Wednesday, September 20, 2017

Journal club: The cortex as a central pattern generator


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
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.