A change in spike rate or timing is a fundamental output characteristic of neuronal response. Neuronal spike output, however, is characterized by a noisy or random nature such that the same environmental stimulus never generates the same precise count spike output. This is particular true for cortical neuronal spike discharge during states when the animal is awake or actively engaged with the environment. In part, the random nature of spike discharge is related to the underlying nature of membrane voltage fluctuations that are generated by seemingly random excitatory and inhibitory synaptic events. A large body of experimental and modeling work has focused on how membrane voltage fluctuations alter the input-output response of neurons. Often, noisy fluctuations in synaptic activity are thought of as """"""""background"""""""" activity that modulates how neurons respond to deterministic set of inputs provided by only a few pre-synaptic neurons that are actively engaged in singling a stimulus. For example, background voltage fluctuations are thought to increase sensitivity to weak inputs in visual cortical neurons and hence provide a form of gain control or contrast invariance. As such, the nature of the background membrane voltage fluctuations plays a fundamental role in how neurons transform synaptic current inputs to spike output. In addressing these issues, previous modeling work has assumed that membrane voltage fluctuations can be described by normal (Gaussian) distributions with power spectra largely determined by the synaptic decay kinetics of excitatory and inhibitory synapses. Our preliminary analyses of in vivo membrane voltage fluctuations recorded in layer II V1 pyramidal cells, however, indicate that fluctuations have positively skewed distributions (i.e. non-Gaussian) and far less power at high frequencies than expected from filtering established through synaptic kinetics or membrane charge time. Given the central role of voltage fluctuations in cortical dynamics and computational models, it is crucial to understand both the nature of in vivo fluctuations and how our new observations concerning distributions and spectra of voltage affect input-output functions of cortical neurons. To address these issues, this project will analyze in vivo membrane voltage fluctuations and model their generation using a novel set of tool kits developed within our dynamic clamp software suite. We will then combine our simulations of synaptic activity with dynamic clamp to inject these forms of background activity to neurons in a slice preparation of layer II V1 cells an assess input-output functions.

Public Health Relevance

Understanding how neurons generate activity in response to different synaptic inputs is a fundamental problem in the field of neuroscience with implications for a wide range of neurological diseases. This project will study how synaptic input properties affect neuron membrane excitability. The study also has the potential to uncover specific roles for molecules involved in excitability, some of which may be new targets for pharmacologic treatments for neurological disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
Project #
Application #
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Glanzman, Dennis L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Biomedical Engineering
Schools of Engineering
Salt Lake City
United States
Zip Code
Melonakos, Eric D; White, John A; Fernandez, Fernando R (2016) Gain Modulation of Cholinergic Neurons in the Medial Septum-Diagonal Band of Broca Through Hyperpolarization. Hippocampus 26:1525-1541
Fernandez, Fernando R; Malerba, Paola; White, John A (2015) Non-linear Membrane Properties in Entorhinal Cortical Stellate Cells Reduce Modulation of Input-Output Responses by Voltage Fluctuations. PLoS Comput Biol 11:e1004188
Gee, J Michael; Smith, Nathan A; Fernandez, Fernando R et al. (2014) Imaging activity in neurons and glia with a Polr2a-based and cre-dependent GCaMP5G-IRES-tdTomato reporter mouse. Neuron 83:1058-72