Journal club: The role of electrical coupling in generating and modulating oscillations in a neuronal network

by Christina Mouser, Amitabha Bose and Farzan Nadim
Mathematical Biosciences 278 (2016) 11–21

Melissa Coleman showed in her 1995 Nature paper that there is an electrical connection between MCN1 and LG. I was a grad student back then. I really liked that paper, but I have forgotten about this electrical connection.  This electrical synapse is voltage-sensitive. It gets stronger when LG was depolarized. It looks opposite to regular EPSPs which usually become smaller when depolarized. This voltage-sensitive electrical synapse seems to act as a positive feedback to LG activity.

   In this paper, Mouser et al. showed that this electrical coupling is very important for LG bursting by using a mathematical model. LG forms a Half-Center Oscillator with Int1 by forming mutually inhibitory synapses. This HCO configuration itself can generate a rhythm, which is influenced by periodic inhibition from pyrolic pacemaker (AB). However, the major finding in this paper is that the LG oscillation can also be generated without the reciprocal inhibition, but with the voltage-dependent electrical coupling between MCN1 and LG. This also indicates that the half-center configuration is not the main element that produces the rhythm; rather it is to form a pattern of activity in left-right alternation. For rhythmogenesis, some sorts of positive feedback system seems more important than mutual inhibition.

   I don't know how electrical coupling gets voltage-sensitive. I assume it not caused by changes in the coupling coefficient, but rather by overall depolarization at dendrites, which may trigger Ca influx and hence enhancing spike width.

Journal club: Mechanisms of oscillation in dynamic clamp constructed two-cell half-center circuits

A. A. Sharp, F. K. Skinner, E. Marder
Journal of Neurophysiology Published 1 August 1996 Vol. 76 no. 2, 867-883

Dynamic clamping is merely current injection triggered by presynaptic voltage. The amount of current is determined mainly by postsynaptic voltage. There is nothing magical.

In this paper, the authors studied how systematic alterations in intrinsic and synaptic parameters affected the network behavior by using their newly-developed "dynamic clamping" on a pair of the gastric mill motor neurons, GMs. They isolated GMs by blocking synaptic transmission with picrotoxin and created reciprocally inhibitory two-cell circuits by the dynamic clamp.

The author demonstrated in this system that there was no bursting without the hyperpolarization-activated inward current (I_H). In the presence of additional I_H, a variety of circuit dynamics, including stable half-center oscillatory activity, was produced. The increase in synaptic conductance increased the burst period, whereas the increase in IH conductance reduced it. Discussion went on about synaptic threshold, saying that changes in the synaptic threshold might play a large role in turning on and off bursting activity. However,  these discussion are not so informative to others because nonspiking synapses are rarely seen other than crustaceans.

The authors often stated that they "depolarized" or "hyperpolarized" the thoreshold for synapse. This is wrong. The threshold does not "polarize." Membrane potential does. They should have stated that the threshold was changed to more depolarized or hyperpolarized levels.

Journal club: Phylogenic plasticity of crustacean stomatogastric circuits

by Pierre Meyrand and Maurice Moulins

J. exp. Biol. 138, 107-132, 133-153 (1988)

This old twin papers describe a neural network that has a very similar designs to that of related species but produces distinct patterns of output. They concluded that the differences in the pattern of motor output depend more on the action of the extrinsic neuromodulation onto individual neurons than the synaptic architecture of the network.

I. Pyloric patterns and pyloric circuit of the shrimp Palaemon serratus
http://jeb.biologists.org/content/138/1/107

To find the general rules of neural circuit function, direct comparison of different circuits may be useful. Finding a common principle or 'building blocks' may help understanding the fundamental mechanisms underlying rhythmic pattern generation. In this study, the authors investigated the stomatogastric nervous system of a shrimp and compared it with those of larger crustaceans such as lobster and crab. They found that pyloric networks are very similar between this shrimp and large crustaceans.

The pattern of their rhythmic outputs are quite different.  In large decapods, the pyrolic circuit generate triphasic rhythm. The pacemaker AB fire in antiphase with the constrictor motoneurones (LP and PY). In shrimp, AB fires in phase with the constrictor neurones because of electrical connection; endogenous oscillatory property was only found in LP.

II. Pyloric patterns and pyloric circuit of the shrimp Palaemon serratus

http://jeb.biologists.org/content/138/1/133

The previous study (above) showed that the fundamental network architectures are almost identical between large decapods and the shrimp. This study investigate how extrinsic modulatory inputs contribut to produce the motor outputs of different patterns.

They found that the shrimp neurons responded differently to muscarinic agonist and dopamin than those in large decapods. For example, oxotremorine activated PY, while dopamine activated PD. In large decapods, muscarinic agnonist causes oscillation in PDs while inhibit PDs. In shrimp, AB neuron is driven by and returns an inhibitory feedback to the commissural pyrolic oscillator. In large decapods, AB is the conditional oscillator and act as the pacemaker.

   Altogether, the phylogenetic plasticity in motor pattern production does not derive from structural differences in the corresponding central neuronal circuits themselves. Rather it is due to the difference in the modulatory system controlling these circuits. 

Variability, compensation and homeostasis in neuron and network function

Eve Marder and Jean-Marc Goaillard

Hebbian learning can be appropriately balanced by stability mechanisms that allow neurons and synaptic connections to be maintained in appropriate operating ranges (by Turrigiano and Nelson, various mechanisms including synaptic scaling and changes in individual ionic currents).

omeostatic tuning rules that maintain a constant activity pattern could, in principle, operate to tune conductances so that an individual neuron remains within a given region of parameter space, although its values for one or more conductances may be substantially
altered.

Variability in channel densities
How can we reconcile the apparent sensitivity of many neurons to rapid pharmacological treatments with new data indicating that individual neurons within a class can differ by as much as two- to fourfold in the densities of many of their currents?
Computational models show that a number of different compensating combinations of conductances can result in similar activity patterns38,51.

In contrast to pharmacological manipulations, slow mechanisms that function during development and over days and weeks can result in a set of compensating conductances that give rise to a target activity pattern.

Figure 2 | Neurons with similar intrinsic properties have different ratios of conductances.

Figure 3 | Comparison of short-term pharmacological manipulations and long-term genetic deletions.

Slow developmental and homeostatic mechanisms can ‘find’ multiple solutions of correlated
and compensating values of membrane conductances consistent with a given activity pattern, even while rapid pharmacological treatments that vary the value of one current at a time result in altered activity57.

Neuromodulator-evoked synaptic metaplasticity in a CPG

Mark D. Kvarta, Ronald M. Harris-Warrick and Bruce R. Johnson

Metaplasticity (Philpot et al. 1999): Characteristics of activity-dependent changes in synaptic strength altered by neuromodulation (Fischer et al. 1997; Kreitzer and Regehr 2000; Parker 2001; Parker and Grillner 1999; Qian and Delaney 1997).

In this study, the authors showed amines (5-HT, DA, and OA) change the properties of homosynaptic plasticity of a specific graded synapse in STG. The synapse used in this study was PD-to-LP synapse. This is apparently due to modification of vesicle traffic dynamics but the authors did not further dig experimentally into the vesicle release dynamics referring to the readily releasable pool sizes and replenishment rates. Recovery rate of homosynaptic depression was also dependent on the presynaptic activity. The authors discussed that maintained presynaptic depolarization would cause more calcium influx, which consequently increases mobilization of the recovery process.

Dopamine had reliable, significant and independent effects to accelerate the time course of synaptic depression onset and recovery from synaptic depression. It consistently accelerated both the onset of, and the recovery from, synaptic depression. This acceleration of onset and recovery from depression did not depend on the sign of the rather variable DA effect on gIPSP amplitudes described above.

DA had weak and highly variable effects on the LP gIPSPs in different preparations. It increased the rate of synaptic depression and of recovery from it. The variability to DA responses cane be caused by the known opposing effects of DA to decrease pre-synaptic PD transmitter release and increase post-synaptic LP input resistance (Harris-Warrick and Johnson 2010), but to differing amounts in different preparations.

DA may be acting postsynaptically to accelerate the kinetics of transmitter receptor desensitization and recovery from desensitization (Papke et al. 2011).

Octopamine - Increased both initial and steady amplitude, slowed the onset of synaptic depression, while speeding up the recovery rate from depression.

- What about contribution of post-synaptic receptors?

Serotonin - Serotonin depresses the synapse and accelerated the time course of synaptic depression measured with square pulse PD stimulation, but not reach statistical significance for oscillation.

The authors stated in the discussion that individual parameters of synaptic strength can be independently modulated by each amine. I disagree. The synaptic strengh should be determined by the fraction of readily releasable pool activated by depolarization, which must be under a strong influence of the vesicle replenishment rates. I don't think they are independent.

Voltage-dependent switching of sensorymotor integration by a lobster central pattern generator

By Romuald Nargeot

- Repeated sensory nerve stimulation gradually and long-lastingly strengthened the bursting of the LP neuron to the detriment of sensory-elicited inactivation.

- This strengthening of pyloric-timed rhytmic activity as enhanced by experimental depolarization of the neuron.

- When the LP neuron was hyperpolarized, the same sensory stimulation paradigm now gradually increased the susceptibility of the pyloric-timed bursting of the network neuron to sensory-elicited inactivation.

- Modulation of depolarization-activated and hyperpolarization-activated ionic conductances that underlie the intrinsic bursting properties of the LP neuron may contribute via differential voltage-dependent recruitment and effects to the respective adaptive processes.

Neuromodulatory inputs maintain expression of a lobster motor pattern-generating network in a modulation-dependent state:

Evidence from long-term decentralization in vitro

By Muriel Thoby-Brisson and John Simmers

The authors suggested that a persistent functional recovery from elimination of some of the central nervous inputs on which network operation normally depends.

Central modulatory inputs exert a long-term influence on the CPG in addition to their short-term permissive action on rethymogenesis.