Distinct patterns of dentate gyrus cell activation distinguish physiologic from aberrant stimuli.

Jason C You,Jin Park,Chia-Hsuan Fu,Kavitha Muralidharan,Xiaohong Zhang,Umberto Tosi,Jeannie Chin,Giuseppe Biagini

doi:10.1371/journal.pone.0232241

Jason C You, Jin Park + Show 6 more

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https://doi.org/10.1371/journal.pone.0232241

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Abstract

Under physiologic conditions, the dentate gyrus (DG) exhibits exceptionally low levels of activity compared to other brain regions. A sparse activation pattern is observed even when the DG is engaged to process new information; for example, only ~1–3% of neurons in the DG granule cell layer (GCL) are activated after placing animals in a novel, enriched environment. Moreover, such physiologic stimulation of GCL neurons recruits young granule cells more readily than older cells. This sparse pattern of cell activation has largely been attributed to intrinsic circuit properties of the DG, such as reduced threshold for activation in younger cells, and increased inhibition onto older cells. Given these intrinsic properties, we asked whether such activation of young granule cells was unique to physiologic stimulation, or could be elicited by general pharmacological activation of the hippocampus. We found that administration of kainic acid (KA) at a low dose (5 mg/kg) to wildtype C57BL/6 mice activated a similarly sparse number of cells in the GCL as physiologic DG stimulation by exposure to a novel, enriched environment. However, unlike physiologic stimulation, 5 mg/kg KA activated primarily old granule cells as well as GABAergic interneurons. This finding indicates that intrinsic circuit properties of the DG alone may not be sufficient to support the engagement of young granule cells, and suggest that other factors such as the specificity of the pattern of inputs, may be involved.

Highlights

The dentate gyrus (DG) of the hippocampal formation plays a vital role in transforming spatial information into neuronal representations of memory
We found a nearly two-fold increase in cFos-expressing dentate granule cells when mice were removed from their home cages and exposed to a novel, enriched environment (EE) for 2 hours, where interaction with new and unfamiliar objects stimulated the DG in a physiologic manner (Fig 1A and 1B)
When testing responses of the DG to varying doses of the excitotoxin kainic acid (KA), we discovered that treating mice with a low, non-seizure-inducing dose of KA (5 mg/kg) can sparsely activate neurons in the granule cell layer (GCL), similar to physiologic stimulation

Summary

Introduction

The dentate gyrus (DG) of the hippocampal formation plays a vital role in transforming spatial information into neuronal representations of memory. Old granule cells ( 8 weeks old), which comprise the majority of cells in the GCL, are efficiently inhibited by GABAergic interneurons and remain largely silent when the DG receives input Such “old” granule cells include granule cells that were born prenatally as well as those born postnatally but have developed and matured for at least 8 weeks. The combination of effects from network inhibition and the more ready engagement of young granule cells contribute to why only ~1– 3% of neurons in the GCL are activated by exposure to physiologic stimuli that trigger new information coding and memory formation [11, 12, 14, 15]. The sparse activation of young granule cells in the GCL under physiologic conditions is thought to contribute to pattern separation, a DG-dependent function that allows similar but distinct memories to be distinguished from one another [13, 16, 17]

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