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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 the model to simulate the effect of hypertonic saline injection.An injection of hypertonic saline causes a rapid increase in osmotic pressure. The rapid increase in input causes some initially slow firing vasopressin cells to shift immediately to fast continuous firing before settling in a phasic pattern after a long delay (∼10 min) [26]. We hypothesise that this is due to insufficient availability of dendritic dynorphin, which takes time to upregulate. We tested this using an extension to the basic model and were able to reproduce the effect observed in vivo. Osmotic pressure was initially set at 295 and increased to 315 by injection at 5 min. We suggest that releasable dynorphin store upregulation is dependent on a slow activity-dependent vesicle transport mechanism, T. The extended dynorphin mechanism uses parameters kT = 0.00001, λT = 500000, kDstore = 0.02, λDstore = 1000000, Dspike = 0.1, Dstorecap = 10, and τO = 200000.
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pcbi-1002740-g007: Using the model to simulate the effect of hypertonic saline injection.An injection of hypertonic saline causes a rapid increase in osmotic pressure. The rapid increase in input causes some initially slow firing vasopressin cells to shift immediately to fast continuous firing before settling in a phasic pattern after a long delay (∼10 min) [26]. We hypothesise that this is due to insufficient availability of dendritic dynorphin, which takes time to upregulate. We tested this using an extension to the basic model and were able to reproduce the effect observed in vivo. Osmotic pressure was initially set at 295 and increased to 315 by injection at 5 min. We suggest that releasable dynorphin store upregulation is dependent on a slow activity-dependent vesicle transport mechanism, T. The extended dynorphin mechanism uses parameters kT = 0.00001, λT = 500000, kDstore = 0.02, λDstore = 1000000, Dspike = 0.1, Dstorecap = 10, and τO = 200000.

Mentions: We simulated the delayed effect of hypertonic saline injection on the rise in osmotic pressure, but could not reproduce these experimental results with our basic model. However, the pool of readily-releasable vesicles in the dendrites of magnocellular neurones is labile, and regulated in an activity-dependent manner. We therefore hypothesised that, in the absence of activity-dependent replenishment of the readily releasable pool, the initial lack of burst termination might be due to insufficient readily releasable stores of dynorphin. Out first attempt at modelling this used a simple mechanism where spike-triggered dynorphin release was directly dependent on a dynorphin store charged by spike activity. However this resulted in shorter, not longer, bursts as input activity increased, and so we developed a more complex mechanism where spike triggered dynorphin release is partially decoupled from the dynamics of the releasable dynorphin store, and using this mechanism we were able to reproduce the initial period of continuous firing before onset of phasic firing (Figure 7). In this mechanism, a slowly accumulating measure of spike activity (T, hypothesised to represent slow activity-driven vesicle translocation) determines the rate at which the readily releasable pool of dynorphin is replenished. While T is too low, the release decoupling element (r in eqn. 12 and 13) makes some spikes fail to trigger dynorphin release, slowing the increase in dynorphin while store replenishment is too slow to keep up with the spike rate. This results in a gradual increase in the amount of dynorphin available for activity-dependent release until it reaches an equilibrium with activity-dependent depletion, at which point it is sufficient to sustain phasic firing.


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

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

Using the model to simulate the effect of hypertonic saline injection.An injection of hypertonic saline causes a rapid increase in osmotic pressure. The rapid increase in input causes some initially slow firing vasopressin cells to shift immediately to fast continuous firing before settling in a phasic pattern after a long delay (∼10 min) [26]. We hypothesise that this is due to insufficient availability of dendritic dynorphin, which takes time to upregulate. We tested this using an extension to the basic model and were able to reproduce the effect observed in vivo. Osmotic pressure was initially set at 295 and increased to 315 by injection at 5 min. We suggest that releasable dynorphin store upregulation is dependent on a slow activity-dependent vesicle transport mechanism, T. The extended dynorphin mechanism uses parameters kT = 0.00001, λT = 500000, kDstore = 0.02, λDstore = 1000000, Dspike = 0.1, Dstorecap = 10, and τO = 200000.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475655&req=5

pcbi-1002740-g007: Using the model to simulate the effect of hypertonic saline injection.An injection of hypertonic saline causes a rapid increase in osmotic pressure. The rapid increase in input causes some initially slow firing vasopressin cells to shift immediately to fast continuous firing before settling in a phasic pattern after a long delay (∼10 min) [26]. We hypothesise that this is due to insufficient availability of dendritic dynorphin, which takes time to upregulate. We tested this using an extension to the basic model and were able to reproduce the effect observed in vivo. Osmotic pressure was initially set at 295 and increased to 315 by injection at 5 min. We suggest that releasable dynorphin store upregulation is dependent on a slow activity-dependent vesicle transport mechanism, T. The extended dynorphin mechanism uses parameters kT = 0.00001, λT = 500000, kDstore = 0.02, λDstore = 1000000, Dspike = 0.1, Dstorecap = 10, and τO = 200000.
Mentions: We simulated the delayed effect of hypertonic saline injection on the rise in osmotic pressure, but could not reproduce these experimental results with our basic model. However, the pool of readily-releasable vesicles in the dendrites of magnocellular neurones is labile, and regulated in an activity-dependent manner. We therefore hypothesised that, in the absence of activity-dependent replenishment of the readily releasable pool, the initial lack of burst termination might be due to insufficient readily releasable stores of dynorphin. Out first attempt at modelling this used a simple mechanism where spike-triggered dynorphin release was directly dependent on a dynorphin store charged by spike activity. However this resulted in shorter, not longer, bursts as input activity increased, and so we developed a more complex mechanism where spike triggered dynorphin release is partially decoupled from the dynamics of the releasable dynorphin store, and using this mechanism we were able to reproduce the initial period of continuous firing before onset of phasic firing (Figure 7). In this mechanism, a slowly accumulating measure of spike activity (T, hypothesised to represent slow activity-driven vesicle translocation) determines the rate at which the readily releasable pool of dynorphin is replenished. While T is too low, the release decoupling element (r in eqn. 12 and 13) makes some spikes fail to trigger dynorphin release, slowing the increase in dynorphin while store replenishment is too slow to keep up with the spike rate. This results in a gradual increase in the amount of dynorphin available for activity-dependent release until it reaches an equilibrium with activity-dependent depletion, at which point it is sufficient to sustain phasic 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