Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding

Abstract

Episodic memory establishes and stores relations among the different elements of an experience, which are often similar and difficult to distinguish. Pattern separation, implemented by the dentate gyrus, is a neural mechanism that allows the discrimination of similar experiences by orthogonalizing synaptic inputs. Granule cells support such disambiguation by sparse rate coding, a process tightly controlled by highly diversified GABAergic neuronal populations, such as somatostatin-expressing cells which directly target the dendritic arbor of granule cells, massively innervated by entorhinal inputs reaching the molecular layer and conveying contextual information. Here, we tested the hypothesis that somatostatin neurons regulate the excitability of the dentate gyrus, thus controlling the efficacy of pattern separation during memory encoding in mice. Indeed, optogenetic suppression of dentate gyrus somatostatin neurons increased spiking activity in putative excitatory neurons and triggered dentate spikes. Moreover, optical inhibition of somatostatin neurons impaired both contextual and spatial discrimination of overlapping episodic-like memories during task acquisition. Importantly, effects were specific for similar environments, suggesting that pattern separation was selectively engaged when overlapping conditions ought to be distinguished. Overall, our results suggest that somatostatin cells regulate excitability in the dentate gyrus and are required for effective pattern separation during episodic memory encoding.Significance statementMemory systems must be able to discriminate stored representations of similar experiences in order to efficiently guide future decisions. This is solved by pattern separation, implemented in the dentate gyrus by granule cells to support episodic memory formation. The tonic inhibitory bombardment produced by multiple GABAergic cell populations maintains low activity levels in granule cells, permitting the process of pattern separation. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the dentate gyrus. Hence, somatostatin cells constitute an ideal candidate to regulate pattern separation. Here, by using optogenetic stimulation in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity

“…Alternatively, this could be tested with a behavioral pattern separation task that can be performed over a few days (spontaneous location recognition or object lure discrimination and mnemonic discrimination testing) rather than a month (the present work). Using a more condensed behavioral pattern separation task would also enable future dissociation of the stages of learning (encoding, consolidation, and retrieval) and factors that regulate each stage (Bekinschtein et al, 2013;Johnson et al, 2018;Morales et al, 2021;Reichelt et al, 2021). (Yassa et al, 2010;Stone et al, 2011;Wilson et al, 2013;Hansen et al, 2018;Yun et al, 2018b;Amani et al, 2021), antidepressant-like behavior (Yun et al, 2018a), and reward-seeking (Ge et al, 2017) (Schultz, 1997;Ungless et al, 2010;Morikawa and Paladini, 2011;Marinelli and McCutcheon, 2014;Keiflin and Janak, 2015;Wise and Jordan, 2021), and S%&$%&3!2"##&3&/$!-.967!+3!-.9%"44+('F4'0!("3(:"$1!'3&!&/<'<&2!:/2&3!…”

“…The upstream EC is considered a functional gatekeeper for the downstream hippocampus (Fernandez and Tendolkar, 2006;Basu et al, 2016;Hansen et al, 2018), feeding multi-sensory and associative information into the DG and other hippocampal regions (Bekinschtein et al, 2013;Morrissey and Takehara-Nishiuchi, 2014;Reagh and Yassa, 2014;Kitamura et al, 2015;Save and Sargolini, 2017;Reagh et al, 2018;Morales et al, 2021;Marks et al, 2022). In addition to the EC being involved in spatial navigation and episodic memory, one study suggests the EC -and particularly the lateral EC (LEC) -is critical for behavioral pattern separation (Vivar et al, 2012).…”

“…LECIIa fan cells are notable as they comprise the only projection from the EC to the DG; they make excitatory synapses in the DG molecular layer (Mol) on the processes of glutamatergic DG granule cells (GCs), adult-born GCs, and mossy cells, and GABAergic interneurons (Witter, 2007;Witter et al, 2017;Vandrey et al, 2020;Traub and Whittington, 2022). All of these DG cell types have been implicated in behavioral pattern separation (Leutgeb et al, 2007;Myers and Scharfman, 2009;Jinde et al, 2012;Schmidt et al, 2012;GoodSmith et al, 2017;Nakazawa, 2017;Morales et al, 2021), and some of them -including adult-born DG GCs -have also been implicated in cognitive flexibility (Burghardt et al, 2012;Swan et al, 2014;Yagi and Galea, 2019;Wingert and Sorg, 2021). This circuit positioning of LECIIa fan cells suggests they are a "loadsensitive" component of the EC-DG circuit in behavioral pattern separation and cognitive flexibility, but this has not yet been tested.…”

The Engram’s Dark Horse: How Interneurons Regulate State-Dependent Memory Processing and Plasticity

“…Consistent with the conclusions of the study described above, several pieces of recent data suggest that hippocampal SST+ interneurons may play a critical role in precisely encoding memories. For example, a recent study showed that optogenetic inhibition of DG SST+ interneurons during training on either a contextual or object-location discrimination task led to deficits at testing 24 h later, but only if the two scenarios being discriminated were highly similar ( Morales et al, 2021 ). Another recent study tested the role of DG SST+ interneurons in the context of encoding foreground contextual fear, where context is the most salient predictor of a foot shock, vs. background contextual fear, where foot shocks are immediately preceded by a tone cue, making context itself less salient ( Raza et al, 2017 ).…”

Neurophotonics Approaches for the Study of Pattern Separation

“…For example, in some cases, neurons that express archaerhodopsin can activate other neurons. Then, optical stimulation can induce suppression of the activity of neurons that express archaerhodopsin but excitation of neurons that are subsequently activated by them (Senzai and Buzsáki, 2017;Morales et al, 2019). This method does not allow the identification of GCs (that excite directly the MCs) but is useful for the identification of MCs.…”