Benjamin L Murphy-Baum

Bio: Benjamin L Murphy-Baum is an academic researcher from University of Victoria. The author has contributed to research in topics: Cholinergic neuron & Inhibitory postsynaptic potential. The author has an hindex of 2, co-authored 6 publications receiving 14 citations.

Rapid multi-directed cholinergic transmission in the central nervous system

Abstract: In many parts of the central nervous system, including the retina, it is unclear whether cholinergic transmission is mediated by rapid, point-to-point synaptic mechanisms, or slower, broad-scale ‘non-synaptic’ mechanisms. Here, we characterized the ultrastructural features of cholinergic connections between direction-selective starburst amacrine cells and downstream ganglion cells in an existing serial electron microscopy data set, as well as their functional properties using electrophysiology and two-photon acetylcholine (ACh) imaging. Correlative results demonstrate that a ‘tripartite’ structure facilitates a ‘multi-directed’ form of transmission, in which ACh released from a single vesicle rapidly (~1 ms) co-activates receptors expressed in multiple neurons located within ~1 µm of the release site. Cholinergic signals are direction-selective at a local, but not global scale, and facilitate the transfer of information from starburst to ganglion cell dendrites. These results suggest a distinct operational framework for cholinergic signaling that bears the hallmarks of synaptic and non-synaptic forms of transmission. Cholinergic neurons may transmit information via fast synaptic, point-to-point signaling or diffuse, slow extra-synaptic signaling. The authors show that ACh from a single vesicle triggers synchronous miniature currents in two neurons, showing that ACh can spread significant distances to drive rapid ‘synaptic’ signals.

The functional organization of excitation and inhibition in the dendrites of mouse direction-selective ganglion cells.

Abstract: Recent studies indicate that the precise timing and location of excitation and inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How synaptic inputs are functionally organized at the subcellular level in intact circuits remains unclear. To address this issue, we took advantage of the retinal direction-selective ganglion cell circuit, where directionally tuned inhibition is known to shape non-directional excitatory signals. We combined two-photon calcium imaging with genetic, pharmacological, and single-cell ablation methods to examine the extent to which inhibition 'vetoes' excitation at the level of individual dendrites of direction-selective ganglion cells. We demonstrate that inhibition shapes direction selectivity independently within small dendritic segments (<10µm) with remarkable accuracy. The data suggest that the parallel processing schemes proposed for direction encoding could be more fine-grained than previously envisioned.

Precise Subcellular Coordination of Excitation and Inhibition Supports Micron-Scale Dendritic Computations

Abstract: Neural computations are shaped by the competing actions of inhibitory and excitatory synapses. Recent studies indicate that the precise timing and location of inhibition (I) and excitation (E) on the dendritic tree significantly alters how they are transformed into spike output. Assessing the degree to which E/I are spatiotemporally coordinated in intact networks, however, is technically challenging. We measured Ca2+ signals in the dendrites of direction-selective ganglion cells in the mouse retina, which are known to rely on E/I balance for their computation. We found the direction of motion to be encoded by a large number of semi-independent, micron-scale subunits (<10 µm) distributed throughout the ganglion cell’s dendritic arbor, indicating dendritic E/I are coordinated on an exceptionally fine spatiotemporal scale. Computational modeling demonstrates that precise E/I coordination enables multiple computations along a single dendritic branch to occur quasi-independently, which enhances the strength and accuracy of direction encoding at the soma.

The functional organization of excitation and inhibition in the dendritic arbors of retinal direction-selective ganglion cells

Abstract: SUMMARY Recent studies indicate that the precise timing and location of excitation and inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How excitatory and inhibitory inputs are functionally organized at the subcellular level in intact circuits remains unclear. To address this issue, we took advantage of the retinal direction-selective ganglion cell circuit, in which directionally tuned inhibitory GABAergic input arising from starburst amacrine cells shape direction-selective dendritic responses. We combined two-photon Ca2+ imaging with genetic, pharmacological, and single-cell ablation methods to examine local E/I. We demonstrate that when active dendritic conductances are blocked, direction selectivity emerges semi-independently within unusually small dendritic segments (

Dendritic organization of sensory input to cortical neurons in vivo

Abstract: In sensory cortex regions, neurons are tuned to specific stimulus features. For example, in the visual cortex, many neurons fire predominantly in response to moving objects of a preferred orientation. However, the characteristics of the synaptic input that cortical neurons receive to generate their output firing pattern remain unclear. Here we report a novel approach for the visualization and functional mapping of sensory inputs to the dendrites of cortical neurons in vivo. By combining high-speed two-photon imaging with electrophysiological recordings, we identify local subthreshold calcium signals that correspond to orientation-specific synaptic inputs. We find that even inputs that share the same orientation preference are widely distributed throughout the dendritic tree. At the same time, inputs of different orientation preference are interspersed, so that adjacent dendritic segments are tuned to distinct orientations. Thus, orientation-tuned neurons can compute their characteristic firing pattern by integrating spatially distributed synaptic inputs coding for multiple stimulus orientations.

Pushing the frontiers: tools for monitoring neurotransmitters and neuromodulators

Abstract: in which NTs and NMs can be tracked at unprecedented spatiotemporal resolution.Here, we review a range of non­ genetically encoded methods (including electrophysiological methods, microdialysis and electrochemical methods) and geneti­ cally encoded indicators that have been developed for monitoring neurotransmission. These complementary tools have become indispensable for gaining insights into the dynamic regulation and function of various NTs and NMs in the highly complex nervous system. At the same time, discoveries using these tools are paving the way to explore novel strategies for preventing, diagnosing and treating a wide range of diseases and conditions. Non- genetically encoded methods Electrophysiological Abstract | Neurotransmitters and neuromodulators have a wide range of key roles throughout the nervous system. However, their dynamics in both health and disease have been challenging to assess, owing to the lack of in vivo tools to track them with high spatiotemporal resolution. Thus, developing a platform that enables minimally invasive, large- scale and long-term monitoring of neurotransmitters and neuromodulators with high sensitivity, high molecular specificity and high spatiotemporal resolution has been essential. Here, we review the methods available for monitoring the dynamics of neurotransmitters and neuromodulators. Following a brief summary of non- genetically encoded methods, we focus on recent developments in genetically encoded fluorescent indicators, highlighting how these novel indicators have facilitated advances in our understanding of the functional roles of neurotransmitters and neuromodulators in the nervous system. These studies present a promising outlook for the future development and use of tools to monitor neurotransmitters and neuromodulators.

Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD

Abstract: Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and repetitive or restricted behaviors. ASD subjects exhibit complex genetic and clinical heterogeneity, thus hindering the discovery of pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity, one hypothesis that has emerged is that ASD arises from a disruption of the neuronal network activity due to perturbation of the synaptic excitation and inhibition (E/I) balance. The development of induced pluripotent stem cell (iPSC) technology and recent advances in neuronal differentiation techniques provide a unique opportunity to model complex neuronal connectivity and to test the E/I hypothesis of ASD in human-based models. Here, we aim to review the latest advances in studying the different cellular and molecular mechanisms contributing to E/I balance using iPSC-based in vitro models of ASD.