GEVI cell‐type specific labelling and a manifold learning approach provide evidence for lateral inhibition at the population level in the mouse hippocampal CA1 area

Abstract

The CA1 area in the mammalian hippocampus is essential for spatial learning. Pyramidal cells are the hippocampus output neurons and their activities are regulated by inhibition exerted by a diversified population of interneurons. Lateral inhibition has been suggested as the mechanism enabling the reconfiguration of pyramidal cell assembly activity observed during spatial learning tasks in rodents. However, lateral inhibition in the CA1 lacks the overwhelming evidence reported in other hippocampal areas such as the CA3 and the dentate gyrus. The use of genetically encoded voltage indicators and fast optical recordings permits the construction of cell-type specific response maps of neuronal activity. Here, we labelled mouse CA1 pyramidal neurons with the genetically encoded voltage indicator ArcLight and optically recorded their response to Schaffer Collaterals stimulation in vitro. By undertaking a manifold learning approach, we report a hyperpolarization-dominated area focused in the perisomatic region of pyramidal cells receiving late excitatory synaptic input.Functional network organization metrics revealed that information transfer was higher in this area. The localized hyperpolarization disappeared when GABA A receptors were pharmacologically blocked. This is the first report where the spatiotemporal pattern of lateral inhibition is visualized in the CA1 by expressing a genetically encoded voltage indicator selectively in principal neurons. Our analysis suggests a fundamental role of lateral inhibition in CA1 information processing.

High-Frequency Head Impact Disrupts Hippocampal Neural Ensemble Dynamics

“…In our experiment, we measured ensemble activations following stimulation by averaging across ROI activity and aligning this activity trace with the stimulus onsets. This analysis revealed a pattern of activity similar to a previous report using genetically encoded voltage indicators (GEVI) in vitro ( Nakajima et al, 2021 ) but, to our knowledge, has not been previously characterized using Thy1-GCaMP6f animals. We broke the activity down into three distinct features that occurred between ∼0 and ∼5 s following stimulus onset and consisted of (1) a first ensemble maximum; a narrow (∼0.2 s) and prominent peak usually between 0 and 1 s following stimulus onset.…”

“…(2) An ensemble minimum; a significant and consistent decrease in ensemble activity, often times even to 0% of the ROIs being active and lasting around 1 s. We attribute this to lateral inhibition in the CA1 field following excitation of somata in the first maximum. This hypothesis is supported by the previous study of CA1 stimulation using GEVI mice as the similar dip in activity following stimulation was sensitive to GABA blockers ( Nakajima et al, 2021 ). This decrease in ensemble activity was the most consistent across slices, groups, and sessions.…”

“…There are several possible mechanisms that could explain this finding. Given that the ensemble minimum is likely due to lateral inhibition in the CA1 field ( Nakajima et al, 2021 ), one possible mechanism to explain the observed increase in the HFHI slices is a disruption in the microcircuit between pyramidal cells and inhibitory interneurons. Given that qualitative pattern of coordinated ensemble activity can differ across slices of the same animal, but not across stimulus intensity within the same slice (see above), we believe that efficacy of lateral inhibition in the CA1 field of HFHI slices may be compromised and lead to the altered ensemble fractions seen in this study.…”

Visualizing Oscillations in Brain Slices With Genetically Encoded Voltage Indicators

“…Injection of the same AAV into PV-cre mice restricted expression to PV+ cells (PV-ArcLight) of the motor cortex. Although not all CaMKIIα+ reactive cells in the motor cortex express cre recombinase in the CaMKIIα-cre mouse, cre recombinase mediated ArcLight expression likely results in most of the pyramidal cells in layers II and III expressing ArcLight ( Jones et al, 1994 ; Wang et al, 2013 ; Nakajima et al, 2021 ). Given that there is virtually no overlap between the CaMKIIα+ and PV+ cells ( Jones et al, 1994 ; Wang et al, 2013 ), CaMKIIα+ cell and PV+ cell specific expression of ArcLight should be mutually exclusive.…”

Presentation_1.pptx

“…ArcLight was therefore used to detect oscillations in distinct cell types of the motor cortex. Although not all CaMKIIα+ reactive cells in the motor cortex express cre recombinase in the CaMKIIα-cre mouse, cre recombinase mediated ArcLight expression likely results in most of the pyramidal cells in layers II and III expressing ArcLight (Jones et al, 1994;Wang et al, 2013;Nakajima et al, 2021). Given that there is virtually no overlap between the CaMKIIα+ and PV+ cells (Jones et al, 1994;Wang et al, 2013), CaMKIIα+ cell and PV+ cell specific expression of ArcLight should be mutually exclusive.…”