| Popis: |
Ionic current levels of identified neurons vary substantially across individual animals. Yet, under similar conditions, neural circuit output remains remarkably similar, particularly in motor circuits. At any time, a neural circuit is influenced by multiple neuromodulators which provide flexibility to its output. These neuromodulators often overlap in their actions by modulating the same channel type or synapse yet have neuron-specific actions resulting from distinct receptor expression. With multiple neuromodulators, however, a common target is more uniformly activated across neurons. We propose that a baseline tonic (non-saturating) level of comodulation by convergent neuromodulators can reduce interindividual variability of circuit output. We tested this hypothesis in the pyloric circuit of the crab Cancer borealis . Multiple excitatory neuropeptides converge to activate the same voltage-gated inward current in this circuit, but different subsets of pyloric neurons have receptors for each peptide. We quantified the interindividual variability of the unmodulated pyloric circuit output by measuring the activity phases, cycle frequency and within-burst spike number and frequency. We then examined the variability in the presence of different combinations and concentrations of three excitatory neuropeptides. We found that at mid-level concentration (30 nM) but not at near-threshold (1 nM) or saturating (1 μM) concentrations, comodulation by multiple neuropeptides reduced the circuit output variability. Notably, the output variability of an isolated neuron was not reduced by comodulation at the mid-level concentration. Therefore, the reduction of circuit output variability is not due to a simple reduction of the variability of individual neuron excitability but emerges as a network effect. 3 SIGNIFICANCE STATEMENT: Behaviors as simple as reflexes or as complex as physiological responses to psychedelics can vary significantly among individuals, even when accounting for genotype and other variables. This behavioral variability results largely from variability of underlying neural circuits. Yet, in most cases, the CNS precisely controls behavior, and significant variability in CNS output may result in outputs deemed dysfunctional. We propose that additive actions of neuromodulators that target the same subcellular targets (comodulation) plays a central role in ensuring that neural circuits produce consistent circuit output in the face of extensive inter-individual variability. |
