How does sensory experience regulate circuit function in the cerebral cortex? This question has been intensively studied in rodent somatosensory (S1) cortex, where whisker experience or deprivation drive plasticity in the whisker receptive field map in layer (L) 2/3, whose basis has been studied at circuit and synaptic levels. Most prior work has focused on excitatory circuits, which undergo classical Hebbian plasticity in response to whisker deprivation. However, recent work shows that experience also drives a rapid reduction in inhibition (disinhibition) in L2/3 following whisker deprivation, which is a major novel step in whisker map plasticity. We do not yet understand the circuit basis for rapid disinhibition, including which projections and synapses are involved, and how disinhibition functionally affects sensory responses in vivo. Here I propose to determine the synaptic and circuit basis of rapid disinhibition within S1. I will use whole-cell neurophysiology and optogenetic techniques to identify whether rapid disinhibition occurs primarily in feed-forward inputs to L2/3, or in L2/3 recurrent circuits, and then to identify the specific synapses whose function is altered by deprivation. These recordings will be performed in transgenic mice with parvalbumin (PV)-positive interneurons fluorescently labeled for efficient targeted recordings. Next, I will determine whether rapid disinhibition produces detectable changes in firing rates or receptive fields of S1 neurons in vivo, using silicon tetrode recordings in anesthetized mice. Finally, I will determine whether feed-forward and recurrent L2/3 circuits in the Fragile X syndrome model mouse, Fmr1 -/-, undergo rapid disinhibition in response to whisker deprivation. These experiments will provide (1) a circuit-level description of which inhibitory circuits in L2/3, (2) and which specific synapses, mediate rapid disinhibiton following whisker deprivation and (3) a description of the spiking correlates of circuit-level disinhibition n the wildtype mouse, and (4) a circuit-level description of rapid disinhibition in the Fmr1 -/- mouse. The results will further our understanding of how the brain responds to changes in sensory input that occur in normal brains during development, injury, and learning and will provide insight on dysregulation in the neurological disorder, Fragile X syndrome. The results will also be relevant to several other neurodevelopmental disorders in which E-I ratio is abnormal, such as epilepsy, autism spectrum disorders, and chronic pain. This proposal will give me valuable optogenetic and electrophysiological training that will build on my previous molecular expertise on plasticity to position me for an independent research career.

Public Health Relevance

This project investigates how sensory experience instructs the development of neural circuits in rodent somatosensory cortex, a major model system. We will use optogenetic and neurophysiological techniques to measure effects of experience on synapses, circuits, and sensory responses with a focus on inhibitory neurotransmission and excitatory-inhibitory balance. Understanding how sensory input regulates neural circuits is critical for understanding normal brain function and neurological diseases related to excitation- inhibition balance, including epilepsy, autism, chronic pain, and Fragile X syndrome, and here, we will determine how sensory experience effects inhibitory transmission in the Fragile X syndrome mouse model, Fmr1 -/-.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS087893-03
Application #
9143176
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gnadt, James W
Project Start
2014-09-19
Project End
2017-09-18
Budget Start
2016-09-19
Budget End
2017-09-18
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Neurosciences
Type
Organized Research Units
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Gainey, Melanie A; Aman, Joseph W; Feldman, Daniel E (2018) Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1. J Neurosci 38:4749-4761
Gainey, Melanie A; Feldman, Daniel E (2017) Multiple shared mechanisms for homeostatic plasticity in rodent somatosensory and visual cortex. Philos Trans R Soc Lond B Biol Sci 372:
Gainey, Melanie A; Wolfe, Renna; Pourzia, Olivia et al. (2016) Whisker Deprivation Drives Two Phases of Inhibitory Synapse Weakening in Layer 4 of Rat Somatosensory Cortex. PLoS One 11:e0148227