The generation of phase differences and frequency changes in a network model of inferior olive subthreshold oscillations

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedicationIt is commonly accepted that the Inferior Olive (IO) provides a timing signal to the cerebellum. Stable subthreshold oscillations in the IO can facilitate accurate timing by phase-locking spikes to the peaks of the oscillation. Several theoretical models accounting for the synchronized subthreshold oscillations have been proposed, however, two experimental observations remain an enigma. The first is the observation of frequent alterations in the frequency of the oscillations. The second is the observation of constant phase differences between simultaneously recorded neurons. In order to account for these two observations we constructed a canonical network model based on anatomical and physiological data from the IO. The constructed network is characterized by clustering of neurons with similar conductance densities, and by electrical coupling between neurons. Neurons inside a cluster are densely connected with weak strengths, while neurons belonging to different clusters are sparsely connected with stronger connections. We found that this type of network can robustly display stable subthreshold oscillations. The overall frequency of the network changes with the strength of the inter-cluster connections, and phase differences occur between neurons of different clusters. Moreover, the phase differences provide a mechanistic explanation for the experimentally observed propagating waves of activity in the IO. We conclude that the architecture of the network of electrically coupled neurons in combination with modulation of the inter-cluster coupling strengths can account for the experimentally observed frequency changes and the phase differences.Peer reviewedFinal Published versio

Longitudinal neuronal organization and coordination in a simple vertebrate: a continuous, semi-quantitative computer model of the central pattern generator for swimming in young frog tadpoles

When frog tadpoles hatch their swimming requires co-ordinated contractions of trunk muscles, driven by motoneurons and controlled by a Central Pattern Generator (CPG). To study this co-ordination we used a 3.5 mm long population model of the young tadpole CPG with continuous distributions of neurons and axon lengths as estimated anatomically. We found that: (1) alternating swimming-type activity fails to self-sustain unless some excitatory interneurons have ascending axons, (2) a rostro-caudal (R-C) gradient in the distribution of excitatory premotor interneurons with short axons is required to obtain the R-C gradient in excitation and resulting progression of motoneuron firing necessary for forward swimming, (3) R-C delays in motoneuron firing decrease if excitatory motoneuron to premotor interneuron synapses are present, (4) these feedback connections and the electrical synapses between motoneurons synchronise motoneuron discharges locally, (5) the above findings are independent of the detailed membrane properties of neurons

Picomolar Amyloid-beta Positively Modulates Synaptic Plasticity and Memory in Hippocampus

Amyloid-beta (A beta) peptides are produced in high amounts during Alzheimer's disease, causing synaptic and memory dysfunction. However, they are also released in lower amounts in normal brains throughout life during synaptic activity. Here we show that low picomolar concentrations of a preparation containing both A beta(42) monomers and oligomers cause a marked increase of hippocampal long-term potentiation, whereas high nanomolar concentrations lead to the well established reduction of potentiation. Picomolar levels of A beta(42) also produce a pronounced enhancement of both reference and contextual fear memory. The mechanism of action of picomolar A beta(42) on both synaptic plasticity and memory involves alpha 7-containing nicotinic acetylcholine receptors. These findings strongly support a model for A beta effects in which low concentrations play a novel positive, modulatory role on neurotransmission and memory, whereas high concentrations play the well known detrimental effect culminating in dementia

Temporal binding via cortical coincidence detection of specific and nonspecific thalamocortical inputs: A voltage-dependent dye-imaging study in mouse brain slices

Voltage-sensitive dye imaging of mouse thalamocortical slices demonstrated that electrical stimulation of the centrolateral intralaminar thalamic nucleus (CL) resulted in the specific activation of thalamic reticular nucleus, striatum/putamen, and cortical layers 5, 6, and 1. By contrast, ventrobasal (VB) thalamic stimulation, while activating the reticular and basal ganglia nuclei, also activated directly layers 4 and deep 5 of the cortex. Conjoined stimulation of the VB and CL nuclei resulted in supralinear summation of the two inputs at cortical output layer 5, demonstrating coincidence detection along the apical dendrites. This supralinear summation was also noticed at gamma band stimulus frequency (≈40 Hz). Direct stimulation of cortical layer 1, after a radial section of the cortex that spared only that layer, was shown to sum supralinearly with the cortical activation triggered by VB stimulation, providing a second demonstration for coincidence detection. Coincidence detection by coactivation of the specific (VB) and nonspecific (CL) thalamic nuclei has been proposed as the basis for the temporal conjunction that supports cognitive binding in the brain

Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling

Modafinil (Provigil, Modiodal), an antinarcoleptic and mood-enhancing drug, is shown here to sharpen thalamocortical activity and to increase electrical coupling between cortical interneurons and between nerve cells in the inferior olivary nucleus. After irreversible pharmacological block of connexin permeability (i.e., by using either 18β-glycyrrhetinic derivatives or mefloquine), modafinil restored electrotonic coupling within 30 min. It was further established that this restoration is implemented through a Ca2+/calmodulin protein kinase II-dependent step