Melibe and Dendronotus Dynamic Clamp paper

My latest paper will appear in Current Biology next weekend.

Artificial Synaptic Rewiring Demonstrates that Distinct Neural Circuit Configurations Underlie Homologous Behaviors
http://www.cell.com/current-biology/fulltext/S0960-9822(17)30552-3
by Akira Sakurai and Paul S. Katz

Behaviors can be homologous just like any other trait can be. This study directly compared neural circuit mechanisms underlying homologous behaviors in two closely-related species.

   This work originates from two questions. First, we wanted to grasp a clue to figure out how species-specific behaviors have evolved. Mollusks are good models to study this because of their wide variety of speciation and the simplicity of the nervous system. In other animal models, functional elements of a neural circuit often consist of a population of neurons having the same function. This makes it difficult to manipulate because there are so many. In contrast, mollusks have one large neuron playing a key role in generating motor output for behavior. Their behaviors are also simple and reliable. The neuronal activity can be precisely manipulated so that one can easily relate one neuron to one behavior. By looking into molluscan species, we hoped we might be able to witness how a species-specific behavior has evolved.
   Secondly, we have been wondering what would happen if we swap a neural circuit of one species with that of the other species. There is a technique called "dynamic clamping", by which one can modify the strength of synapses or membrane conductances by injecting electrical current into neurons. The amount of the injected current is calculated in real-time by a computer based on the membrane potential that is being recorded. With this technique, we hoped we could reveal a crucial element that provides a neural circuit function.

   In this paper, we compared two neural circuits underlying swimming behaviors of two nudibranchs, Melibe leonina and Dendronotus iris. These sea slugs swim by flexing their body from left to right. These behaviors are likely to be homologous because both species belong to a clade that consists only of families that contain species that swim in the same way.
   We found that their swimming behaviors are produced by distinct neural circuit mechanisms. In Melibe, one of the neurons called Si3 makes an inhibitory synapse to fine-tune the rhythm made by other neurons.  In Dendoronotus, Si3 provides excitatory drive to other neurons to induce their rhythmic activities. When the Si3 synapses were blocked by curare, the swim rhythm slowed down in Melibe; whereas in Dendronotus, curare abolished the motor pattern. Replacing these synapses by artificial computer-generated synapses using "dynamic clamping" immediately restored the motor pattern. Using the dynamic clamp, we also rewired the Dendronotus circuit to the Melibe circuit. Then the Dendronotus neurons started to burst like the Melibe neurons in curare.

   From the results, we discussed that the neural mechanisms underlying homologous behaviors appear to have diverged but are still interchangeable in the other species. This has important significance for making inferences into neural mechanisms based on behavior. It also provides a real life instantiation for a prediction based on models, that there are multiple circuit architectures that can produce the same pattern of activity.

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: Gap junctions compensate for sublinear dendritic integration in an inhibitory network

Koen Vervaeke, Andrea Lőrincz, Zoltan Nusser, R. Angus Silver

Science 30 Mar 2012:

Vol. 335, Issue 6076, pp. 1624-1628

DOI: 10.1126/science.1215101

This paper describe how dendrites of cerebellar Golgi cells enhance synaptic signals by sharing them with neighboring Golgi cells via gap junctions rather than boosting them by generating action potentials.

Golgi cells are the inhibitory interneurons in the granular layer of the cerebellar cortex. They receive excitatory input from mossy fibres and parallel fibers.  In this study, the authors studied how the excitatory synaptic inputs onto Golgi cells are integrated by the dendrites and by electrical connections to other Golgi cells. Forming the gap junctions with neighboring cells counteracts with the dendritic attenuation due to membrane conductance.

The author first examined the efficiency of passive dendritic conduction of a local synaptic potential evoked by two-photon uncaging of glutamate. They found that the dendrite of Golgi cell is quite passive. Substantial attenuation of the electrotonic signals when occurred at many places at once.  This weakens the impact of distal excitatory inputs. 

 

However, the high density of dendritic gap junctions enables the synaptic potentials spread to the dendrites of neighboring GoCs. This gap junction-mediated lateral excitation counteracts the effects of sublinear dendritic behavior. Thus, electrical connections among GoCs counteract the dendritic attenuation without the need to boost electrically remote synaptic input with active dendritic conductances.  The combination of passive dendrites and dendritic gap junctions facilitates the excitatory synaptic signals by involving a larger number of interneurons to respond to localized patches of synaptic excitation.

The results also revealed how gap junctions on inhibitory interneuron dendrites could contribute to spatial averaging, which has been proposed in the retina, excitatory olfactory neurons in insects, and to the broad tuning of inhibitory interneurons in cortex.  These mechanisms are also likely to contribute to gain control in the granule cell layer through parallel-fiber mediated feedback.  The interneurons do not operate as fully independent neuronal units but share charge during chemical synaptic excitation and thus exhibit features of a syncitium.

 

Reveiw: Cortical reorganization after spinal cord injury: Always for good?

Neuroscience 283 (2014) 78–94

K. A. Moxon, A. Oliviero, J. Aguilar, and G. Foffani

http://dx.doi.org/10.1016/j.neuroscience.2014.06.056

This review paper gave me a vivid image of the plastic nature in brain function. The cortical map is not a static representation. It represents dynamic equilibrium of continuous interactions of the brain and the external world. Such fluidic nature of the brain is remarkable during the sensorimotor learning.  It becomes especially important when the brain goes through functional recovery after injury and rehabilitation. Upon spinal cord injury, a change in brain state occurs immediately to start cortical reorganization. 

   A complete thoracic spinal cord transection immediately changes the state of the brain, decreasing cortical spontaneous activity as evidenced by a slowing of the frequency of anesthesia-induced oscillations, while increases the cortical responses to stimuli delivered above the level of the lesion. The increased responses could be due to a change in the equilibrium between excitation and inhibition at cortical and subcortical levels.

   There is a species differences in the cortical reorganization. In human, the spinal lesion induces an enlargement of cortical sensorimotor areas representing preserved muscles above the level of lesion. Primates brain may be more flexible than rodents, in which spontaneous cortical reorganization is more limited.

   The authors discussed potential therapy that involves 5-HT and exercises. Activation of 5-HT receptors facilitates cortical reorganization by restructuring connections that could be relevant for behavioral recovery. Cortical reorganization can also be promoted by exercise therapy, which increases brain BDNF levels. This peptide and 5-HT together favors cortical reorganization and functional recovery after spinal cord injury.

Molluscan Memory of Injury: Evolutionary Insights into Chronic Pain

 Brain Behav Evol 2009; 74: 206-218

DOI: 10.1159/000258667

Edgar T. Walters and Leonid L. Moroz

In this paper, the authors raise an interesting hypothesis that the plasticity mechanisms underlying learning and memory in higher organisms may have evolved from adaptive responses that repair damaged neuronal processes or body parts. Persistent nociceptive sensitization in Aplysia nervous system displays many functional similarities to alterations in mammalian nociceptors associated with the clinical problem of chronic pain. The original responses induced regrowth of damaged axon, increased excitability, enhanced release of transmitter, and reorganization of cellular network. Such compensatory responses would be critical for survival in the early age.

Before discussing about the origin of chronic pain and synaptic plasticity, the authors also described how great Aplysia is. They compared molluscs with other model systems like arthropod and nematode by comparing the number of gene homologues that are shared by mammals, and their evolutionary distances from mammals. Mollucs are closer to mammals because they split earlier. Slower rate of gene evolution provided molluscs more homologous genes associated with human disease than Drosophila or C. elegans. DNA methylation can also be seen in molluscs. Thus, integration of genomics and physiological studies in molluscan neurons offers a powerful comparative approach to address molecular and cellular aspects of selected neurological problems.

Altogether, molluscan preparations should become increasingly useful for comparative studies across phyla that can provide insight into cellular functions of clinically important genes.

Review: New genes from old: asymmetric divergence of gene duplicates and the evolution of development

Holland PW, Marlétaz F, Maeso I, Dunwell TL, Paps J. 2017

Phil. Trans. R. Soc. B 372: 20150480.

http://dx.doi.org/10.1098/rstb.2015.0480

Genome or genes sometimes get duplicated just partially within a single cell even when it is not dividing. The gene duplication and divergence provide a critical source of genetic novelty during evolution. This review paper discusses the fates of duplicated homeobox genes, focusing on asymmetric divergence after gene duplication. Duplicated genes differentiate independently (or asymmetrically) to different degrees. They often become key genes of new functions.
   One of the copied genes can mutate and sometimes acquires a new function, while the others may lose their function. Overall number of genes changes as a result of total duplication-modification and deletions. Repetition of this process over millions of years result in a whole family of genes in a single genome. Duplicate copies often change asymmetrically to have different functions. Their expression becomes different in time and loci. This is how orthologs and paralogs were made.

This review provides examples are Hox genes in Lepidoptera, TALE-class genes in molluscs, extra PRD-class genes in placental mammas.  Tapeworms have lost around one-third of all homeobox genes generally present in bilaterian animals. The evolution of the globulin gene family shows how DNA duplications contribute to the evolution of organisms (Molecular Biology of the Cell, pp461).

Production of redundant copies and repurposing them for other functions sounds similar to the neural circuit evolution.  It seems like evolution is all about repurposing of given resources to create new functions.