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Gorur-Shandilya, S.

Publications and source records attributed to Gorur-Shandilya, S..

4 recordsLinked to original sources

Mapping circuit dynamics during function and dysfunction

Neural circuits can generate many spike patterns, but only some are functional. The study of how circuits generate and maintain functional dynamics is hindered by a poverty of description of circuit dynamics across functional and dysfunctional states. For example, although the regular oscillation of a central pattern generator is well characterized by its frequency and the phase relationships between its neurons, these metrics are ineffective descriptors of the irregular and aperiodic dynamics that circuits can generate under perturbation or in disease states. By recording the circuit dynamics of the well-studied pyloric circuit in C. borealis, we used statistical features of spike times from neurons in the circuit to visualize the spike patterns generated by this circuit under a variety of conditions. This unsupervised approach captures both the variability of functional rhythms and the diversity of atypical dynamics in a single map. Clusters in the map identify qualitatively different spike patterns hinting at different dynamical states in the circuit. State probability and the statistics of the transitions between states varied with environmental perturbations, removal of descending neuromodulation, and the addition of exogenous neuromodulators. This analysis reveals strong mechanistically interpretable links between complex changes in the collective behavior of a neural circuit and specific experimental manipulations, and can constrain hypotheses of how circuits generate functional dynamics despite variability in circuit architecture and environmental perturbations.

neuroscience↗

Controlling and measuring dynamic odorant stimuli in the laboratory

Animals experience complex odorant stimuli that vary widely in composition, intensity and temporal properties. However, stimuli used to study olfaction in the laboratory are much simpler. This mismatch arises from the challenges in measuring and controlling them precisely and accurately. Even simple pulses can have diverse kinetics that depend on their molecular identity. Here, we introduce a model to describe how stimulus kinetics depend on the molecular identity of the odorant and the geometry of the delivery system. We describe methods to deliver dynamic odorant stimuli of several types, including broadly distributed stimuli that reproduce some of the statistics of naturalistic plumes, in a reproducible and precise manner. Finally, we introduce a method to calibrate a Photo-Ionization Detector to any odorant it can detect, using no additional components. Our approaches are affordable and flexible and can be used to advance our understanding of how olfactory neurons encode real-world odor signals.

neuroscience↗

Xolotl: An Intuitive and Approachable Neuron and Network Simulator for Research and Teaching

Conductance-based models of neurons are used extensively in computational neuroscience. Working with these models can be challenging due to their high dimensionality and large number of parameters. Here, we present a neuron and network simulator built on a novel automatic type system that binds object-oriented code written in C++ to objects in MATLAB. Our approach builds on the tradition of uniting the speed of languages like C++ with the ease-of-use and feature-set of scientific programming languages like MATLAB. Xolotl allows for the creation and manipulation of hierarchical models with components that are named and searchable, permitting intuitive high-level programmatic control over all parts of the model. The simulators architecture allows for the interactive manipulation of any parameter in any model, and for visualizing the effects of changing that parameter immediately. Xolotl is fully featured with hundreds of ion channel models from the electrophysiological literature, and can be extended to include arbitrary conductances, synapses, and mechanisms. Several core features like bookmarking of parameters and automatic hashing of source code facilitate reproducible and auditable research. Its ease of use and rich visualization capabilities make it an attractive option in teaching environments. Finally, xolotl is written in a modular fashion, includes detailed tutorials and worked examples, and is freely available at https://github.com/sg-s/xolotl, enabling seamless integration into the workflows of other researchers.

neuroscience↗

Regulation of Eag by calcium/calmodulin controls presynaptic excitability in Drosophila

Drosophila ether-a-go-go (eag) is the founding member of a large family of voltage-gated K+ channels, the KCNH family, which includes Kv10, 11 and 12, (Ganetzky et al. 1999). Concurrent binding of calcium/calmodulin (Ca2+/CaM) to N-and C-terminal sites inhibits mammalian EAG1 channels at sub-micromolar Ca2+ concentrations (Schonherr et al. 2000), likely by causing pore constriction (Whicher and MacKinnon 2016). Although the Drosophila EAG channel was believed to be Ca2+-insensitive (Schonherr et al. 2000), both the N-and C-terminal sites are conserved. Here we show that Drosophila EAG is inhibited by high Ca2+ concentrations that are only present at plasma membrane Ca2+ channel microdomains. To test the role of this regulation in vivo, we engineered mutations that block CaM-binding to the major C-terminal site of the endogenous eag locus, disrupting Ca2+-dependent inhibition. eag CaMBD mutants have reduced evoked release from larval motor neuron presynaptic terminals and show decreased Ca2+ influx in stimulated adult projection neuron presynaptic terminals, consistent with an increase in K+ conductance. These results are predicted by a conductance-based multi-compartment model of the presynaptic terminal in which some fraction of EAG is localized to the Ca2+ channel microdomains that control neurotransmitter release. The reduction of release in the larval neuromuscular junction drives a compensatory increase in motor neuron somatic excitability. This misregulation of synaptic and somatic excitability has consequences for systems-level processes and leads to defects in associative memory formation in adults.\n\nNew and NoteworthyRegulation of excitability is critical to tuning the nervous system for complex behaviors. We demonstrate here that the EAG family of voltage-gated K+ channels exhibit conserved gating by Ca2+/CaM. Disruption of this inhibition in Drosophila results in decreased evoked neurotransmitter release due to truncated Ca2+ influx in presynaptic terminals. In adults, disrupted Ca2+ dynamics cripples memory formation. These data demonstrate that the biophysical details of channels have important implications for cell function and behavior.

neuroscience↗