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Phasic firing in vasopressin cells: understanding its functional significance through computational models.

MacGregor DJ, Leng G - PLoS Comput. Biol. (2012)

Bottom Line: By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input.Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response.These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing.

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Using simulated antidromic spikes to trigger and terminate bursts.The data here uses the model fitted to cell v4, repeated using the same random synaptic input. Antidromic stimulation (as in [21]) is simulated by adding spikes to the model, at a specified frequency and time. In the left column, spikes are added during the silent period, attempting to trigger a burst. In the right column, spikes are added during the second burst, attempting to terminate the burst. Burst triggering is more likely when stimulated later into the silent period, or using a more intense stimulation. Generally, burst termination requires a more intense stimulation than burst triggering. Successful termination is more likely later into the burst, when there is more dynorphin accumulation, or with a more intense stimulation. The competing effects of spike-triggered increases in [Ca2+]i and dynorphin cause a delay before termination occurs, unless the stimulation is sufficiently intense to trigger a large AHP, which immediately terminates spike firing.
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pcbi-1002740-g005: Using simulated antidromic spikes to trigger and terminate bursts.The data here uses the model fitted to cell v4, repeated using the same random synaptic input. Antidromic stimulation (as in [21]) is simulated by adding spikes to the model, at a specified frequency and time. In the left column, spikes are added during the silent period, attempting to trigger a burst. In the right column, spikes are added during the second burst, attempting to terminate the burst. Burst triggering is more likely when stimulated later into the silent period, or using a more intense stimulation. Generally, burst termination requires a more intense stimulation than burst triggering. Successful termination is more likely later into the burst, when there is more dynorphin accumulation, or with a more intense stimulation. The competing effects of spike-triggered increases in [Ca2+]i and dynorphin cause a delay before termination occurs, unless the stimulation is sufficiently intense to trigger a large AHP, which immediately terminates spike firing.

Mentions: In vivo experiments have shown that bursting can be both initiated and terminated by triggering increased spike firing, either by evoking spikes antidromically by electrical stimulation of the axons [4], or by stimulating increased synaptic input [20]. It is an important test of the model to be able to reproduce this, as these effects have clear implications for information coding. Figure 5 shows simulated antidromic spikes in a typical model cell. The model has the advantage that its noisy input activity can be repeated precisely, so that the effects of interventions can be tested against known times of burst initiation and termination. In the model cell illustrated, stimulating at 10 Hz for 0.5 s has no effect early in the silent period, but more intense stimulation (10 Hz for 2 s) or stimulation later in the silent period, causes early burst initiation. Triggering early burst termination requires stronger stimulation than burst initiation, but shows a similar pattern, requiring either a more intense stimulation (20 Hz for 2 s) or stimulation at a later point in the burst. There is still a delay before the burst stops, due to the opposing effects of [Ca2+]i and dynorphin: the activity-induced increase in [Ca2+]i sustains the burst before the longer lasting activity-dependent dynorphin increase causes termination. Such delayed terminations are an experimentally-observed feature of bursts that are truncated by modest stimulation (see Figure 3A of [20]). Applying a very intense stimulation (50 Hz for 2 s) causes a more rapid termination by increasing the AHP sufficiently to block spike firing.


Phasic firing in vasopressin cells: understanding its functional significance through computational models.

MacGregor DJ, Leng G - PLoS Comput. Biol. (2012)

Using simulated antidromic spikes to trigger and terminate bursts.The data here uses the model fitted to cell v4, repeated using the same random synaptic input. Antidromic stimulation (as in [21]) is simulated by adding spikes to the model, at a specified frequency and time. In the left column, spikes are added during the silent period, attempting to trigger a burst. In the right column, spikes are added during the second burst, attempting to terminate the burst. Burst triggering is more likely when stimulated later into the silent period, or using a more intense stimulation. Generally, burst termination requires a more intense stimulation than burst triggering. Successful termination is more likely later into the burst, when there is more dynorphin accumulation, or with a more intense stimulation. The competing effects of spike-triggered increases in [Ca2+]i and dynorphin cause a delay before termination occurs, unless the stimulation is sufficiently intense to trigger a large AHP, which immediately terminates spike firing.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475655&req=5

pcbi-1002740-g005: Using simulated antidromic spikes to trigger and terminate bursts.The data here uses the model fitted to cell v4, repeated using the same random synaptic input. Antidromic stimulation (as in [21]) is simulated by adding spikes to the model, at a specified frequency and time. In the left column, spikes are added during the silent period, attempting to trigger a burst. In the right column, spikes are added during the second burst, attempting to terminate the burst. Burst triggering is more likely when stimulated later into the silent period, or using a more intense stimulation. Generally, burst termination requires a more intense stimulation than burst triggering. Successful termination is more likely later into the burst, when there is more dynorphin accumulation, or with a more intense stimulation. The competing effects of spike-triggered increases in [Ca2+]i and dynorphin cause a delay before termination occurs, unless the stimulation is sufficiently intense to trigger a large AHP, which immediately terminates spike firing.
Mentions: In vivo experiments have shown that bursting can be both initiated and terminated by triggering increased spike firing, either by evoking spikes antidromically by electrical stimulation of the axons [4], or by stimulating increased synaptic input [20]. It is an important test of the model to be able to reproduce this, as these effects have clear implications for information coding. Figure 5 shows simulated antidromic spikes in a typical model cell. The model has the advantage that its noisy input activity can be repeated precisely, so that the effects of interventions can be tested against known times of burst initiation and termination. In the model cell illustrated, stimulating at 10 Hz for 0.5 s has no effect early in the silent period, but more intense stimulation (10 Hz for 2 s) or stimulation later in the silent period, causes early burst initiation. Triggering early burst termination requires stronger stimulation than burst initiation, but shows a similar pattern, requiring either a more intense stimulation (20 Hz for 2 s) or stimulation at a later point in the burst. There is still a delay before the burst stops, due to the opposing effects of [Ca2+]i and dynorphin: the activity-induced increase in [Ca2+]i sustains the burst before the longer lasting activity-dependent dynorphin increase causes termination. Such delayed terminations are an experimentally-observed feature of bursts that are truncated by modest stimulation (see Figure 3A of [20]). Applying a very intense stimulation (50 Hz for 2 s) causes a more rapid termination by increasing the AHP sufficiently to block spike firing.

Bottom Line: By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input.Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response.These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.

ABSTRACT
Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing.

Show MeSH
Related in: MedlinePlus