Download Does spike-time dependant plasticity occurs in dorsal horn neurons

Does spike-time dependent plasticity occur in dorsal horn
neurons? An approach to chronic pain modeling
Aydin Farajidavar1, Shahriar Gharibzadeh1, Farzad Towhidkhah2, Parisa Hasanain3,
Mohsen Parviz4
Neuromuscular Systems Laboratory, Faculty of Biomedical Engineering, Amirkabir University of Technology (Tehran
Polytechnic ); 2 Biological Systems Modeling Laboratory, Faculty of Biomedical Engineering, Amirkabir University of
Technology (Tehran Polytechnic); 3Biology department, Basic sciences college, BuAli Sina University, Hamadan, Iran;
Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran..
1
Keywords: wind-up; Aβ fiber; pain relief; STDP; TENS
Summary
Activity-dependent synaptic modification is critical for the development and functioning
of the nervous system. Recent experimental discoveries suggest that both the extent and
the direction of modification may depend on the precise timing of pre- and postsynaptic
action potentials (spikes). This phenomenon, termed spike timing-dependent plasticity
(STDP), provides a new, quantitative interpretation of Hebb’s rule and raises intriguing
questions regarding the fundamental processes of cellular signaling.
On the other hand, there are two phenomena in hyperalgesic state pain, Aβ wind up and
pain depression following Aβ fiber electrical stimulation (PDFES), that we think are a
form of STDP in spinal cord. Aβ wind up is a kind of potentiation and PDFES is a kind
of depression and both occur with the electrical stimulation of Aβ fibers under different
frequencies. Our new hypothesis tries to describe the synaptic timing characterisitics of
these phenomena. Simulating this hypothesis by means of dynamic synapse models
would properly lead to chronic pain modeling. Furthermore, it seems that our results can
be used to optimize transcutaneous electrical nerve stimulation. Surely, future clinical
studies are needed to validate these predictions.
INTRODUCTION
Rational treatment of chronic pain depends on understanding of the pathophysiological
mechanisms underlying the various characteristics of chronic pain, among which central
sensitization has received great attention in recent years. The experimental models used
to explore mechanisms of central sensitization include the study of wind-up in animals
and temporal summation of pain in humans. Temporal summation of repeated painful
stimuli has been regarded as a psychophysical correlate of wind-up in humans [4].
A novel type of wind-up has been evoked by the stimulation of Aβ fibers in hyperalgesic
states induced by peripheral injury or inflammation [14, sprouting]. Aβ wind up was
observed with trains of stimuli applied at 1 Hz, but not at 0.3 or 0.1 Hz, indicating that
the Aβ wind up has the same frequency dependence as C-fiber evoked wind up [5]. In
addition, Several authors have reviewed the electrophysiological and behavioral data
indicating a significant role of N-methyl-D-aspartate (NMDA) receptor in wind-up
[3,16].Therefore, Wind-up is a long-lasting phenomenon that resembles a potentiation in
dorsal horn.
Furthermore, the introduction of the gate control theory of pain by Melzack and Wall in
1965 provided a convincing theory about the nature of pain and offered a theoretical basis
for the effectiveness of transcutaneous electrical nerve stimulation (TENS) in pain relief.
The theory suggests that stimulating large myelinated primary afferent fibers will inhibit
input from nociceptive primary afferent fibers through neurons located in the spinal cord
dorsal horn. TENS stimulation frequency is about 4 Hz (low frequency) or 100 Hz (high
frequency), which is different from the Aβ wind up frequency [Ellen]. Altogether, TENS
would cause depression in dorsal horn and NMDA receptors are responsible for this
depression [R? sandkuhler].
Synaptic plasticity consists of any change in the synaptic connections between neurons,
including strengthening and weakening of synapses, changes in the distribution of
receptor proteins and postsynaptic signal transduction mechanisms, and even changes in
the number and distribution of synapses formed between pairs of neurons.
One kind of synaptic plasticity, Spike timing-dependent plasticity (STDP), is
characterized by synaptic weight changes that depend on the precise timing of spikes
fired by pre- and post-synaptic cells.
Figure 1 illustrates a pairing experiment with cultured hippocampal neurons where the
presynaptic neuron (j) and the postsynaptic neuron (i) are forced to fire spikes at time tj(f)
and ti(f) , respectively (Bi and Poo, 1998). The resulting change in the synaptic efficacy
Δwij after several repetitions of the experiment, turns out to be a function of the spike
time differences tj(f) -ti(f). The amplitude and even the direction of the change depend on
the relative timing of presynaptic spike arrival and postsynaptic triggering of action
potentials []. The synapse is strengthened if the presynaptic spike occurs shortly before
the postsynaptic neuron fires, but the synapse is weakened if the sequence of spikes is
reversed.
In this paper, we consider both Aβ wind-up potentiation and PDFES and try to explain
why different frequencies of electrical sitmulation induces this synaptic plasticity of the
dorsal horn neuron. We intend to show that more or less a form of STDP exists in the
spinal cord.
The HYPOTHESIS
In this theory we assume a C fiber as j neuron (presynaptic) and dorsal horn neuron as i
(postsynaptic).
In the case of wind-up, presynaptic spikes from Aβ fibers cause a fast depolarization on
dorsal horn neuron, this depolarization cannot lead to any postsynaptic spike firing and
action potential of the dorsal horn, but it up-regulates the NMDA receptors which are
located on dorsal horn. Then a spike from C fiber fires, this spike plays the role of the
presynaptic firing. Occurrence of this spike in the presynaptic space with the help of upregulated NMDAR would trigger a postsynaptic action potential. If we name the C fiber
as j (like above) and dorsal horn neuron as i, we observe that the similar things happen
and cause potentiation. This is absolutely compatible with the potentiation process of
STDP and cause the potentiation in the synapse between C fibers and the dorsal horn
neuron. Therefore, painful stimuli from C fibers would strengthen and wind-up happens.
In the case of PDFES presynaptic Spikes from Aβ fibers cause triggering of action
potential in dorsal horn neuron hence the post synaptic fires. This firing down regulates
the NMDA receptors, so when the spikes from C fibers receive to the synapses between
C fibers and dorsal horn (presynaptic spikes) this synapse would depress. Thus, painful
stimuli from C fibers weaken and pain relief happens.
As it is apparent, stimulations with different frequencies to the same fibers lead to
different phenomena. We think this is because of different spike timing which occurs on
the synapse of dorsal horn neuron.
The HYPOTHESIS
For the purpose of simplicity, we call the afferent C fiber as "j" neuron and the dorsal
horn neuron as "i".
In the case of wind-up, presynaptic spikes from Aβ fibers cause a fast depolarization in
the dorsal horn neurons. This depolarization cannot lead to any postsynaptic action
potential in the dorsal horn, but up-regulates the NMDA receptors, which are located on
the dorsal horn. Then, spikes from C fiber excite the dorsal horn neuron. In other words,
it plays the role of presynaptic firing. The occurrence of this spike in the presynaptic
space with the help of up-regulated NMDA receptors would trigger a postsynaptic action
potential. If we name the C fiber as j (like above) and dorsal horn neuron as i, we observe
that similar events, compatible with a classic STDP happens in wind up. Therefore,
painful stimuli from C fibers would strengthen and induce wind-up.
In the case of TENS, depression presynaptic Spikes from Aβ fibers cause triggering of
action potential in dorsal horn neuron hence the post synaptic fires. This firing down
regulates the NMDA receptors, so when the spikes from C fibers receive to the synapses
between C fibers and dorsal horn (presynaptic spikes) this synapse would depress.
As it is apparent, stimulations with different frequencies to the same fibers lead to
different phenomena. We think this is because of different spike timing which occurs on
the synapse of dorsal horn neuron.
Consequences of hypothesis
Recently, there has been a substantial advance in the neurophysiological studies on
synaptic plasticity, mainly exploring a function of the relative timing between the pre and
post-synaptic spikes (reviewed in [1,8]). Consequently, research in computational
modelling has build upon that and derived synaptic plasticity rules capable of tuning
neurons to respond to specific spatio-temporal input patterns [2–6].
Temporal relationships between neuronal firing and plasticity have received significant
attention in recent decades. Neurophysiological studies have shown the phenomenon of
spike-timing-dependent plasticity (STDP). Various models were suggested to implement
an STDP-like learning rule in artificial networks based on spiking neuronal
representations.
Modeling wind-up with the STDP hypothesis can ensue to the modeling of chronic pain
with artficial neural networks that are dynamics and use dynamic weights. In this regard
the weights of the artificial neural network (ANN) should be a function of input neuron
and output neuron and weights do not fix even after training.
On the other hand using STDP models for TENS can lead to manage better frequencies
for TENS. With this modeling you can tune TENS frequency with regards to timing of
potentiation and depression.
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The most famous rule of synaptic modification was
proposed by Donald Hebb [1]: ‘‘When an axon of cell A
is near enough to excite a cell B and repeatedly or
persistently takes part in firing it, some growth process or
metabolic change takes place in one or both cells such that
A’s efficiency, as one of the cells firing B, is increased.’’
This ‘‘neurophysiological postulate’’ has since become a