@article {65081, title = {Bright and photostable chemigenetic indicators for extended in vivo voltage imaging.}, journal = {Science}, volume = {365}, year = {2019}, month = {2019 Aug 13}, pages = {699-704}, abstract = {

Imaging changes in membrane potential using genetically encoded fluorescent voltage indicators (GEVIs) has great potential for monitoring neuronal activity with high spatial and temporal resolution. Brightness and photostability of fluorescent proteins and rhodopsins have limited the utility of existing GEVIs. We engineered a novel GEVI, "Voltron", that utilizes bright and photostable synthetic dyes instead of protein-based fluorophores, extending the combined duration of imaging and number of neurons imaged simultaneously by more than tenfold relative to existing GEVIs. We used Voltron for in vivo voltage imaging in mice, zebrafish, and fruit flies. In mouse cortex, Voltron allowed single-trial recording of spikes and subthreshold voltage signals from dozens of neurons simultaneously, over 15 min of continuous imaging. In larval zebrafish, Voltron enabled the precise correlation of spike timing with behavior.

}, issn = {1095-9203}, doi = {10.1126/science.aav6416}, author = {Abdelfattah, Ahmed S and Kawashima, Takashi and Singh, Amrita and Novak, Ondrej and Liu, Hui and Shuai, Yichun and Huang, Yi-Chieh and Campagnola, Luke and Seeman, Stephanie C and Yu, Jianing and Zheng, Jihong and Grimm, Jonathan B and Patel, Ronak and Friedrich, Johannes and Mensh, Brett D and Paninski, Liam and Macklin, John J and Murphy, Gabe J and Podgorski, Kaspar and Lin, Bei-Jung and Chen, Tsai-Wen and Turner, Glenn C and Liu, Zhe and Koyama, Minoru and Svoboda, Karel and Ahrens, Misha B and Lavis, Luke D and Schreiter, Eric R} } @article {49294, title = {Distinct cell types in the superficial superior colliculus project to the dorsal lateral geniculate and lateral posterior thalamic nuclei.}, journal = {Journal of Neurophysiology}, volume = {120}, year = {2018}, month = {2018 Jun 13}, pages = {1286-92}, abstract = {

The superficial layers of the superior colliculus (sSC) receive retinal input and project to thalamic regions - the dorsal lateral geniculate (dLGN) and lateral posterior (LP; or pulvinar) nuclei -that convey visual information to cortex. A critical step towards understanding the functional impact of sSC neurons on these parallel thalamo-cortical pathways is determining whether different classes of sSC neurons, which are known to respond to different features of visual stimuli, innervate overlapping or distinct thalamic targets. Here, we identified a transgenic mouse line that labels sSC neurons that project to dLGN but not LP. We utilized selective expression of fluorophores and channelrhodopsin in this and previously characterized mouse lines to demonstrate that distinct cell types give rise to sSC projections to dLGN and LP. We further show that the glutamatergic sSC cell type that projects to dLGN also provides input to the sSC cell type that projects to LP. These results clarify the cellular origin of parallel sSC-thalamo-cortical pathways and reveal an interaction between these pathways via local connections within the sSC.

}, issn = {1522-1598}, doi = {10.1152/jn.00248.2018}, author = {Gale, Samuel D and Murphy, Gabe J} } @article {48468, title = {Active dendritic properties and local inhibitory input enable selectivity for object motion in mouse superior colliculus neurons.}, journal = {The Journal of Neuroscience : the Official Journal of the Society for Neuroscience}, volume = {36}, year = {2016}, month = {2016 Aug 31}, pages = {9111-23}, abstract = {

UNLABELLED: Neurons respond to specific features of sensory stimuli. In the visual system, for example, some neurons respond to motion of small but not large objects, whereas other neurons prefer motion of the entire visual field. Separate neurons respond equally to local and global motion but selectively to additional features of visual stimuli. How and where does response selectivity emerge? Here, we show that wide-field (WF) cells in retino-recipient layers of the mouse superior colliculus (SC) respond selectively to small moving objects. Moreover, we identify two mechanisms that contribute to this selectivity. First, we show that input restricted to a small portion of the broad dendritic arbor of WF cells is sufficient to trigger dendritic spikes that reliably propagate to the soma/axon. In vivo whole-cell recordings reveal that nearly every action potential evoked by visual stimuli has characteristics of spikes initiated in dendrites. Second, inhibitory input from a different class of SC neuron, horizontal cells, constrains the range of stimuli to which WF cells respond. Horizontal cells respond preferentially to the sudden appearance or rapid movement of large stimuli. Optogenetic reduction of their activity reduces movement selectivity and broadens size tuning in WF cells by increasing the relative strength of responses to stimuli that appear suddenly or cover a large region of space. Therefore, strongly propagating dendritic spikes enable small stimuli to drive spike output in WF cells and local inhibition helps restrict responses to stimuli that are both small and moving.

SIGNIFICANCE STATEMENT: How do neurons respond selectively to some sensory stimuli but not others? In the visual system, a particularly relevant stimulus feature is object motion, which often reveals other animals. Here, we show how specific cells in the superior colliculus, one synapse downstream of the retina, respond selectively to object motion. These wide-field (WF) cells respond strongly to small objects that move slowly anywhere through a large region of space, but not to stationary objects or full-field motion. Action potential initiation in dendrites enables small stimuli to trigger visual responses and inhibitory input from cells that prefer large, suddenly appearing, or quickly moving stimuli restricts responses of WF cells to objects that are small and moving.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0645-16.2016}, author = {Gale, Samuel D and Murphy, Gabe J} } @article {47487, title = {Shared and distinct retinal input to the mouse superior colliculus and dorsal lateral geniculate nucleus.}, journal = {Journal of Neurophysiology}, volume = {116}, year = {2016}, month = {2016 May 11}, pages = {602-10}, abstract = {

The mammalian retina conveys the vast majority of information about visual stimuli to two brain regions: the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC). The degree to which retinal ganglion cells (RGCs) send similar or distinct information to the two areas remains unclear despite the important constraints that different patterns of RGC input place on downstream visual processing. To resolve this ambiguity we injected a glycoprotein-deficient rabies virus coding for the expression of a fluorescent protein into the dLGN or SC; rabies virus labeled a smaller fraction of RGCs than lipophilic dyes like DiI but, crucially, did not label RGC axons of passage. ~80\% of the RGCs infected by rabies virus injected into the dLGN were co-labeled with DiI injected into the SC, suggesting that many dLGN-projecting RGCs also project to the SC. However, functional characterization of RGCs revealed that the SC receives input from several classes of RGCs that largely avoid the dLGN - in particular, RGCs in which (1) sustained changes in light intensity elicit transient changes in firing rate and/or (2) a small range of stimulus sizes or temporal fluctuations in light intensity elicit robust activity. Taken together, our results illustrate several unexpected asymmetries in the information that the mouse retina conveys to two major downstream targets and suggest that differences in the output of dLGN and SC neurons reflect, at least in part, differences in the functional properties of RGCs that innervate the SC but not the dLGN.

}, issn = {1522-1598}, doi = {10.1152/jn.00227.2016}, author = {Ellis, Erika M and Gauvain, Gregory and Sivyer, Benjamin and Murphy, Gabe J} } @article {46658, title = {Projection-specific characteristics of retinal input to the brain.}, journal = {The Journal of Neuroscience}, volume = {35}, year = {2015}, month = {2015 Apr 22}, pages = {6575-83}, abstract = {

The brain receives information about the direction of object motion from several types of retinal ganglion cells (RGCs). On-Off direction-selective (DS) RGCs respond preferentially to stimuli moving quickly in one of four directions and provide a significant (but difficult to quantify) fraction of RGC input to the SC. On DS RGCs, in comparison, respond preferentially to stimuli moving slowly in one of three directions and are thought to only target retinorecipient nuclei comprising the accessory optic system, e.g., the medial terminal nucleus (MTN). To determine the fraction of SC-projecting RGCs that exhibit direction selectivity, and the specificity with which On-Off and On DS RGCs target retinorecipient areas, we performed optical and electrophysiological recordings from RGCs retrogradely labeled from the mouse SC and MTN. We found, surprisingly, that both On-Off and On DS RGCs innervate the SC; collectively they constitute nearly 40\% of SC-projecting RGCs. In comparison, only On DS RGCs project to the MTN. Subsequent experiments revealed that individual On DS RGCs innervate either the SC or MTN and exhibit robust projection-specific differences in somatodendritic morphology, cellular excitability, and light-evoked activity; several projection-specific differences in the output of On DS RGCs correspond closely to differences in excitatory synaptic input the cells receive. Our results reveal a robust projection of On DS RGCs to the SC, projection-specific differences in the response properties of On DS RGCs, and biophysical and synaptic mechanisms that underlie these functional differences.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.4298-14.2015}, author = {Gauvain, Gregory and Murphy, Gabe J} } @article {45686, title = {Distinct representation and distribution of visual information by specific cell types in mouse superficial superior colliculus.}, journal = {The Journal of Neuroscience}, volume = {34}, year = {2014}, month = {2014 Oct 1}, pages = {13458-71}, abstract = {

The superficial superior colliculus (sSC) occupies a critical node in the mammalian visual system; it is one of two major retinorecipient areas, receives visual cortical input, and innervates visual thalamocortical circuits. Nonetheless, the contribution of sSC neurons to downstream neural activity and visually guided behavior is unknown and frequently neglected. Here we identified the visual stimuli to which specific classes of sSC neurons respond, the downstream regions they target, and transgenic mice enabling class-specific manipulations. One class responds to small, slowly moving stimuli and projects exclusively to lateral posterior thalamus; another, comprising GABAergic neurons, responds to the sudden appearance or rapid movement of large stimuli and projects to multiple areas, including the lateral geniculate nucleus. A third class exhibits direction-selective responses and targets deeper SC layers. Together, our results show how specific sSC neurons represent and distribute diverse information and enable direct tests of their functional role.

}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.2768-14.2014}, author = {Gale, Samuel D and Murphy, Gabe J} } @article {4228, title = {Electrical synaptic input to ganglion cells underlies differences in the output and absolute sensitivity of parallel retinal circuits.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {31}, year = {2011}, month = {2011 Aug 24}, pages = {12218-28}, abstract = {

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{\textquoteright} intrinsic properties or the chemical synaptic input the cells received; indeed, differences in the cells{\textquoteright} 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.

}, keywords = {Animals, Cell Communication, Electrical Synapses, Inbred C57BL, Ionotropic Glutamate, Mice, Neural Pathways, Ocular, Organ Culture Techniques, Photic Stimulation, Receptors, Retina, Retinal Ganglion Cells, Sensitivity and Specificity, Sensory Thresholds, Synaptic Transmission, Vision, Visual Pathways}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.3241-11.2011}, author = {Murphy, Gabe J and Rieke, Fred} } @article {1976, title = {Signals and noise in an inhibitory interneuron diverge to control activity in nearby retinal ganglion cells.}, journal = {Nature Neuroscience}, volume = {11}, year = {2008}, month = {2008 Mar}, pages = {318-26}, abstract = {

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.

}, keywords = {Action Potentials, Amacrine Cells, Animals, Artifacts, Inbred C57BL, Interneurons, Light, Lighting, Mice, Neural Inhibition, Neural Pathways, Ocular, Organ Culture Techniques, Photic Stimulation, Reaction Time, Retinal Bipolar Cells, Retinal Ganglion Cells, Retinal Rod Photoreceptor Cells, Synaptic Transmission, Vision}, issn = {1097-6256}, doi = {10.1038/nn2045}, author = {Murphy, Gabe J and Rieke, Fred} } @article {1980, title = {Network variability limits stimulus-evoked spike timing precision in retinal ganglion cells.}, journal = {Neuron}, volume = {52}, year = {2006}, month = {2006 Nov 9}, pages = {511-24}, abstract = {

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.

}, keywords = {Action Potentials, Animals, Dose-Response Relationship, Electric Stimulation, Inbred C57BL, Mice, Models, Neurological, Patch-Clamp Techniques, Photic Stimulation, Radiation, Retinal Ganglion Cells, Synapses, Synaptic Transmission, Visual Pathways}, issn = {0896-6273}, doi = {10.1016/j.neuron.2006.09.014}, author = {Murphy, Gabe J and Rieke, Fred} } @article {1985, title = {Intraglomerular inhibition: signaling mechanisms of an olfactory microcircuit.}, journal = {Nature Neuroscience}, volume = {8}, year = {2005}, month = {2005 Mar}, pages = {354-64}, abstract = {

Microcircuits composed of principal neuron and interneuron dendrites have an important role in shaping the representation of sensory information in the olfactory bulb. Here we establish the physiological features governing synaptic signaling in dendrodendritic microcircuits of olfactory bulb glomeruli. We show that dendritic gamma-aminobutyric acid (GABA) release from periglomerular neurons mediates inhibition of principal tufted cells, retrograde inhibition of sensory input and lateral signaling onto neighboring periglomerular cells. We find that L-type dendritic Ca(2+) spikes in periglomerular cells underlie dendrodendritic transmission by depolarizing periglomerular dendrites and activating P/Q type channels that trigger GABA release. Ca(2+) spikes in periglomerular cells are evoked by powerful excitatory inputs from a single principal cell, and glutamate release from the dendrites of single principal neurons activates a large ensemble of periglomerular cells.

}, keywords = {1, 3-Pyridinecarboxylic acid, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Animals, Bicuculline, Cadmium, Calcium, Calcium Channel Agonists, Calcium Channel Blockers, Calcium Signaling, Chelating Agents, Dendrites, Diagnostic Imaging, Dihydropyridines, Dose-Response Relationship, Drug, Drug Interactions, Egtazic Acid, Electric Stimulation, GABA Antagonists, gamma-Aminobutyric Acid, Membrane Potentials, Methyl ester, Neural Conduction, Neural Inhibition, Neural Networks (Computer), Neurons, Newborn, Nickel, Nimodipine, Olfactory Bulb, Patch-Clamp Techniques, Phosphinic Acids, Potassium, Propanolamines, Pyrimidines, Rats, Signal Transduction, Sprague-Dawley, Synapses, Synaptic Transmission, Tetrodotoxin, Time Factors, Valine}, issn = {1097-6256}, doi = {10.1038/nn1403}, author = {Murphy, Gabe J and Darcy, Daniel P and Isaacson, Jeffry S} } @article {1986, title = {Sensory neuron signaling to the brain: properties of transmitter release from olfactory nerve terminals.}, journal = {The Journal of Neuroscience: The Official Journal of the Society for Neuroscience}, volume = {24}, year = {2004}, month = {2004 Mar 24}, pages = {3023-30}, abstract = {

Olfactory receptor neurons (ORNs) convey sensory information directly to the CNS via conventional glutamatergic synaptic contacts in olfactory bulb glomeruli. To better understand the process by which information contained in the odorant-evoked firing of ORNs is transmitted to the brain, we examined the properties of glutamate release from olfactory nerve (ON) terminals in slices of the rat olfactory bulb. We show that marked paired pulse depression is the same in simultaneously recorded periglomerular and tufted neurons, and that this form of short-term plasticity is attributable to a reduction of glutamate release from ON terminals. We used the progressive blockade of NMDA receptor (NMDAR) EPSCs by MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine hydrogen maleate] and stationary fluctuation analysis of AMPA receptor (AMPAR) EPSCs to determine the probability of release (P(r)) of ON terminals; both approaches indicated that P(r) is unusually high (\>/=0.8). The low-affinity glutamate receptor antagonists gamma-d-glutamylglycine and l-amino-5-phosphonovaleric acid blocked ON-evoked AMPAR- and NMDAR-mediated EPSCs, respectively, to the same extent under conditions of low and high P(r), suggesting that multivesicular release is not a feature of ON terminals. Although release from most synapses exhibits a highly nonlinear dependence on extracellular Ca(2+), we find that the relationship between glutamate release and extracellular Ca(2+) at ON terminals is nearly linear. Our results suggest that ON terminals have specialized features that may contribute to the reliable transmission of sensory information from nose to brain.

}, keywords = {Afferent, AMPA, Animals, Brain, Calcium, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Glutamate, Glutamic Acid, N-Methyl-D-Aspartate, Neuronal Plasticity, Neurons, Neurotransmitter Agents, Olfactory Bulb, Olfactory Nerve, Presynaptic Terminals, Rats, Receptors, Sprague-Dawley, Synaptic Transmission}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.5745-03.2004}, author = {Murphy, Gabe J and Glickfeld, Lindsey L and Balsen, Zev and Isaacson, Jeffry S} } @article {1987, title = {Presynaptic cyclic nucleotide-gated ion channels modulate neurotransmission in the mammalian olfactory bulb.}, journal = {Neuron}, volume = {37}, year = {2003}, month = {2003 Feb 20}, pages = {639-47}, abstract = {

Cyclic nucleotide-gated channels (CNGCs) on the dendritic cilia of olfactory receptor neurons (ORNs) are critical for sensory transduction in the olfactory system. Do CNGCs also play a role in the axons and/or nerve terminals of ORNs? We find that the cyclic nucleotides cAMP and cGMP can both facilitate and depress synaptic transmission between olfactory nerve fibers and their targets in olfactory bulb glomeruli. Cyclic nucleotides increase intracellular Ca(2+) in ORN terminals and enhance spontaneous transmitter release; at higher concentrations, cyclic nucleotides depress evoked transmission by altering olfactory nerve excitability. Cyclic nucleotides have no effect on transmission or nerve excitability, however, in mice lacking olfactory CNGCs. Taken together, our results identify a novel role for presynaptic CNGCs in modulating neurotransmission.

}, keywords = {Animals, Calcium, Cyclic, Cyclic GMP, Electric Stimulation, Enzyme Inhibitors, Excitatory Postsynaptic Potentials, Forskolin, GABA Agonists, Inbred C57BL, Ion Channel Gating, Ion Channels, Mice, Nucleotides, Olfactory Bulb, Patch-Clamp Techniques, Presynaptic Terminals, Rats, Sprague-Dawley, Synaptic Transmission}, issn = {0896-6273}, author = {Murphy, Gabe J and Isaacson, Jeffry S} }