Consistent neural circuit output through convergent co-modulation

• Applicant: Dr. Anna Caren Schneider
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 421701165

Neuromodulators tune neuronal and synaptic properties to provide flexibility to neural circuit activity and behavior. Expression of modulator receptors, and of modulator targets like ion channels, can vary considerably across individuals. Circuit output, and how modulators shape it, needs to be stable and consistent in the face of this variability. Therefore, neuromodulation does not just provide flexibility, but also needs to ensure stable and consistent circuit activation. Neural circuits are likely under control of multiple modulators at any time, making it important to understand how they interact at subcellular and cellular targets, and at the level of circuit activity. I propose that co-modulation is one mechanism underlying output consistency, aiming to provide a first analysis of co-modulatory effects on the flexibility and robustness of circuit activity.Different modulators may target specific subsets of neurons, and hence elicit a specific circuit output. In addition to this divergence across cell types, they may target different subcellular components in a given neuron. However, many modulators converge onto the same targets. If the effects of each modulator on a common target vary independently across individuals, co-modulation may lead to consistent responses by averaging out variability.I will test the hypothesis that convergent modulation reduces circuit output variability using the rhythmically active pyloric circuit of the crab stomatogastric ganglion. Modulators influence circuits at multiple levels: the component level of intrinsic and synaptic ionic conductances, the cellular level of synaptic strength and neuronal excitability, and the circuit activity level. I will measure interindividual variability in different co-modulatory conditions at all levels to understand whether variability is reduced at each level, and if a reduction of circuit output variability emerges from reduced component variability.I will use three neuropeptides, which affect overlapping subsets of neurons in the pyloric circuit. In neurons with receptors to two or three of these peptides, they converge onto the same voltage-gated current that increases neuron excitability. In addition, they converge onto and strengthen synapses. The individual actions of the peptides are well described, but their co-modulatory effects on component and circuit output variability have not been investigated. In addition to monitoring circuit activity, I will conduct voltage- and current-clamp experiments to examine the variability of ionic currents, as well as neuron excitability and synaptic function. I will use the dynamic clamp to mimic modulator-activated conductances to examine their role in reducing variability. The knowledge of co-modulatory actions provided by these experiments has ramifications for all neural systems, including large networks of the mammalian brain, by providing a novel viewpoint and approach to understand robustness of nervous system activity.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Dr. Dirk Bucher; Professor Dr. Farzan Nadim