In particular, by examining (1) the biophysical properties of neurons devoted to processing of sensory information and (2) attributes that govern the efficacy and specifivity with which these neurons communicate with one another, we seek a comprehensive understanding of the factors that govern how, if, and when signals elicited by sensory stimuli propagate through (and are modified) by neural circuits.
These observations raise at least two important questions: What enables, and what limits, the fidelity with which neural activity in the CNS encodes information about characteristics of sensory stimuli?
To answer these questions we identify mechanisms that govern the response of neurons and neural circuits to features of sensory stimuli. We focus on areas of the CNS in which neural activity can be modulated accurately and reproducibly by external cues and the source of stimulus-evoked synaptic input a given neuron receives is known or highly constrained; our current efforts are focused on the retina and superior colliculs, two regions in which these criteria are satisfied. While the area in which we perform experiments varies, a general question—to what degree does the sensitivity and specificity with which a neuron responds to sensory stimuli reflect intrinsic properties of that neuron versus properties of the input it receives?—permeates nearly all of our research.
For example, in the retina and superior colliculus (and other areas), electrical activity of neurons is influenced by visual stimuli emanating from particular regions of the external world. The organization, shape, and size of these regions, called receptive fields, provide an important constraint on the spatial resolution with which the origin of sensory information can be determined—i.e., given the same degree of overlap between adjacent receptive fields, spatial resolution increases as receptive field size decreases.
Receptive field size varies considerably (and often predictably) within a class of neuron as well as between distinct classes of neurons; what factors underlie these differences is largely unknown. Examining light-evoked activity in retinal ganglion cells (RGCs), the neurons through which information about all light stimuli is transmitted to the brain, provides an unusually good opportunity to distinguish the relative degree to which circuit, synaptic, and cellular properties underlie RGC receptive fields. Decades of detailed anatomical studies, and new techniques to label and manipulate specific sets of neurons, enable us to measure and control the source and properties of signals that a given RGC receives in response to physiological stimuli. Additional techniques—e.g., simultaneous patch-clamp recordings from multiple neurons; release of caged neurotransmitters via multiphoton excitation—permit us to control the temporal and spatial properties of synaptic input more precisely than is possible with light stimuli alone. Utilized together, these biological and technical features enable us to parse the relative degree to which synaptic, cellular, and network properties contribute to RGC receptive fields.
A similar approach will also help us to identify mechanisms that govern the range and specificity of light stimuli to which neurons downstream of the retina respond. In particular, we have begun to determine to what degree differences in the receptive fields of neurons in the superior colliculus reflect properties of the neurons themselves, the collicular networks in which they are embedded, and/or the characteristics and source of synaptic input they receive from RGCs. These studies will help (1) characterize the propagation and transformation of signals through multiple levels of the early visual system and (2) identify the precise circuit and cellular mechanisms that govern the sets of stimuli that do and do not elicit activity in particular classes of neurons.
Working in the superior colliculus represents a new, and exciting, direction for us. Indeed, the flexibility and resources to initiate a new research endeavor is part of what attracted us to the Janelia environment. Equally attractive is the opportunity to work directly with groups that are using distinct approaches to ask similar questions—e.g., the labs of Jeff Magee, Josh Dudman, Dima Rinberg, Michael Reiser, and Adam Hantman. The perspectives and techniques represented in these (and other) groups has both expanded the diversity of questions we can ask as well as increase the detail and rigor with which we can answer questions of common interest.
Written by Lakshmi Ramasamy in ID&F
We see this tool as a good alternative to conventional fluorescence-guided whole cell patch clamp recordings; it subjects the tissue to a minimum of light and enables one to optimize images for fluorescence and contrast separately (rather than manage trade-offs associated with optimizing one at the expense of the other). We've also benefitted from the significant expertise and effort on campus to use Arduino style microcontrollers (http://www.arduino.cc/) to receive input from and provide command signals to hardware devices; the Murphy and Dudman labs, with the help of ID&F's Magnus Karlsson, have developed an Arduino-based system for dynamic (or conductance) clamp recordings, for example.
Electrical synaptic input to ganglion cells underlies differences in the output and absolute sensitivity of parallel retinal circuits.The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 2011
G. J. Murphy, and F. Rieke The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 31:12218-28 (2011)
Parallel circuits throughout the CNS exhibit distinct sensitivities and responses to sensory stimuli. Ambiguities in the source and properties of signals elicited by physiological stimuli, however, frequently obscure the mechanisms underlying these distinctions. We found that differences in the degree to which activity in two classes of Off retinal ganglion cell (RGC) encode information about light stimuli near detection threshold were not due to obvious differences in the cells' intrinsic properties or the chemical synaptic input the cells received; indeed, differences in the cells' light responses were largely insensitive to block of fast ionotropic glutamate receptors. Instead, the distinct responses of the two types of RGCs likely reflect differences in light-evoked electrical synaptic input. These results highlight a surprising strategy by which the retina differentially processes and routes visual information and provide new insight into the circuits that underlie responses to stimuli near detection threshold.
Prior Publications (2)
Information about sensory stimuli is represented by spatiotemporal patterns of neural activity. The complexity of the central nervous system, however, frequently obscures the origin and properties of signals and noise that underlie these activity patterns. We minimized this constraint by examining mechanisms governing correlated activity in mouse retinal ganglion cells (RGCs) under conditions in which light-evoked responses traverse a specific circuit, the rod bipolar pathway. Signals and noise in this circuit produced correlated synaptic input to neighboring On and Off RGCs. Temporal modulation of light intensity did not alter the degree to which noise in the input to nearby RGCs was correlated, and action potential generation in individual RGCs was largely insensitive to differences in network noise generated by dynamic and static light stimuli. Together, these features enable noise in shared circuitry to diminish simultaneous action potential generation in neighboring On and Off RGCs under a variety of conditions.
Visual, auditory, somatosensory, and olfactory stimuli generate temporally precise patterns of action potentials (spikes). It is unclear, however, how the precision of spike generation relates to the pattern and variability of synaptic input elicited by physiological stimuli. We determined how synaptic conductances evoked by light stimuli that activate the rod bipolar pathway control spike generation in three identified types of mouse retinal ganglion cells (RGCs). The relative amplitude, timing, and impact of excitatory and inhibitory input differed dramatically between On and Off RGCs. Spikes evoked by repeated somatic injection of identical light-evoked synaptic conductances were more temporally precise than those evoked by light. However, the precision of spikes evoked by conductances that varied from trial to trial was similar to that of light-evoked spikes. Thus, the rod bipolar pathway modulates different RGCs via unique combinations of synaptic input, and RGC temporal variability reflects variability in the input this circuit provides.