Direct Cortical Inputs to Hippocampal Area CA1 Transmit Complementary Signals for Goal-directed Navigation

Abstract

SummaryThe entorhinal cortex (EC) is central to the brain’s navigation system. Its subregions are conventionally thought to compute dichotomous representations for spatial processing: medial entorhinal cortex (MEC) provides a global spatial map, while lateral entorhinal cortex (LEC) encodes specific sensory details of experience. While local recordings of EC circuits have amassed a vast catalogue of specialized cell types that could support navigation computations in the brain, we have little direct evidence for how these signals are actually transmitted outside of the EC to its primary downstream reader, the hippocampus, which itself is critical for the formation of spatial and episodic memories. Here we exploitin vivosub-cellular imaging to directly record from EC axon terminals as they locally innervate hippocampal area CA1, while mice performed navigational and spatial learning tasks in virtual reality. We find both distinct and overlapping representations of task, location, and context in both MEC and LEC axons. While MEC transmitted a highly location- and context-specific code, LEC inputs were strongly biased by ongoing navigational goals and reward. Surprisingly, the position of the animal could be accurately decoded from either entorhinal subregion. Our results challenge prevailing dogma on the routing of spatial and non-spatial information from the cortex to the hippocampus, indicating that cortical interactions upstream of the hippocampus are critical for combining these processing streams to support navigation and memory.

Lateral entorhinal cortex subpopulations represent experiential epochs surrounding reward

“…This latter group of goal departure cells may be unique to spatial navigation tasks. In another recent study, axons from LEC and MEC were imaged in CA1 during a reward navigation task in virtual reality 76 , similar to the task used here. They found that the CA1-projecting axons from layer III of the LEC represented reward but also strongly coded spatial position as well.…”

behaviorMate: An Intranet of Things Approach for Adaptable Control of Behavioral and Navigation-Based Experiments

“…Finally, many published studies have relied on this system and the resulting data collected (Bowler & Losonczy 2023, Tuncdemir et al 2023, Vancura et al 2023, Priestley et al 2022, O’Hare et al 2022, Rolotti et al 2022a, Tuncdemir et al 2022, Rolotti et al 2022b, Terada et al 2022, Geiller et al 2022, Blockus et al 2021, Grosmark et al 2021, Dudok et al 2021a,b, Geiller et al 2020, Kaufman et al 2020 a , Turi et al 2019, Zaremba et al 2017, Danielson et al 2017, 2016). These paradigms varied greatly and included random foraging, goal-oriented learning, multi-modal cue presentations, and context switches (both in VR environments and physical treadmills).…”

“…The system further allows for simultaneous delivery of multi-modal stimuli simultaneously such as audio and visual. Thus, our system comprises an adaptable framework for probing the function of navigational circuits in the brain and the relationship between goal and context representations (Bowler & Losonczy 2023).…”

Synaptic Basis of Behavioral Timescale Plasticity

“…The VR system was designed as previously described 34,35 . Mice were head-fixed above a running wheel surrounded by 5 LCD computer monitors, each of which displayed a fraction of a VR scene that continuously updated as the position of the animal advanced.…”

“…As described above, we introduced the genetically encoded glutamate release sensor (pCAG-SFVenus-iGluSnFr-A184S) and the calcium indicator (pCAG-jRGECO1a) to estimate the spatial tuning properties of inputs received by individual dendritic spines and changes in synaptic weight following an experimentally evoked plateau potential produced by the excitatory opsin, bReaChes (pCAG-bReaChes-mRuby3) 21 . Using a head-fixed spatial navigation task in a 3 meter-long virtual reality (VR) environment 34,35 , we carried out two-photon (2P) imaging of synaptic activity dynamics from basal ( stratum oriens , SO) and oblique ( stratum radiatum , SR) dendrites, which receive the majority of spatially tuned inputs from upstream intrahippocampal regions CA2/CA3 and are thought to be the primary inputs acted upon by rapid plasticity mechanisms to generate PFs 23 (Fig. 1b, c).…”