Biology subjects

Nadim, F.

Publications and source records attributed to Nadim, F..

13 recordsLinked to original sources

bioRxiv2024

Electrical Synapse Rectification Enables Dual-Network Activity in the crab Cancer borealis

Flexibility of rhythmic networks includes neuromodulator-elicited changes in neuronal participation between networks. We are examining the role of rectifying electrical synapses in this neuronal switching. Electrical synapses can have complex, non-intuitive effects on network output. However, it is often difficult to measure and manipulate rectification across conditions to determine their functional contributions. Here, we use the Jonah crab Cancer borealis to investigate rectification in well-described rhythmic networks. In an established modulatory state, stimulating the projection neuron MCN5 or bath applying its neuropeptide Gly1-SIFamide causes the two LPG neurons to switch from pyloric rhythm-only (food filtering, [~]1 Hz) activity to dual pyloric and gastric mill rhythm (chewing, [~]0.1 Hz) activity. Typically, LPG is co-active with the two PD and single AB pyloric pacemaker neurons due to rectifying electrical coupling. In Gly1-SIFamide, LPG continues to burst in pyloric time with AB/PD but periodically "escapes" and generates intrinsic longer-duration gastric mill-timed bursts, decreasing its overall synchrony with AB/PD, while AB/PD retain their synchronous pyloric timing. Using two-electrode voltage clamp recordings, we find that Gly1-SIFamide does not alter electrical coupling strength or the rectification between LPG and AB/PD. However, in a computational model, rectification is necessary for LPG to escape AB/PD electrical coupling and generate longer, gastric mill-timed bursts. This was confirmed in the biological system by adding a dynamic clamp non-rectifying electrical synapse between LPG and PD, which decreased LPGs escape from AB/PD and its gastric mill-timed activity. Thus, rectification between electrically coupled oscillators can underlie modulator-elicited changes in their synchrony. Significance statementBehavioral adaptability includes rapid changes in neural circuit composition. Unlike chemical synapses, little is known about electrical synapse contributions to circuit flexibility. Here, we identify an important role for electrical coupling rectification (asymmetrical current flow between coupled neurons) in regulating neuronal participation between neural circuits. A neuromodulator causes the activity of two sets of electrically-coupled neurons participating in an oscillatory neural circuit to diverge, allowing one set to additionally participate in a second oscillatory circuit at a distinct frequency. Using mathematical modeling and the dynamic clamp technique, we show that this transition depends on rectification. This newly-identified function of electrical synapse rectification may have implications for oscillatory networks underlying a range of functions, due to the prevalence of electrical coupling.

neuroscience↗

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

Neuropeptides with different cellular targets elicit similar output in a central pattern generating circuit

Neuromodulation lends flexibility to neural circuit operation but the general notion that different neuromodulators sculpt neural circuit activity into distinct and characteristic patterns is complicated by interindividual variability. In addition, some neuromodulators converge onto the same signaling pathways, with similar effects on neurons and synapses. We compared the effects of three neuropeptides on the rhythmic pyloric circuit in the crab Cancer borealis stomatogastric nervous system. Proctolin (PROC), crustacean cardioactive peptide (CCAP), and red pigment concentrating hormone (RPCH) all activate the same modulatory inward current, IMI, and have convergent actions on synapses. However, while PROC targets all four neuron types in the core pyloric circuit, CCAP and RPCH target the same subset of only two neurons. After removal of spontaneous neuromodulator release, none of the neuropeptides restored the control cycle frequency, but all restored the relative timing between neuron types. Consequently, differences between neuropeptide effects were mainly found in the spiking activity of different neuron types. We performed statistical comparisons using the Euclidean distance in the multidimensional space of normalized output attributes to obtain a single measure of difference between modulatory states. Across preparations, circuit output in PROC was distinguishable from CCAP and RPCH, but CCAP and RPCH were not distinguishable from each other. However, we argue that even between PROC and the other two neuropeptides, population data overlapped enough to prevent reliable identification of individual output patterns as characteristic for a specific neuropeptide. We confirmed this notion by showing that blind classifications by machine learning algorithms were only moderately successful. Significance StatementIt is commonly assumed that distinct behaviors or circuit activities can be elicited by different neuromodulators. Yet it is unknown to what extent these characteristic actions remain distinct across individuals. We use a well-studied circuit model of neuromodulation to examine the effects of three neuropeptides, each known to produce a distinct activity pattern in controlled studies. We find that, when compared across individuals, the three peptides elicit activity patterns that are either statistically indistinguishable or show too much overlap to be labeled characteristic. We ascribe this to interindividual variability and overlapping subcellular actions of the modulators. Because both factors are common in all neural circuits, these findings have broad significance for understanding the chemical neuromodulatory actions while considering interindividual variability.

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↗

bioRxiv2022

Cerebellum Directly Modulates the Substantia Nigra Dopaminergic Activity

Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show that the Cb-SNc form monosynaptic glutamatergic synapses with both dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation Cb-SNc axons in the SNc rapidly increases SNc activity, elevates striatal dopamine levels, and increases the probability of locomotion. During ongoing behavior, Cb-SNc axons are bilaterally activated prior to ambulation and unilateral lever manipulation. The Cb-SNc axons show prominent activation to water reward, and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly, and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor, and possibly reward processing.

neuroscience↗

bioRxiv2022

Inter-animal variability in activity phase is constrained by synaptic dynamics in an oscillatory network

The levels of voltage-gated and synaptic currents in the same neuron type can vary substantially across individuals. Yet, the phase relationships between neurons in oscillatory circuits are often maintained, even in the face of varying oscillation frequencies. We examined whether synaptic and intrinsic currents are matched to maintain constant activity phases across preparations, using the lateral pyloric (LP) neuron of the stomatogastric ganglion of the crab, Cancer borealis. LP produces stable oscillatory bursts upon release from inhibition, with an onset phase that is independent of oscillation frequency. We quantified the parameters that define the shape of the synaptic current inputs across preparations and found no linear correlations with voltage-gated currents. However, several synaptic parameters were correlated with oscillation period and burst onset phase, suggesting they may play a role in phase maintenance. We used the dynamic clamp to apply artificial synaptic inputs and found that those synaptic parameters correlated with phase and period were ineffective in influencing burst onset. Instead, parameters that showed the least variability across preparations had the greatest influence. Thus, parameters that influence circuit phasing are constrained across individuals, while those that have little effect simply co-vary with phase and frequency.

neuroscience↗

bioRxiv2021

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↗

bioRxiv2019

Short-Term Synaptic Dynamics Control the Activity Phase of Neurons in an Oscillatory Network

In oscillatory systems, neuronal activity phase is often independent of network frequency. Such phase maintenance requires adjustment of synaptic input with network frequency, a relationship that we explored using the crab, Cancer borealis, pyloric network. The burst phase of pyloric neurons is relatively constant despite a >2-fold variation in network frequency. We used noise input to characterize how input shape influences burst delay of a pyloric neuron, and then used dynamic clamp to examine how burst phase depends on the period, amplitude, duration, and shape of rhythmic synaptic input. Phase constancy across a range of periods required a proportional increase of synaptic duration with period. However, phase maintenance was also promoted by an increase of amplitude and peak phase of synaptic input with period. Mathematical analysis shows how short-term synaptic plasticity can coordinately change amplitude and peak phase to maximize the range of periods over which phase constancy is achieved.

neuroscience↗

bioRxiv2019

The differential contribution of pacemaker neurons to synaptic transmission in the pyloric network of the Jonah crab, Cancer borealis

Many neurons receive synchronous input from heterogeneous presynaptic neurons with distinct properties. An instructive example is the crustacean stomatogastric pyloric circuit pacemaker group, consisting of the anterior burster (AB) and pyloric dilator (PD) neurons, which are active synchronously and exert a combined synaptic action on most pyloric follower neurons. Although the stomatogastric system of the crab Cancer borealis has become a preferred model system for exploration of cellular and synaptic basis of circuit dynamics, in this species, the identity of the PD neuron neurotransmitter and its contribution to the total pacemaker group synaptic output remain unexplored. We examined the synaptic properties of the crab PD neuron using a combination of single cell mRNA analysis, electrophysiology and pharmacology. The crab PD neuron expresses high levels of choline acetyltransferase and the vesicular acetylcholine transporter mRNAs, hallmarks of cholinergic neurons. Conversely, the AB neuron does not express either of these cholinergic markers, and expresses high levels of vesicular glutamate transporter mRNA, consistent with a glutamatergic phenotype. Notably, in the combined synapses to the LP and PY neurons, the major contribution is from the glutamatergic AB neuron and only between 25-30% of the synaptic strength is due to the PD neuron. However, there was no difference between the short-term synaptic plasticity in the total pacemaker synapse compared to that of the PD neuron alone. These findings provide a guide for similar explorations of heterogeneous synaptic connections in other systems and a baseline in this system for the exploration of the differential influence of neuromodulators.

neuroscience↗

bioRxiv2019

Membrane potential resonance arising from responses of neuronal models to oscillatory inputs in current versus voltage clamp

Action potential generation in neuron depends on a membrane potential threshold, and therefore on how subthreshold inputs influence this voltage. In oscillatory networks, for example, many neuron types have been shown to produce membrane potential (Vm) resonance: a maximum subthreshold response at a nonzero frequency. Resonance is usually measured by recording Vm in response to a sinusoidal current (Iapp), applied at different frequencies (f), an experimental setting known as current clamp (I-clamp). Several recent studies, however, use the voltage clamp (V-clamp) method to control Vm with a sinusoidal input at different frequencies (Vapp(f)) and measure the total membrane current (Im). The two methods obey systems of differential equations of different dimensionality and, while I-clamp provides a measure of electrical impedance (Z(f) = Vm(f)/Iapp(f)), V-clamp measures admittance (Y (f) = Im(f)/Vapp(f)). We analyze the relationship between these two measurement techniques. We show that, despite different dimensionality, in linear systems the two measures are equivalent: Z = Y-1. However, nonlinear model neurons produce different values for Z and Y-1. In particular, nonlinearities in the voltage equation produce a much larger difference between these two quantities than those in equations of recovery variables that describe activation and inactivation kinetics. Neurons are inherently nonlinear and, notably, with ionic currents that amplify resonance, the voltage clamp technique severely underestimates the current clamp response. We demonstrate this difference experimentally using the PD neurons in the crab stomatogastric ganglion. These findings are instructive for researchers who explore cellular mechanisms of neuronal oscillations.

neuroscience↗

bioRxiv2018

Co-modulation of synapses and voltage-gated ionic currents by combined actions of multiple neuromodulators follow distinct rules

Different neuromodulators usually activate distinct receptors but can have overlapping targets. Consequently, circuit output depends on neuromodulator interactions at shared targets, a poorly understood process. We explored quantitative rules of co-modulation of two principal targets: voltage-gated and synaptic ionic currents. In the stomatogastric ganglion of the crab Cancer borealis, the neuropeptides proctolin and CCAP modulate synapses of the pyloric circuit, and activate a voltage-gated current (IMI) in multiple neurons. We examined the validity of a simple dose-dependent quantitative rule that co-modulation by proctolin and CCAP is predicted by the linear sum of the individual effects of each modulator, up to saturation. We found that this rule is valid for co-modulation of synapses, but not for the activation of IMI, where co-modulation was sublinear. Given the evolutionary conservation of neuromodulator receptors and signaling pathways, such distinct rules for co-modulation of different targets are likely to be common across neuronal circuits.

neuroscience↗

bioRxiv2017

A Balance Of Outward And Linear Inward Ionic Currents Is Required For The Generation Of Slow Wave Oscillations

Regenerative inward currents help produce slow oscillations through a negative-slope conductance region of their current-voltage relationship that is well approximated by a linear negative conductance. We used dynamic clamp injections of a linear current with this conductance, INL, to explore why some neurons can generate intrinsic slow oscillations whereas others cannot. We addressed this question, in synaptically isolated neurons of the crab Cancer borealis, after blocking action potentials. The pyloric network consists of distinct pacemaker group and follower neurons, all of which express the same complement of ionic currents. When the pyloric dilator (PD) neuron, a member of the pacemaker group, was injected with INL using dynamic clamp, it consistently produced slow oscillations. In contrast, the lateral pyloric (LP) or ventral pyloric (VD) follower neurons, failed to oscillate with INL. To understand these distinct behaviors, we compared outward current levels of PD, LP and VD neurons. We found that LP and VD neurons had significantly larger high-threshold potassium currents (IHTK) than PD, and LP had lower transient potassium current, IA. Reducing IHTK pharmacologically enabled both LP and VD neurons to produce oscillations with INL, whereas modifying IA levels did not affect INL-induced oscillations. Using phase-plane and bifurcation analysis of a simplified model cell, we demonstrate that large levels of IHTK can block INL-induced oscillatory activity, whereas generation of oscillations is almost independent of IA levels. These results demonstrate the importance of a balance between inward pacemaking currents and high-threshold K+current levels in determining slow oscillatory activity.

neuroscience↗

bioRxiv2017

Mechanisms of generation of membrane potential resonance in a neuron with multiple resonant ionic currents

Neuronal membrane potential resonance (MPR) is associated with subthreshold and network oscillations. A number of voltage-gated ionic currents can contribute to the generation or amplification of MPR, but how the interaction of these currents with linear currents contributes to MPR is not well understood. We explored this in the pacemaker PD neurons of the crab pyloric network. The PD neuron MPR is sensitive to blockers of H- (IH) and calcium-currents (ICa). We used the impedance profile of the biological PD neuron, measured in voltage clamp, to constrain parameter values of a conductance-based model using a genetic algorithm and obtained many optimal parameter combinations. Unlike most cases of MPR, in these optimal models, the values of resonant- (fres) and phasonant- (f{varphi}=0) frequencies were almost identical. Taking advantage of this fact, we linked the peak phase of ionic currents to their amplitude, in order to provide a mechanistic explanation the dependence of MPR on the ICa gating variable time constants. Additionally, we found that distinct pairwise correlations between ICa parameters contributed to the maintenance of fres and resonance power (QZ). Measurements of the PD neuron MPR at more hyperpolarized voltages resulted in a reduction of fres but no change in QZ. Constraining the optimal models using these data unmasked a positive correlation between the maximal conductances of IH and ICa. Thus, although IH is not necessary for MPR in this neuron type, it contributes indirectly by constraining the parameters of ICa.\n\nAuthor SummaryMany neuron types exhibit membrane potential resonance (MPR) in which the neuron produces the largest response to oscillatory input at some preferred (resonant) frequency and, in many systems, the network frequency is correlated with neuronal MPR. MPR is captured by a peak in the impedance vs. frequency curve (Z-profile), which is shaped by the dynamics of voltage-gated ionic currents. Although neuron types can express variable levels of ionic currents, they may have a stable resonant frequency. We used the PD neuron of the crab pyloric network to understand how MPR emerges from the interplay of the biophysical properties of multiple ionic currents, each capable of generating resonance. We show the contribution of an inactivating current at the resonant frequency in terms of interacting time constants. We measured the Z-profile of the PD neuron and explored possible combinations of model parameters that fit this experimentally measured profile. We found that the Z-profile constrains and defines correlations among parameters associated with ionic currents. Furthermore, the resonant frequency and amplitude are sensitive to different parameter sets and can be preserved by co-varying pairs of parameters along their correlation lines. Furthermore, although a resonant current may be present in a neuron, it may not directly contribute to MPR, but constrain the properties of other currents that generate MPR. Finally, constraining model parameters further to those that modify their MPR properties to changes in voltage range produces maximal conductance correlations.

biophysics↗