Biology subjects

Itani, O.

Publications and source records attributed to Itani, O..

4 recordsLinked to original sources

bioRxiv2023

Comodulation reduces interindividual variability of circuit output

2Ionic current levels of identified neurons vary substantially across individual animals. Yet, under similar conditions, neural circuit output can be remarkably similar, as evidenced in many motor systems. All neural circuits are influenced by multiple neuromodulators which provide flexibility to their 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. Because of this different receptor expression pattern, in the presence of multiple convergent neuromodulators, a common downstream target would be activated more uniformly in circuit neurons across individuals. We therefore 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 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 intraburst spike number and frequency. We then examined the variability in the presence of different combinations and concentrations of three neuropeptides. We found that at mid-level concentration (30 nM) but not at near-threshold (1 nM) or saturating (1 M) concentrations, comodulation by multiple neuropeptides reduced the circuit output variability. Notably, the interindividual variability of response properties of an isolated neuron was not reduced by comodulation, suggesting that the reduction of output variability may emerge as a network effect. 3 Significance StatementNeuromodulation has been explored as a mechanism to provide flexibility to the output of neural circuits. All neural circuits are subject to neuromodulation by multiple substances. Here, we propose a different but complimentary role for neuromodulation. We use two general facts about neuromodulation to show that convergent comodulation at tonic mid-concentration levels reduces interindividual variability of neural circuit output. These facts are that 1) Multiple neuromodulators can have convergent actions on the same subcellular substrates and 2) Neurons express different neuromodulator receptors at different levels.

neuroscience↗

bioRxiv2023

Distinct Mechanisms Underlie Electrical Coupling Resonance and Its Interaction with Membrane Potential Resonance

Neurons in oscillatory networks often exhibit membrane potential resonance, a peak impedance at a non-zero input frequency. In electrically coupled oscillatory networks, the coupling coefficient (the ratio of post- and prejunctional voltage responses) could also show resonance. Such coupling resonance may emerge from the interaction between the coupling current and resonance properties of the coupled neurons, but this relationship has not been clearly described. Additionally, it is unknown if the gap-junction mediated electrical coupling conductance may have frequency dependence. We examined these questions by recording a pair of electrically coupled neurons in the oscillatory pyloric network of the crab Cancer borealis. We performed dual current- and voltage-clamp recordings and quantified the frequency preference of the coupled neurons, the coupling coefficient, the electrical conductance, and the postjunctional neuronal response. We found that all components exhibit frequency selectivity, but with distinct preferred frequencies. Mathematical and computational analysis showed that membrane potential resonance of the postjunctional neuron was sufficient to give rise to resonance properties of the coupling coefficient, but not the coupling conductance. A distinct coupling conductance resonance frequency therefore emerges either from other circuit components or from the gating properties of the gap junctions. Finally, to explore the functional effect of the resonance of the coupling conductance, we examined its role in synchronizing neuronal the activities of electrically coupled bursting model neurons. Together, our findings elucidate factors that produce electrical coupling resonance and the function of this resonance in oscillatory networks.

neuroscience↗

bioRxiv2021

Parameter estimation in the age of degeneracy and unidentifiability

Parameter estimation from observable or experimental data is a crucial stage in any modeling study. Identifiability refers to ones ability to uniquely estimate the model parameters from the available data. Structural unidentifiability in dynamic models, the opposite of identifiability, is associated with the notion of degeneracy where multiple parameter sets produce the same pattern. Therefore, the inverse function of determining the model parameters from the data is not well defined. Degeneracy is not only a mathematical property of models, but it has also been reported in biological experiments. Classical studies on structural unidentifiability focused on the notion that one can at most identify combinations of unidentifiable model parameters. We have identified a different type of structural degeneracy/unidentifiability present in a family of models, which we refer to as the Lambda-Omega ({Lambda}-{Omega}) models. These are an extension of the classical lambda-omega ({lambda}-{omega}) models that have been used to model biological systems, and display a richer dynamic behavior and waveforms that range from sinusoidal to square-wave to spike-like. We show that the {Lambda}-{Omega} models feature infinitely many parameter sets that produce identical stable oscillations, except possible for a phase-shift (reflecting the initial phase). These degenerate parameters are not identifiable combinations of unidentifiable parameters as is the case in structural degeneracy. In fact, reducing the number of model parameters in the {Lambda}-{Omega} models is minimal in the sense that each one controls a different aspect of the model dynamics and the dynamic complexity of the system would be reduced by reducing the number of parameters. We argue that the family of {Lambda}-{Omega} models serves as a framework for the systematic investigation of degeneracy and identifiability in dynamic models and for the investigation of the interplay between structural and other forms of unidentifiability resulting on the lack of information from the experimental/observational data.

systems biology↗

bioRxiv2021

A Hypoxia Sensitive to Hypoxia Resistant Transformation in Long-Lived Germline Mutants

Signals from the germline play a significant role in determining longevity in numerous animal models. In C. elegans, ablation of the germline leads to long life span and various other types of stress resistance. It has been reported that mutations that block oogenesis or an upstream step in germline development confer strong resistance to hypoxia. We report here that the hypoxia resistance of sterile mutants is dependent on developmental stage and age. In just a 12-hour period, sterile animals transform from hypoxia sensitive L4 larvae into highly hypoxia resistant adults. Since this transformation occurs in animals with no germline, the physiological programs that determine hypoxia sensitivity must occur independently of germline signals and instead rely on developmental signals from somatic tissues. Furthermore, we found two distinct mechanisms of hypoxia resistance in long-lived germline deficient animals. First, a DAF-16/FoxO independent mechanism that occurs in all hypoxia resistant sterile adults and, second, a DAF-16/FoxO dependent mechanism that confers an added layer of resistance, or "super-resistance", to animals with no germline as they age past day 1 of adulthood. RNAseq data showed that nearly all genes involved in both cytosolic and mitochondrial protein translation, as well as in mitochondrial protein import, are repressed in germline deficient adults and further repressed as they age. The hypoxia super-resistance of aging germline deficient animals was suppressed by dual mutation of ncl-1 and larp-1, two regulators of nucleolar biology and protein translation, demonstrating that the hypoxia super-resistance mechanism involves reduced protein translation. These studies provide novel insight into a profound physiological transformation that takes place in germline mutants during development, showing that some of the unique physiological properties of these long-lived animals are dependent on developmental repression of genes involved in protein translation, which operate independently of germline signals. AUTHOR SUMMARYIn addition to being extremely long lived, germline deficient animals have other extraordinary properties, such as robust resistance to oxygen deprivation. Here we provide new insight into the mechanisms of hypoxia resistance in germline deficient animals. We demonstrate that, in just a 12-hour period, germline mutants transform from hypoxia sensitive larvae into highly hypoxia resistant adults. Therefore, hypoxia resistance is not a general property of germline ablated animals, but is instead "switched on" only in adult animals. We have found two distinct mechanisms of hypoxia resistance in germline deficient animals and both mechanisms are mediated by signals from somatic tissues and do not require the germline. We have determined that reduced transcription of genes involved in protein translation is one of the mechanisms of hypoxia resistance. Like hypoxia resistance, repression of protein translation genes only occurs in adults. Our findings establish that the unique physiological properties of germline-deficient animals are "switched" on in adults and therefore must be mediated by developmental signals from somatic tissues. We conclude that the L4/adult developmental switch in germline ablated animals presents an excellent system for investigating the longevity and hypoxia resistance of germline deficient animals.

genetics↗