Throughout the nervous system, neural inputs and outputs are shaped, tuned and integrated by highly diversified sets of ion channels. Remarkably, how ion channels compose the algorithms of neural codes and how these codes translate into behavior remain central mysteries of neural processing. Here, we aim to determine how ion channels control the neural representation of external space, a representation essential to spatial memory and navigation, and impacted by neurodegenerative diseases such as Alzheimer's disease and depression. The neural basis for the representation of space depends, in part, on neural circuits in the medial entorhinal cortex, which translate the external environment into an internal map of space. Medial entorhinal grid cells provide the neural metric of this map, encoding distance traveled as a periodic pattern of firing activity that tiles the entire environment. My previous work explicitly demonstrated that spatially selective medial entorhinal neurons use ion channel kinetics for spatial scaling, giving my lab unprecedented access to a system ideal for studying the connections between ion channel substrates, coding and behavior. Here, we propose to combine in vivo electrophysiology with region specific gene manipulations to delete the set of ion channels that, when lost, modify medial entorhinal grid cell spatial representations. Our data is interpreted in the context of multiple computational models, which use different single-cell properties to generate grid coding properties. Subsequent behavioral paradigms will test the effects ion channel manipulations have on spatial memory and navigation. These studies will provide important insights into the molecular underpinnings of neural codes and computations in a high-order cortical region and elucidate how these computational codes impact the cognitive processes of spatial memory and self-localization.

Public Health Relevance

The representation of external space exists in many elements of our memories, from recalling where you parked your car to encoding a sequence of locations that help you navigate to work each day. The experiments in this proposal will test the mechanisms and function of neural circuit organization medial entorhinal cortex, a brain region that is both highly associated with spatial navigation and memory and implicated in Alzheimer's disease, mood disorders and epilepsy. Understanding how normal medial entorhinal circuits develop and contribute to behavior could lead to new methods for treating the memory-related symptoms of neural diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH106475-01A1
Application #
9027488
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Osborn, Bettina D
Project Start
2015-09-25
Project End
2020-07-31
Budget Start
2015-09-25
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$396,334
Indirect Cost
$146,334
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Campbell, Malcolm G; Ocko, Samuel A; Mallory, Caitlin S et al. (2018) Principles governing the integration of landmark and self-motion cues in entorhinal cortical codes for navigation. Nat Neurosci 21:1096-1106
Mallory, Caitlin S; Giocomo, Lisa M (2018) Heterogeneity in hippocampal place coding. Curr Opin Neurobiol 49:158-167
Mallory, Caitlin S; Hardcastle, Kiah; Bant, Jason S et al. (2018) Grid scale drives the scale and long-term stability of place maps. Nat Neurosci 21:270-282
Ocko, Samuel A; Hardcastle, Kiah; Giocomo, Lisa M et al. (2018) Emergent elasticity in the neural code for space. Proc Natl Acad Sci U S A 115:E11798-E11806
Campbell, Malcolm G; Giocomo, Lisa M (2018) Self-motion processing in visual and entorhinal cortices: inputs, integration, and implications for position coding. J Neurophysiol 120:2091-2106
Hardcastle, Kiah; Ganguli, Surya; Giocomo, Lisa M (2017) Cell types for our sense of location: where we are and where we are going. Nat Neurosci 20:1474-1482
Hardcastle, Kiah; Maheswaranathan, Niru; Ganguli, Surya et al. (2017) A Multiplexed, Heterogeneous, and Adaptive Code for Navigation in Medial Entorhinal Cortex. Neuron 94:375-387.e7