dyrk1a alleles were deleted showed that viral downregulation of Ablim3 reversed the social recognition impairment (Figure 2K).…”

“…Prior work has shown that experience or learning increases dentate granule cell (DGC) recruitment of parvalbumin inhibitory neurons (PV IN) mediated perisomatic inhibition of CA3 neurons (Guo et al, 2018). Anatomically, this manifests as an increase in number of mossy fiber terminal (MFT) filopodial contacts with PV INs and increase in number of PV IN perisomatic contacts in CA3 (Acsady et al, 1998; Caroni, 2015; Guo et al, 2018; Ruediger et al, 2012; Ruediger et al, 2011; Twarkowski et al, 2022). PV mediated perisomatic inhibitory synaptic transmission in downstream principal neurons (CA3/CA2) may facilitate encoding, routing and consolidation of experiential information in distinct neuronal ensembles by imposing a sparse activity regimen (Mori et al, 2007; Neubrandt et al, 2017; Pelkey et al, 2017; Torborg et al, 2010), synchronizing activity of principal cells and generation of network oscillations (Amilhon et al, 2015; Buzsaki, 2015; Cardin et al, 2009; Csicsvari et al, 2000; de la Prida et al, 2006; Gan et al, 2016; Hu et al, 2014; Klausberger et al, 2003; Ognjanovski et al, 2017; Sohal et al, 2009).…”

Fear engrams and NPYergic circuit in the dorsal dentate gyrus determine remote fear memory generalization

“…It can lead to inappropriate anxiety (4) and disturb the ability to discriminate threats from safety (5). Strikingly, remote memories are more generalized than recent ones, which suggests a time-dependent reorganization in hippocampal-cortical networks (6)(7)(8)(9)(10). Therefore, a better understanding of such remote memory generalization mechanisms may thus guide the search for an effective new intervention strategies.…”