Wednesday, September 20, 2017

Journal club: The cortex as a central pattern generator




NATURE REVIEWS NEUROSCIENCE 6(6) 2005

by Rafael Yuste, Jason N. MacLean, Jeffrey Smith and Anders Lansner


A vast number of neurons in the brain cortex together generates synchronized oscillatory activity. In this review paper, the authors discuss how the neocortex neural network shares basic designs with the central pattern generator circuits in the spinal cord and brain stem.

For rhythmogenesis in a neural network, it seems like the general rule that self-boosting excitation within a functional unit is more important than reciprocal inhibition.  In the neocortical circuit, a population of neurons forms an excitatory kernel by being interconnected through recurrent excitation. Such excitatory neuronal population is capable of producing synchronized oscillatory activity through their active membrane properties and short-term synaptic plasticity. This circuit architecture is similar to the CPGs in the spinal cord and brain stem of vertebrates. The inhibitory connections are necessary for the regulation of the rhythm and spatiotemporal pattern of the network output.

The extent of spatial distribution is one of the major differences between the cortical network and the CPG in the brain stem/spinal cord.  In the cortex, the recurrent excitatory network is widely spread out over the neocortex, whereas in those for locomotion and breathing have bilaterally-grouped functional units. The other difference is high plasticity in the cortical network in contrast to the hard-wired CPGs in the spinal cord and brain stem. The connectivity in the cortex develops through activity-dependent Hebbian plasticity. We can call the cortex network as a learning CPG that is based on Hebbian assemblies and is specialized for learning and storing or retrieving memories.  Because of these properties, the neocortex network is highly fluidic.


Tuesday, August 29, 2017

Journal Club: Fast Silencing Reveals a Lost Role for Reciprocal Inhibition in Locomotion




By Peter R. Moult, Glen A. Cottrell, and Wen-Chang Li
Neuron Volume 77, Issue 1, 9 January 2013, Pages 129-140

Reciprocal inhibition is considered as a fundamental building block in neural circuits for rhythmic motor pattern generation. Despite commonality in many rhythmic systems, however, the reciprocal inhibition is often found to be not a necessary component for rhythmogenesis. This is because a network is often capable of exhibiting rhythmic activity even when the reciprocal inhibition was removed mechanically or pharmacologically. The excitatory synaptic components within each half of the network are more crucial.  In this study, Wen-Chang Li's group challenged this idea by using optogenetics to hyperpolarize the entire population of neurons in one side of the spinal cord in a tadpole.

When the entire half of the spinal cord was suppressed by flashing yellow light, the other half also stopped bursting. This indicates that, in this reciprocally inhibitory network, the excitation in one side is necessary for the excitation of the other. Firing in one side would cause a bombardment of IPSPs, which induce post-inhibitory rebound. The authors also get a similar result by giving a strong hyperpolarizing current into one of the reciprocally inhibitory neurons. They concluded that the reciprocal inhibition is necessary in the tadpole swim circuit; it induces rebound excitation in the contralateral neurons.

In this paper, it is noteworthy that the author also mentioned about the "functional homeostasis" of the neural circuit. They said the rhythmic activity recovers after half an hour by itself without the reciprocal inhibition. The mechanism of the recovery still unknown.




Friday, July 14, 2017

Journal club: An increased extrasynaptic NMDA tone inhibits A-type K+ current and increases excitability of hypothalamic neurosecretory neurons in hypertensive rats.



by Meng Zhang, Vinicia C. Bianchardi and Javier E. Stern
DOI: 10.1113/JP274327

In this paper the authors tried to elucidate the mechanism of how the magnocellular neurosecretory neurons become hyperexcitable under pathological condition that could lead to high blood pressure and heart failure.

   Magnocellular neurosecretory cells (MNCs) in hypothalamus release vasopressin and oxytocin, which control fluid balance, and cardio-vascular and reproductive homeostasis. The MNC activity is fine-tuned by intrinsic membrane property, by extrasynaptic inputs, and by the activity of neighbouring astrocytes. MNCs have A-current, which pulls down MNCs from firing action potentials.
   In this study, the authors showed that the activation of eNMDARs inhibited A-current in sham MNCs, but not in MNCs from renovascular hypertensive (RVH) rats. However, neither the exogenously evoked NMDA current nor the expression of NMDAR subunits were altered in RVH rats.  Instead, a larger endogenous glutamate tone, which was not due to blunted glutamate transport activity, led to the sustained activation of eNMDARs. This tonically inhibited A-current and contributed in turn to higher firing activity in RVH rats.

   In this study, they did not show the inactivation curve for the A-current. If I were a referee, I would ask them to show it, because the Glu tone should act very slowly. A-current can inactivated under such condition.

   So, the basal Glu level appears to be very important in regulating the homeostatic functions. It might not be just in the brain. If the extrasynaptic GluRs play similar roles in other nervous system, I can speculate that chronic consumption of MSG might have some bad effects on the peripheral nervous systems such as those controlling guts.

Friday, May 26, 2017

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.




Thursday, April 13, 2017

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.

Sunday, February 26, 2017

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 (IH). In the presence of additional IH, 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.

Friday, February 17, 2017

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

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.

 

Wednesday, February 1, 2017

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

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.

Saturday, January 28, 2017

Molluscan Memory of Injury: Evolutionary Insights into Chronic Pain

 Brain Behav Evol 2009; 74: 206-218

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.

Friday, January 20, 2017

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.

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. 

Wednesday, January 11, 2017

Review: Vertebrate brains and evolutionary connectomics: on the origins of the mammalian 'neocortex'

Phil. Trans. R. Soc. B 370: 20150060.  (2015)
http://dx.doi.org/10.1098/rstb.2015.0060

by Harvey J. Karten

This review paper covers not just the history of studies on avian brain which dates back to the Darwin era, but it also tells the story of the author's long quest for the answer of how laminar structure of mammalian neocortex was developed and it had diverged from the nuclear structures of avian brain.

   Mammalian brain and avian brain are very different in forebrain organization. The mammalian brain has laminated cortex structure. In contrast, the avian brain has nuclear clusters that are interconnected. Despite such differences, both animals can perform complex cognitive behaviors, such as sensory perception, decision making, and language capability.
   Recent studies have suggested homology in the molecular features of neurons and the structures of microcircuits (Wang et al., 2010). This "nucleus to layer" hypothesis was further supported by Dugus-Ford et al. (2012) showing that each of the distinct nuclei of the avian telencephalon also expressed various genetic molecular features that very closely match those of layers of the mammalian neocortex to which they were speculatively linked. Such homology can track back to fish. Calabrese and Woolley (2015) demonstrated that the avian auditory pallium exhibits the same information-processing principles that define the canonical cortical microcircuit, which is similar to the lamina-specific properties of mammalian cortex. They provided a physiological explanation for the evolution of neural processes that give rise to complex behavior in both mammals and birds.
  The author has also stated several times in this paper that the microcircuit structure that is commonly seen in vertebrate brains may have originated from the age that is older than the ancestoral reptile of avian and mammals. It is fun to imagine how birds and mammals employed microcircuit as a common building block to built their own brains.

Overall, the paper was mostly written in plain English and it was fun to read. 

Sunday, January 8, 2017

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
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. 


Thursday, January 5, 2017

Journal club: Recent Clione papers



Arshavsky published a series of studies on the Clione swim CPG. Those papers are "must read" for researchers who work on CPG. I pay the highest respect to them.They were published in late 80's and now can be categorized as classical papers.
   More recently, there came a series of papers performing more detailed(?) analyses on this system. The following are my impressions with regard to those recent Clione papers.

2004
"Cellular mechanisms underlying swim acceleration in the pteropod mollusk Clione limacina"
by Pirtle and Satterlie
Integr. Comp. Biol. (2004) 44 (1): 37-46. doi: 10.1093/icb/44.1.37

Clione can swim faster when attacking a prey. It had been suggested that 5-HT mediates the acceleration of the swim motor pattern. In this study, the authors examined what membrane current components were modified by 5-HT.
   It seems to me that the experiments were not well designed. The way they compared the effects of drugs seems problematic (e.g., Fig. 7D). Figures were not well arranged. A control swim activity was not presented in Fig. 2 but then shown in Fig. 3. The authors called ion channel blockers as "antagonists." Antagonists are for receptors. No description of what neurons they used. The introduction was great, though.


2006
"The contribution of the pleural type 12 interneuron to swim acceleration in Clione limacina"
by Pirtle and Satterlie
Invert Neurosci (2006) 6:161–168. DOI 10.1007/s10158-006-0029-8

In this paper, the authors examined the role of type-12 neurons in the swim acceleration.
   Type-12 neuron is recruited into the type7/8 half-center network when the CPG gets into the fast swim mode. Arshavsky et al. (1985) suggested that this neuron plays an important role in the swim acceleration by rewiring the circuit. It turned out that activation of type-12 had only a transient effect on the swim cycle frequency. They suggested that type 12 has rather minor roles in maintaining the fast swim mode. Its function may be bilateral coordination or to increase the stability of the network. Despite negative results, this paper is more interesting than the other two.


2010
"A hyperpolarization-activated inward current alters swim frequency of the pteropod mollusk Clione limacina"
Pirtle, Willingham, and Satterlie
Comparative Biochemistry and Physiology, Part A 157 (2010) 319–327. DOI:10.1016/j.cbpa.2010.07.025

I don't see much difference between this and the previous 2004 paper. The only change was that they now show ZD7288 data instead of CsCl. In Fig. 5E. They stated ZD7288 blocked the 5-HT effect. I cannot agree with that. If compared with Fig. 4D data, I see that 5-HT still increases the swim cycle frequency even in the presence of ZD7288. Oh and again they were still calling ZD7288 as an "antagonist" for Ih current.

Tuesday, January 3, 2017

Journal club: Development of the nervous system in Solenogastres (Mollusca) reveals putative ancestral spiralian features

Redl et al. EvoDevo 2014 5:48
DOI: 10.1186/2041-9139-5-48

Background: The evolutionary emergence of the Mollusca is unclear.  Some have proposed that molluscs stem from unsegmented organisms, while others say they stem from a segmented annelid-like ancestor. 
   In this study, the authors investigated the development of the nervous system in two species of solenogasters to describe the larval nervous system and also to test the hypotheses on segmented or unsegmented ancestry of molluscs. 

Observations: During the embryonic development, first neurons appear at the apical and abapical pole; the flask-shaped cells of the apical organ and the large cells associated with the suprarectal commissure are lost.
   The neuropile beneath the apical organ develops into the cerebral commissure. The cellular posterior connection of the lateral neurite bundles becomes the suprarectal commissure.
   Interestingly early nervous system development in the polychaetes shows strong similarity to the mode of neural development described here for solenogasters. They both develop apical organ with flask-shaped cells, and a single pair of longitudinal neurite bundles. Similarity in the pattern of serotonin-like immunoreactivity, and formation of the CNS from anterior and posterior ends. 

Conclusions: This study supports a nonsegmented ancestry of molluscs, but there is similarities between solenogasters and polychaetes during early nervous system development, such as the formation of the nervous system from an apical and abapical neurogenic domain.
   The authors suggest that they share neural features descent from the last common ancestor, which had no segmentation.  Segmentation may have evolved only along the line leading to the annelids.