Neural circuit mechanisms of sensorimotor disability in cancer treatment

Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)–induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.

Computational simulations and Ca2+ imaging reveal that slow synaptic depolarizations (slow EPSPs) inhibit fast EPSP evoked action potentials for most of their time course in enteric neurons

Transmission between neurons in the extensive enteric neural networks of the gut involves synaptic potentials with vastly different time courses and underlying conductances. Most enteric neurons exhibit fast excitatory post-synaptic potentials (EPSPs) lasting 20-50 ms, but many also exhibit slow EPSPs that last up to 100 s. When large enough, slow EPSPs excite action potentials at the start of the slow depolarization, but how they affect action potentials evoked by fast EPSPs is unknown. Furthermore, two other sources of synaptic depolarization probably occur in enteric circuits, activated via GABAA or GABAC receptors; how these interact with other synaptic depolarizations is also unclear. We built a compartmental model of enteric neurons incorporating realistic voltage-dependent ion channels, then simulated fast EPSPs, slow EPSPs and GABAA or GABAC ligand-gated Cl- channels to explore these interactions. Model predictions were tested by imaging Ca2+ transients in myenteric neurons ex vivo as an indicator of their activity during synaptic interactions. The model could mimic firing of myenteric neurons in mouse colon evoked by depolarizing current during intracellular recording and the fast and slow EPSPs in these neurons. Subthreshold fast EPSPs evoked spikes during the rising phase of a slow EPSP, but suprathreshold fast EPSPs could not evoke spikes later in a slow EPSP. This predicted inhibition was confirmed by Ca2+ imaging in which stimuli that evoke slow EPSPs suppressed activity evoked by fast EPSPs in many myenteric neurons. The model also predicted that synchronous activation of GABAA receptors and fast EPSPs potentiated firing evoked by the latter, while synchronous activation of GABAC receptors with fast EPSPs, potentiated firing and then suppressed it. The results reveal that so-called slow EPSPs have a biphasic effect being likely to suppress fast EPSP evoked firing over very long periods, perhaps accounting for prolonged quiescent periods seen in enteric motor patterns.Author SummaryThe gastrointestinal tract is the only organ with an extensive semi-autonomous nervous system that generates complex contraction patterns independently. Communication between neurons in this “enteric” nervous system is via depolarizing synaptic events with dramatically different time courses including fast synaptic potentials lasting around 20-50 ms and slow depolarizing synaptic potentials lasting for 10 – 120 s. Most neurons have both. We explored how slow synaptic depolarizations affect generation of action potentials by fast synaptic potentials using computational simulation of small networks of neurons implemented as compartmental models with realistic membrane ion channels. We found that slow synaptic depolarizations have biphasic effects; they initially make fast synaptic potentials more likely to trigger action potentials, but then actually prevent action potential generation by fast synaptic potentials with the inhibition lasting several 10s of seconds. We confirmed the inhibitory effects of the slow synaptic depolarizations using live Ca imaging of enteric neurons from mouse colon in isolated tissue. Our results identify a novel form of synaptic inhibition in the enteric nervous system of the gut, which may account for the vastly differing time courses between signalling in individual gut neurons and rhythmic contractile patterns that often repeat at more than 60 s intervals.

The mirtron miR-1010 functions in concert with its host gene SKIP to maintain synaptic homeostasis

SummaryMirtrons are non-canonical miRNAs arising by splicing and debranching from short introns. A plethora of introns have been inferred by computational analyses as potential mirtrons. Yet, few have been experimentally validated and their functions, particularly in relation to their host genes, remain poorly understood. Here, we found that larvae lacking the mirtron miR-1010 are unable to grow properly and pupariate. We show that miR-1010 downregulates nAcRβ2. Increase of cortical nAcRβ2 mediated by neural activity elevates the level of intracellular Ca2+, which in turn activates CaMKII and, further downstream, the transcription factor Adf-1. We reveal that Adf-1 initiates the expression of SKIP, the host gene of miR-1010. Preventing synaptic potentials from overshooting their optimal range requires both SKIP to temper synaptic potentials (incoherent feedforward loop) and miR-1010 to reduce nAcRβ2 mRNA levels (negative feedback loop). Our results demonstrate how a mirtron, in coordination with its host gene, contributes to maintaining homeostasis.

Reconstruction of post-synaptic potentials by reverse modeling of local field potentials

Among electrophysiological signals, Local Field Potentials (LFPs) are extensively used to study brain activity, either in vivo or in vitro. LFPs are recorded with extracellular electrodes implanted in brain tissue. They reflect intermingled excitatory and inhibitory processes in neuronal assemblies. In cortical structures, LFPs mainly originate from the summation of post-synaptic potentials (PSPs), either excitatory (ePSPs) and inhibitory (iPSPs) generated at the level of pyramidal cells. The challenging issue, addressed in this paper, is to estimate, from a single extracellularly-recorded signal, both ePSP and iPSP components of the LFP. The proposed method is based on a model-based reverse engineering approach in which the measured LFP is fed into a physiologically-grounded neural mass model (mesoscopic level) in order to estimate the synaptic activity of a sub-population of pyramidal cells interacting with local GABAergic interneurons. The method was first validated using simulated LFPs for which excitatory and inhibitory components are known a priori and can thus serve as a ground truth. It was then evaluated on in vivo data (PTZ-induced seizures, rat; PTZ-induced excitability increase, mouse; epileptiform discharges, mouse) and on in clinico data (human seizures recorded with depth-EEG electrodes). Under these various conditions, results showed that the proposed reverse engineering method provides a reliable estimation of the average excitatory and inhibitory post-synaptic potentials at the origin of the measured LFPs. They also indicated that the method allows for monitoring of the excitation/inhibition ratio. The method has potential for multiple applications in neuroscience, typically when a time tracking of local excitability changes is required.

Electrodiffusion model of synaptic potentials in dendritic spines

ABSTRACTWhen modeling electric current flow in neurons and excitable cells, traditional cable theory ignores electrodiffusion (i.e. the interaction between electric fields and ionic diffusion) as it assumes that concentration changes associated with ionic currents are negligible. This assumption, while true for large neuronal compartments, fails when applied to femto-liter size compartments such as dendritic spines - small protrusions that form the main site of synaptic inputs in the brain. Here, we use the Poisson (P) and Nernst-Planck (NP) equations, which relate electric field to charge and couple Fick’s law of diffusion to the electric field, to model ion concentration dynamics in dendritic spines. We use experimentally measured voltage transients from spines with nanoelectrodes to explore these dynamics with realistic parameters. We find that (i) passive diffusion and electrodiffusion jointly affect the kinetics of spine excitatory post-synaptic potentials (EPSPs); (ii) spine geometry plays a key role in shaping EPSPs; and, (iii) the spine-neck resistance dynamically decreases during EPSPs, leading to short-term synaptic facilitation. Our formulation can be easily adopted to model ionic biophysics in a variety of nanoscale bio-compartments.