Central Pattern Generators III: Role of Modulation in a Central Pattern Generator

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Introduction

  • You have now gotten some feeling for the work needed to establish the connections among neurons in a circuit, as well as the much greater work that needs to be done to understand the actual circuit dynamics, the flow of excitation and inhibition throughout the circuit.
  • In our earlier discussion of synaptic transmission, we mainly focused on transmitters that acted to excite or inhibit other neurons.
  • However, there are a very large class of responses to chemical messengers that act on nerve cells that are neither excitatory nor inhibitory; they are modulatory, that is, they alter the responsiveness of a neuron to subsequent messages.
  • In this third and final unit on the Tritonia swim circuit, we will discuss some of the properties of neuromodulation, and then focus on the way in which neuromodulation plays a critical role in the normal function of the swim circuit.

Neuromodulation

  • A word about terminology. The term neuromodulation has been in regular use among the neuroscience community for decades, but recently it has been co-opted by engineers who use electrical stimulation to supplement or alter the activity of the nervous system. This overloading of the term is not very helpful, and when reading the literature, you will need to be sure which usage is correct by careful examination of the larger context.
  • Neuromodulation is most easily defined in contrast to neurotransmission. In neurotransmission, a neuron either excites or inhibits another cell, as we saw in the earlier unit on postsynaptic mechanisms. In contrast, in response to neuromodulation, the target cell's cellular or synaptic properties are changed so that it may behave differently in response to inputs, or the very nature of the cell may change in the absence of stimuli. For example, a synapse may be strengthened or weakened, or a tonically active cell may be switched to bursting, by playing on the multiple conductances that we studied previously. Neuromodulators may act through second messenger systems, such as cAMP, and change the state of ion channels (e.g., by adding or removing a phosphate group, which changes the responsiveness of the ion channel to other inputs).
  • What is the source of neuromodulation? In extrinsic neuromodulation, a neuron that is outside of the circuit has a neuromodulatory effect on neurons within the circuit; thus one can talk about the normal behavior of the circuit with and without neuromodulation. In contrast, in intrinsic neuromodulation, a neuron within the circuit has a neuromodulatory effect on the circuit; thus neuromodulation plays a vital role in the normal function of the circuit, which cannot be understood without an analysis of the role of neuromodulation. This was one of the major discoveries of Katz and Frost, who found that the Tritonia swim circuit used the same transmitter, serotonin, both as a standard neurotransmitter and as a neuromodulator. In the absence of neuromodulation, the swim circuit did not function properly.
  • To show neurotransmission between two neurons, one needs to demonstrate that individual spikes in the first neuron cause excitatory or inhibitory post-synaptic potentials in the second neuron. In contrast, to demonstrate neuromodulation, one needs to show that activity of one neuron causes a complex change in other neurons that goes beyond simple excitation or inhibition. For example, Katz and Frost demonstrated that DSI stimulation could increase the strength of the synapse between C2 and one of the dorsal flexor motor neurons. Moreover, they showed that neuromodulation could differentially affect excitatory and inhibitory components of the postsynaptic response.
  • An excellent review of the difference between intrinsic and extrinsic modulation is here, and a more recent review stresses that the evidence, in both vertebrates and invertebrates, that neuromodulation is not merely a tuning of the circuit, but actually transforms the circuit, so that the actual number of distinct modes a neural circuit can assume is vastly increased by neuromodulation. In turn, this also suggests the reason that establishing connections is not enough to understand the dynamics and function of a neural circuit, as is emphasized by this recent review by Eve Marder, one of the pioneers who initiated the study of the role of neuromodulation in neural circuitry.

Analyzing the Role of Modulation

  • You now have the information you need to explore the effects of neuromodulation on the Tritonia swim circuit. Here is the simulation you used in the previous unit:
  • Question 1. How do the three neurons interact with one another, and how would this generate a swim pattern? Let us begin by examining the effect of the DSI on the other two neurons, when the circuit is not modulated, and then when it is subjected to modulation.
    • A. Click the button "Unmodulated Swim Defaults".
      • Set the C2 Current clamp parameters as follows: Stimulus Delay, 0 ms; Stimulus current, -1.5 nA; Pulse duration, 10000 ms; Inter-stimulus interval, 500 ms; and number of pulses, 1.
      • Set the DSI Current clamp parameters as follows: Stimulus Delay, 0 ms; Stimulus current, 0 nA; Pulse duration, 0 ms; Inter-stimulus interval, 0 ms; and number of pulses, 0.
      • Set the VSI-B Current clamp parameters as follows: Stimulus Delay, 0 ms; Stimulus current, 0 nA; Pulse duration, 0 ms; Inter-stimulus interval, 0 ms; Number of pulses, 1.
      • Set the number of DRI pulses to 0. Set the duration of the simulation to 10000 ms. Run the simulation.
      • What is the effect of the action potentials in DSI on the other two cells? Record the potentials of the two postsynaptic cells (C2 and VSI-B), and measure the sizes of their postsynaptic responses to the DSI.
      • How can DSI fire if no current is injected into it? Explain.
    • B. Now, click the button “Modulated Swim Defaults”.
      • Set the C2 Current clamp parameters as follows: Stimulus Delay, 0 ms; Stimulus current, -1.5 nA; Pulse duration, 10000 ms; Inter-stimulus interval, 500 ms; and number of pulses, 1.
      • Set the DSI Current clamp parameters as follows: Stimulus Delay, 1000 ms; Stimulus current, 1 nA; Pulse duration, 20 ms; Inter-stimulus interval, 2000 ms; and number of pulses, 4.
      • Set the VSI-B Current clamp as follows: Stimulus delay, 0 ms; Stimulus current, 0 nA; Pulse duration, 10000 ms; Inter-stimulus interval, 500 ms; and Number of pulses, 1.
      • Set the number of DRI pulses to 0. Set the duration of the simulation to 10000 ms. Run the simulation.
      • Explain the results you obtain. Again measure the size of the postsynaptic responses in C2 and VSI-B to activity in DSI. How has modulation affected these responses? How could these changes alter the circuit function in comparison to what you observed in part A of the problem? Explain.


  • Question 2. How does the C2 neuron affect the other two neurons in the unmodulated and the modulated states?
    • A. Click the button “Unmodulated Swim Defaults”
      • Set the C2 Current Clamp parameters as follows: Stimulus delay, 5000 ms; Stimulus current, 4 nA; Pulse duration, 20 ms; Inter-stimulus interval, 5000 ms; Number of pulses, 3.
      • Set the DSI Current Clamp parameters as follows: Stimulus delay, 0 ms; Stimulus current, -4 nA; Pulse duration, 20000 ms; Inter-stimulus interval, 500 ms; Number of pulses, 1.
      • Set the VSI-B Current clamp parameters as follows: Stimulus delay, 0 ms; Stimulus current, -4 nA; Pulse duration, 20000; Inter-stimulus interval, 500 ms; Number of pulses, 1.
      • Set the DRI Number of pulses to 0, and set the Total duration to 20000 ms. Run the simulation.
      • What is the effect of the C2 neuron on the other two neurons? Measure the size of the postsynaptic potentials.
    • B. Click the button "Modulated Swim Defaults".
      • Set the C2 Current clamp parameters as follows: Stimulus Delay, 2000 ms; Stimulus current, 4 nA; Pulse duration, 20 ms; Inter-stimulus interval, 1000 ms; and number of pulses, 4.
      • Set the DSI Current clamp parameters as follows: Stimulus Delay, 0 ms; Stimulus current, -3.9 nA; Pulse duration, 10000 ms; Inter-stimulus interval, 5000 ms; and number of pulses, 1.
      • Set the VSI-B Current clamp parameters as follows: Stimulus delay, 0 ms; Stimulus current, -4 nA; Pulse duration, 10000 ms; Inter-stimulus interval, 5000 ms; and Number of pulses, 1.
      • Set the number of DRI pulses to 0. Set the duration of the simulation to 10000 ms. Run the simulation.
      • Measure the size of the PSPs, and compare to the unmodulated PSPs you measured in part A. What is the effect of modulation?
      • How does the response of the DSI neuron differ from the response of the VSI-B neuron to the inputs from C2? Explain.
      • How could these changes alter the circuit function in comparison to what you observed in part A of the problem? Explain.


  • Question 3. How does the VSI-B affect the other two neurons when they are unmodulated or modulated?
    • A. Click the button “Unmodulated Swim Defaults”.
      • Set the C2 Current Clamp parameters as follows: Stimulus delay, 0 ms; Stimulus current, 0 nA; Pulse duration, 0 ms; Inter-stimulus inteval, 0 ms. Number of pulses, 1.
      • Set the DSI Current Clamp parameters as follows: Stimulus delay, 0 ms; Stimulus current, -0.1 nA, Pulse duration, 10000 ms; Inter-stimulus interval, 500 ms, and Number of pulses, 1.
      • Set the VSI-B Current Clamp parameters as follows: Stimulus delay, 2000 ms; Stimulus current, 7 nA; Pulse duration, 20 ms; Inter-stimulus interval, 2000 ms, and Number of pulses, 4.
      • Set the Number of pulses for the DRI to 0. Set the Total duration to 10000 ms. Run the simulation.
      • Measure the postsynaptic potentials that VSI-B induces in C2 and the DSI. How do the responses of these two neurons to VSI-B differ from one another?
    • B. Click the button "Modulated Swim Defaults".
      • Set the C2 Current clamp parameters as follows: Stimulus Delay, 0 ms; Stimulus current, 0 nA; Pulse duration, 0 ms; Inter-stimulus interval, 0 ms; and number of pulses, 1.
      • Set the DSI Current clamp parameters as follows: Stimulus Delay, 500 ms; Stimulus current, -0.03 nA; Pulse duration, 10000 ms; Inter-stimulus interval, 500 ms; and number of pulses, 1.
      • Set the VSI-B Current clamp parameters as follows: Stimulus delay, 2000 ms; Stimulus current, 7 nA; Pulse duration, 20 ms; Inter-stimulus interval, 2000 ms; and Number of pulses, 4.
      • Set the number of DRI pulses to 0. Set the duration of the simulation to 10000 ms. Run the simulation
      • How does the VSI-B affect the other two neurons when they are modulated as compared to unmodulated? How could these changes alter the circuit function in comparison to what you observed in part A of the problem? Explain.


  • Question 4. Now that you have analyzed the synaptic connections in the unmodulated and the modulated network, can you predict how it functions?
    • A. Based on your sketch of the neural circuit from the first Tritonia unit, predict the effects of exciting the DSI neurons on the response of the other neurons, and on the DSI itself. Which neuron will fire immediately after the DSI fires? What neuron is likely to respond more slowly? Once the VSI-B fires, what is likely to happen to the activity in the network? How will modulation affect the interactions within the network? Write down your answers to these questions before doing the experiments in parts B and C of this question.
    • B. Click on the “Unmodulated Swim Defaults” button.
      • Set the DSI Current Clamp Stimulus current to 1 nA, the Pulse duration to 500 ms; set the Number of DRI pulses to 0; set the simulation duration to 10000 ms. Run the simulation. What do you observe? Does this support your hypothesis? Explain.
    • C. Click on the “Modulated Swim Defaults” button.
      • Set the DSI Current Clamp Stimulus current to 1 nA, the Pulse duration to 500 ms; set the Number of DRI pulses to 0; set the simulation duration to 10000 ms. Run the simulation. What do you observe? Does this support your hypothesis? Explain.
      • How do the results that you observe in the modulated network differ from those in the unmodulated network? Explain based on your schematic diagram, and the results you obtained from answering Questions 1, 2, and 3.
      • Is modulation essential for the function of the network? Explain.
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