Synaptic plasticity is thought to play a key role in learning and memory, the development of the nervous system, and the recovery of sensory, motor, and cognitive functions after injury. Therefore manipulations that enhance synaptic plasticity have the potential for broad application in the treatment of disorders of learning and development, and for facilitating rehabilitation in cases of disease or injury to the nervous system or periphery. Indeed, there are examples in experimental animals where the enhancement of synaptic plasticity improves learning. Yet there are also examples where the enhancement of synaptic plasticity impairs learning. This project will analyze the factors favoring enhanced versus impaired behavioral outcomes when synaptic plasticity is enhanced. A factor that may limit the ability of enhanced synaptic plasticity to support adaptive changes in the nervous system is the recent history of activity in the neural circuit and the extent to which it saturates the relevant synaptic plasticity mechanism(s). This hypothesis will be tested in the context of the vestibular control of movements, and will leverage the well-characterized circuitry and signaling in that system. The experiments will utilize mice deficient in MHC Class I genes, which have enhanced synaptic plasticity and an impaired ability to adaptively recalibrate their vestibular reflexes through cerebellum-dependent motor learning. Neural activity in the cerebellum will be manipulated behaviorally or directly using optogenetics to manipulate the extent to which plasticity is saturated. A biochemical marker of synaptic plasticity will be used t assess the effect of the recent history of activity on the level of plasticity, and on the capacityfor subsequent vestibular adaptation, in both normal mice and in mice with enhanced synaptic plasticity in the cerebellum. It has been known for many years that the enhancement of synaptic plasticity can, in some cases, enhance learning, but in other cases impair learning, yet there has only been speculation about why this might be the case. This project will provide a rigorous experimental analysis of factors that determine the learning outcome under conditions of enhanced plasticity. In doing so, it will advance our fundamental understanding of how the properties of a synaptic plasticity mechanism, such as its threshold for induction, influence its function in the context of the neural activity in an intact neural circuit. The results can also gude the design of more effective approaches for vestibular rehabilitation, and, more generally, for enhancing plasticity to aid recovery of a wide range of functions after damage to the nervous system.

Public Health Relevance

The possibility of enhancing synaptic plasticity holds great potential for improving learning and memory in health and disease, and especially for enhancing the recovery of sensory, motor, and cognitive function after injury. However, in many cases where synaptic plasticity has been enhanced experimentally, learning is impaired rather than enhanced. This project analyzes why this is the case, in order to guide the design of more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004154-17
Application #
9632794
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Poremba, Amy
Project Start
1999-09-30
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
17
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Suvrathan, Aparna; Payne, Hannah L; Raymond, Jennifer L (2018) Timing Rules for Synaptic Plasticity Matched to Behavioral Function. Neuron 97:248-250
Nguyen-Vu, Td Barbara; Zhao, Grace Q; Lahiri, Subhaneil et al. (2017) A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity. Elife 6:
Suvrathan, Aparna; Payne, Hannah L; Raymond, Jennifer L (2016) Timing Rules for Synaptic Plasticity Matched to Behavioral Function. Neuron 92:959-967
Katoh, Akira; Shin, Soon-Lim; Kimpo, Rhea R et al. (2015) Purkinje cell responses during visually and vestibularly driven smooth eye movements in mice. Brain Behav 5:e00310
Shin, Soon-Lim; Zhao, Grace Q; Raymond, Jennifer L (2014) Signals and learning rules guiding oculomotor plasticity. J Neurosci 34:10635-44
Kimpo, Rhea R; Rinaldi, Jacob M; Kim, Christina K et al. (2014) Gating of neural error signals during motor learning. Elife 3:e02076
Guo, Christine C; Ke, Michael C; Raymond, Jennifer L (2014) Cerebellar encoding of multiple candidate error cues in the service of motor learning. J Neurosci 34:9880-90
Conner, Alana L; Cook, Karen S; Correll, Shelley J et al. (2014) Obscuring gender bias with ""choice"". Science 343:1200
Nguyen-Vu, T D Barbara; Kimpo, Rhea R; Rinaldi, Jacob M et al. (2013) Cerebellar Purkinje cell activity drives motor learning. Nat Neurosci 16:1734-6
Guo, Cong C; Raymond, Jennifer L (2010) Motor learning reduces eye movement variability through reweighting of sensory inputs. J Neurosci 30:16241-8

Showing the most recent 10 out of 18 publications