Biology subjects

Canavier, C. C.

Publications and source records attributed to Canavier, C. C..

7 recordsLinked to original sources

bioRxiv2024

Persistent Interruption in Parvalbumin Positive Inhibitory Interneurons: Biophysical and Mathematical Mechanisms

Persistent activity in principal cells is a putative mechanism for maintaining memory traces during working memory. We recently demonstrated persistent interruption of firing in fast-spiking parvalbumin-expressing interneurons (PV-INs), a phenomenon which could serve as a substrate for persistent activity in principal cells through disinhibition lasting hundreds of milliseconds. Here, we find that hippocampal CA1 PV-INs exhibit type 2 excitability, like striatal and neocortical PV-INs. Modelling and mathematical analysis showed that the slowly inactivating potassium current Kv1 contributes to type 2 excitability, enables the multiple firing regimes observed experimentally in PV-INs, and provides a mechanism for robust persistent interruption of firing. Using a fast/slow separation of times scales approach with the Kv1 inactivation variable as a bifurcation parameter shows that the initial inhibitory stimulus stops repetitive firing by moving the membrane potential trajectory onto a co-existing stable fixed point corresponding to a non-spiking quiescent state. As Kv1 inactivation decays, the trajectory follows the branch of stable fixed points until it crosses a subcritical Hopf bifurcation then spirals out into repetitive firing. In a model describing entorhinal cortical PV-INs without Kv1, interruption of firing could be achieved by taking advantage of the bistability inherent in type 2 excitability based on a subcritical Hopf bifurcation, but the interruption was not robust to noise. Persistent interruption of firing is therefore broadly applicable to PV-INs in different brain regions but is only made robust to noise in the presence of a slow variable. Significance StatementPersistent activity in neuronal networks is thought to provide a substrate for multiple forms of memory. The architecture of neuronal networks across many brain regions involves a small number of inhibitory neurons that control many principal neurons. We propose that persistent silencing of fast-spiking parvalbumin-expressing inhibitory interneurons (PVINs) can result in persistent activity of principal neurons. We use a mathematical approach and computer simulations to investigate the mechanisms governing persistent interruption of firing in hippocampal and cortical PV-INs. We show how a slowly changing state of a particular ion channel controls the long-lasting silence imposed by persistent interruption. Overall, our results provide a conceptual framework that positions the persistent interruption of PV-INs firing as a potential mechanism for persistent activity in principal cells.

neuroscience↗

bioRxiv2024

Phase Resetting Curves Determine Stability of Synchrony in One and Two Clusters of Pulse Coupled Oscillators with Delays

Phase Response Curves (PRCs) have been useful in determining and analyzing various phase-locking modes in networks of oscillators under pulse-coupling assumptions, as reviewed in Mathematical Biosciences, 226:77-96, 2010. Here, we update that review to include progress since 2010 on pulse coupled oscillators with conduction delays. We then present original results that extend the derivation of the criteria for stability of global synchrony in networks of pulse-coupled oscillators to include conduction delays. We also incorporate conduction delays to extend previous studies that showed how an alternating firing pattern between two synchronized clusters could enforce within cluster synchrony, even for clusters unable to synchronize themselves in isolation. To obtain these results, we used self-connected neurons to represent clusters. These results greatly extend the applicability of the stability analyses to networks of pulse-coupled oscillators since conduction delays are ubiquitous and strongly impact the stability of synchrony. Although these analyses only strictly apply to identical oscillators with identical connections to other oscillators, the principles are general and suggest how to promote or impede synchrony in physiological networks of neurons, for example. Heterogeneity can be interpreted as a form of frozen noise, and approximate synchrony can be sustained despite heterogeneity. The pulse-coupled oscillator model can not only be used to describe biological neuronal networks but also cardiac pacemakers, lasers, fireflies, artificial neural networks, social self-organization, and wireless sensor networks. AMS Subject Classification37N25, 39A06, 39A30, 92B25, 92C20

neuroscience↗

bioRxiv2023

Synchrony in Networks of Type 2 Interneurons is More Robust to Noise with Hyperpolarizing Inhibition Compared to Shunting Inhibition in Both the Stochastic Population Oscillator and the Coupled Oscillator Regimes

Synchronization in the gamma band (30-80 Hz) is mediated by PV+ inhibitory interneurons, and evidence is accumulating for the essential role of gamma oscillations in cognition. Oscillations can arise in inhibitory networks via synaptic interactions between individual oscillatory neurons (mean-driven) or via strong recurrent inhibition that destabilizes the stationary background firing rate in the fluctuation-driven balanced state, causing an oscillation in the population firing rate. Previous theoretical work focused on model neurons with Hodgkins type 1 excitability (integrators) connected by current-based synapses. Here we show that networks comprised of simple type 2 oscillators (resonators) exhibit a supercritical Hopf bifurcation between synchrony and asynchrony and a gradual transition via cycle skipping from coupled oscillators to stochastic population oscillator, as previously shown for type 1. We extended our analysis to homogeneous networks with conductance rather than current based synapses and found that networks with hyperpolarizing inhibitory synapses were more robust to noise than those with shunting synapses, both in the coupled oscillator and stochastic population oscillator regime. Assuming that reversal potentials are uniformly distributed between shunting and hyperpolarized values, as observed in one experimental study, converting synapses to purely hyperpolarizing favored synchrony in all cases, whereas conversion to purely shunting synapses made synchrony less robust except at very high conductance strengths. In mature neurons the synaptic reversal potential is controlled by chloride cotransporters that control the intracellular concentrations of chloride and bicarbonate ions, suggesting these transporters as a potential therapeutic target to enhance gamma synchrony and cognition. Significance StatementBrain rhythms in the gamma frequency band (30-80 Hz) depend on the activity of inhibitory interneurons and evidence for a causal role for gamma oscillations in cognitive functions is accumulating. Here we extend previous studies on synchronization mechanisms to interneurons that have an abrupt threshold frequency below which they cannot sustain firing. In addition to current based synapses, we examined inhibitory networks with conductance based synapses. We found that if the reversal potential for inhibition was below the average membrane potential (hyperpolarizing), synchrony was more robust to noise than if the reversal potential was very close to the average potential (shunting). These results have implications for therapies to ameliorate cognitive deficits.

neuroscience↗

bioRxiv2022

Cholinergic Modulation Shifts the Response of CA1 Pyramidal Cells to Depolarizing Ramps via TRPM4 Channels with Implications for Place Field Firing

A synergistic combination of in vitro electrophysiology and multicompartmental modeling of rat CA1 pyramidal neurons identified TRPM4 channels as major drivers of cholinergic modulation of the firing rate during a triangular current ramp, which emulates the bump in synaptic input received while traversing the place field. In control, fewer spikes at lower frequencies are elicited on the down-ramp compared to the up-ramp due to long-term inactivation of the NaV channel. The cholinergic agonist carbachol (CCh) removes or even reverses this spike rate adaptation, causing more spikes to be elicited on the down-ramp than the up-ramp. CCh application during Schaffer collateral stimulation designed to simulate a ramp produces similar shifts in the center of mass of firing to later in the ramp. The non-specific TRP antagonist flufenamic acid and the TRPM4-specific blockers CBA and 9-phenanthrol, but not the TRPC-specific antagonist SKF96365, reverse the effect of CCh; this implicates the Ca2+-activated nonspecific cation current, ICAN, carried by TRPM4 channels. The cholinergic shift of the center of mass of firing is prevented by strong intracellular Ca2+ buffering but not by antagonists for IP3 and ryanodine receptors, ruling out a role for known mechanisms of release from intracellular Ca2+ stores. Pharmacology combined with modeling suggest that [Ca2+] in a nanodomain near the TRPM4 channel is elevated through an unknown source that requires both muscarinic receptor activation and depolarization-induced Ca2+ influx during the ramp. Activation of the regenerative inward TRPM4 current in the model qualitatively replicates and provides putative underlying mechanisms for the experimental observations.

neuroscience↗

bioRxiv2022

Interneuronal network model of theta-nested fast oscillations predicts differential effects of heterogeneity, gap junctions and short term depression for hyperpolarizing versus shunting inhibition

Theta and gamma oscillations in the hippocampus have been hypothesized to play a role in the encoding and retrieval of memories. Recently, it was shown that an intrinsic fast gamma mechanism in medial entorhinal cortex can be recruited by optogenetic stimulation at theta frequencies, which can persist with fast excitatory synaptic transmission blocked, suggesting a contribution of interneuronal network gamma (ING). We calibrated the passive and active properties of a 100-neuron model network to capture the range of passive properties and frequency/current relationships of experimentally recorded PV+ neurons in the medial entorhinal cortex (mEC). The strength and probabilities of chemical and electrical synapses were also calibrated using paired recordings, as were the kinetics and short-term depression (STD) of the chemical synapses. Gap junctions that contribute a noticeable fraction of the input resistance were required for synchrony with hyperpolarizing inhibition; these networks exhibited theta-nested high frequencies ([~]200 Hz) similar to the putative ING observed experimentally in the optogenetically-driven PV-ChR2 mice. With STD included in the model, fast oscillations were only observed before the peak of the theta drive, whereas without STD, they were observed symmetrically before and after the peak. Because hyperpolarizing synapses provide a synchronizing drive that contributes to robustness in the presence of heterogeneity, synchronization decreases as the hyperpolarizing inhibition becomes weaker. In contrast, networks with shunting inhibition required non-physiological levels of gap junctions to synchronize using conduction delays within the measured range; synaptic depression of shunting synapses facilitated fast oscillations, suggesting that shunting inhibition in mEC is desynchronizing. Author SummaryFast oscillations nested within slower oscillations have been hypothesized to play a role in the encoding and retrieval of memories by chunking information within each fast cycle; networks of parvalbumin positive inhibitory interneurons contribute to the generation of fast oscillations. We show that, in the entorhinal cortex, the intrinsic dynamical properties of these neurons are sufficiently heterogeneous that electrical synapses are likely required to synchronize fast oscillations. Moreover, synchrony likely requires the chemical synapses to have a reversal potential that is negative relative to the action potential threshold of individual neurons during these oscillations. We show that the range of slow phases that support a fast oscillation is controlled by short term synaptic depression. The precise phase locking of the fast oscillation within the slow oscillations is hypothesized to allow for multiplexing of information.

neuroscience↗

bioRxiv2021

Long-Term Inactivation of Sodium Channels as a Mechanism of Adaptation in CA1 Pyramidal Neurons

Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially-tuned, temporally-diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats in vitro (slice electrophysiology) and in silico (multi-compartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared to somatic ramps. We incorporated a four-state Markov scheme for NaV1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to explain the difference in dendritic versus somatic ramps. Long-term inactivation reduced the firing frequency by decreasing open-state occupancy, and reduced spike amplitude during trains by decreasing occupancy in closed states, which comprise the available pool. PKC activator phorbol-dibutyrate, known to reduce NaV long-term inactivation, removed spike amplitude attenuation in vitro more visibly in dendrites and greatly reduced adaptation, consistent with our hypothesized mechanism. Intracellular application of a peptide inducing long-term NaV inactivation elicited spike amplitude attenuation during spike trains in the soma and greatly enhanced adaptation. Our synergistic experimental/computational approach shows that long-term inactivation of NaV1.6 is a key mechanism of adaptation in CA1 pyramidal cells. Significance statementThe hippocampus plays an important role in certain types of memory, in part through context-specific firing of "place cells"; these cells were first identified in rodents as being particularly active when an animal is in a specific location in an environment, called the place field of that neuron. In this in vitro/in silico study, we found that long-term inactivation of sodium channels causes adaptation in the firing rate that could potentially skew the firing of CA1 hippocampal pyramidal neurons earlier within a place field. A computational model of the sodium channel revealed differential regulation of spike frequency and amplitude by long-term inactivation, which may be a general mechanism for spike frequency adaptation in the central nervous system.

neuroscience↗

bioRxiv2019

Mechanisms of Synchrony in Heterogeneous Inhibitory Interneuronal Networks for Type 1 versus Type 2 Excitability

PV+ fast spiking basket interneurons are often implicated in gamma rhythms. Here we focus on mechanisms present in purely inhibitory networks. Neurons with type 1 excitability can fire arbitrarily slowly, whereas those with type 2 excitability cannot fire below a minimum frequency. We systematically examine how excitability type affects synchronization of individual spikes to a population rhythm in the presence of heterogeneity and noise, using model neurons of each type with matched F/I curve, input resistance, time constant and action potential shape. Population synchrony in noisy heterogeneous networks is maintained because neurons either fire within a tight time window or skip that cycle. Type 2 neurons with hyperpolarizing inhibition skip cycles due to their intrinsic dynamics; we show here the cycle skipping mechanism for type 1 neurons or type 2 neurons with shunting inhibition is synaptic and not intrinsic. Type 2 neurons are more resistant than type 1 to partial and complete suppression in networks with hyperpolarizing inhibition that exhibit network gamma. Moreover, type 2 neurons are recruited more rapidly and more completely into theta-nested gamma. In contrast, type 1 networks perform better with shunting inhibition on both counts, because the nonlinear dynamics in that case favor suppression of type 2 compared to type 1 neurons. Conductances that control excitability type may provide a therapeutic target to improve spatial and working memory and other tasks that rely on gamma synchrony or phase amplitude coupling.\n\nAuthor SummaryThe collective, synchronized activity of neurons produces brain rhythms. These rhythms are thought to subserve cognitive functions such as attention and memory encoding and retrieval. Faster rhythms are nested in slower rhythms as a putative way of chunking information. A subset of neurons called fast spiking basket cells tend to inhibit other neurons from firing. These neurons play an important role in oscillations, and in the coupling of faster oscillations to slower ones. In some brain regions these neurons can fire arbitrarily slowly (type 1 dynamics) whereas in others they cannot fire below a minimum cutoff frequency (type 2 dynamics). Mathematically, these distinct origins of rhythmic firing are signatures of very different dynamics. Here, we show that these distinct excitability types affect the ability of networks of these neurons to synchronize their fast oscillatory activity, as well as the ability of slower oscillations to modulate these fast oscillations. The exact nature of the inhibitory coupling, which may vary between brain regions, determines which type synchronizes better and is modulated better.

neuroscience↗