# Probing synaptic and circuit mechanisms of hippocampal plasticity with all-optical electrophysiology

> **NIH NIH K99** · STANFORD UNIVERSITY · 2023 · $118,377

## Abstract

Project Summary
The ability of the brain to learn from and remember experiences lies at the heart of our existence and individuality.
Learning has been associated with changes in synaptic strength and circuit dynamics, yet the precise learning
rules recruited for behaviorally-relevant information storage in the mammalian brain have remained largely
unclear. It has been hypothesized that learning involves alteration in the efficacy of specific synaptic connections
through a process called synaptic plasticity, and that memory is thereupon stored as a distribution of altered
synaptic strengths in neural circuitry. Numerous forms of synaptic plasticity exist in mammals and have been
intensively studied, but in vivo preparations have not been conducive to identifying the specific synaptic changes
supporting behaviorally-relevant plasticity in behaving mammals. The objective of this proposal is to measure
and manipulate synaptic strength in behaving mammals, and to link activity patterns in specific cells
directly and causally with changes in synaptic strengths during association formation. To achieve this,
my approach is to develop and apply novel sophisticated all-optical electrophysiological methods, by
pairing optogenetic manipulation with genetically targeted voltage imaging. I have developed all-optical
electrophysiological methods to all-optically induce and record hippocampal behavioral time scale plasticity in
behaving mammals. In the K99 mentored phase, I will develop a novel all-optical technique to measure synaptic
strength between genetically targeted CA2/3 and CA1 cells. Real-time synaptic strength and circuit dynamics
between CA2/3 and CA1 will be monitored as hippocampal behavioral time scale plasticity occurs in behaving
mammals. Using optogenetic stimulation, I will manipulate both pre- and post-synaptic cell spike timing and
quantify the relationship between spiking timing and the behavioral time scale plasticity. Through the
development of the novel all-optical electrophysiological systems, I will then have the unique capability to
measure inhibitory synaptic plasticity of specific cell types during learning in the R00 independent phase.
Together, these studies will define the specific synaptic and circuit changes recruited for information storage
during learning and provide fundamental insights into how the brain encodes memory and how this process can
malfunction during mental illness. During the proposed research and career training plan, I will be mentored by
Dr. Karl Deisseroth and co-mentored by Dr. Ivan Soltesz, and advised by an exceptional advisory team. With
their support and the tremendous scientific environment at Stanford University, I will gain technical and
conceptual training in systems neuroscience, hippocampal physiology, synaptic physiology, and computational
neuroscience. These training and skills will put me uniquely at the junction of technology development and
systems neuroscience and prepare me well for my lo...

## Key facts

- **NIH application ID:** 10644885
- **Project number:** 1K99MH132871-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Linlin Fan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $118,377
- **Award type:** 1
- **Project period:** 2023-04-13 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10644885

## Citation

> US National Institutes of Health, RePORTER application 10644885, Probing synaptic and circuit mechanisms of hippocampal plasticity with all-optical electrophysiology (1K99MH132871-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10644885. Licensed CC0.

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