Thursday, November 21, 2024
11/21/2024
Inter-individual variability is a common observation in studying neural systems but is often ignored in favor of developing a general understanding of properties and responses that are the mean across individuals. This is because we accept that neural circuits should produce stable, robust, and consistent activity, characteristic for each behavioral context. All neural activity results from ionic currents that shape the outputs of individual neurons or produce synaptic interactions. However, within the same neuron type, these currents and the channels that underlie their expression show considerable variability across individuals. It remains unclear how neurons with variable levels of ionic currents and synaptic interactions could produce consistent circuit output activity with low inter-individual variability of output attributes. The inter-individual variability of ionic currents is not a static problem, as neuromodulators tune those currents, thereby providing flexibility to neural circuit activity and behavior. While neuromodulation itself can be a source of inter-individual variability, functional circuit output should not only be similar across individuals at some basic level but should also respond similarly to neuromodulators that shape it into different modes of operation, adaptive to different behavioral contexts. While the role neuromodulators play in providing flexibility of circuits in individuals is well studied, the role of neuromodulation in producing consistent functional circuit output across individuals is not. Multiple neuromodulators act on a neural circuit at the same time. Such comodulation is understood to enhance flexibility by increasing the number of possible circuit states. We propose that comodulation with excitatory modulators that have convergent cellular effects promotes consistency and robustness of circuit output. An increase in the number of circuit elements that are targeted results in more consistent overall circuit activation, and an overall increase in excitability pushes individuals closer to shared upper boundaries of neuron and synapse activation. We will test this hypothesis in the stomatogastric nervous system, which has been instrumental in establishing the general organizing principles of convergent and divergent comodulation and is an ideal testbed for understanding neural circuit dynamics. We will use electrophysiological methods to determine the effects of single and multiple neuromodulators on individual circuit components, circuit operation, and output activity. We will apply different sequences of increasing numbers of modulators, either with converging or diverging cellular and synaptic actions, and determine the effects on inter-individual variability and mean similarity of circuit output attributes. In parallel, we will use biophysical approaches, computational modeling and mathematical analysis to understand the underlying cellular and ionic mechanisms in circuit components that account for consistent circuit output. This work will produce a general framework to understand the role of comodulation in the production of robust and consistent circuit output.
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