Springer, Mitchell
(2013)
Modulation of Synaptic Amplification in Sympathetic Ganglia.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The purpose of this dissertation was to assess synaptic integration in neurons from the rat superior cervical ganglion (SCG) using complex temporal patterns of virtual synaptic activity that mimic in vivo conditions. The SCG is a paravertebral ganglion that innervates different targets in the head. One of its important roles is to regulate vascular tone. Previous reports have concluded that SCG neurons behave as simple relays between preganglionic synaptic activity from the spinal cord and postganglionic control of end organs. We have tested the hypotheses that (1) postganglionic convergence of strong and weak nicotinic synapses produces variable synaptic amplification in SCG neurons; (2) entrainment of preganglionic activity to the cardiac cycle through arterial baroreceptors increases synaptic gain; (3) the contribution of weak nicotinic synapses to postganglionic integration has been underestimated in vivo due to membrane damage caused by sharp microelectrodes; and (4) angiotensin II (AngII) acts postsynaptically to increase ganglionic synaptic amplification.
The approach to creating virtual synapses relied on dynamic clamp. Using whole-cell recordings of SCG neurons in short-term cultures, we found evidence for activity dependent synaptic gain and for the enhancement of gain by cardiac entrainment. Based on this approach, a computational model was developed to simulate human data – this showed that the statistics of human firing patterns could be accounted for by a model that includes secondary synapses and synaptic amplification. Cellular damage was simulated with dynamic clamp by implementing a non-depolarizing shunt conductance. This revealed that damage introduced by microelectrode recordings transformed the intrinsic firing properties of sympathetic neurons and obscured the contribution of weak nicotinic synapses to synaptic gain. Finally, G-protein coupled receptors for AngII increased postganglionic excitability, which facilitated the integration of weak synaptic activity and enhanced synaptic gain.
These results have implications for understanding human blood pressure regulation during exercise and hypertension. Until now, the SCG had been discounted as a regulator of blood pressure. Data in this thesis supports an integrative role for synaptic convergence in sympathetic ganglia and the modulation of gain by AngII. These results suggest that future efforts to control blood pressure and treat hypertension could target ganglionic mechanisms.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
19 July 2013 |
| Date Type: |
Publication |
| Defense Date: |
12 July 2013 |
| Approval Date: |
19 July 2013 |
| Submission Date: |
16 July 2013 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
145 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Superior Cervical Ganglion, Dynamic Clamp, Angiotensin II, Sympathetic Motor System, Synaptic Gain, Cardiac Rhythmicity |
| Date Deposited: |
19 Jul 2013 17:13 |
| Last Modified: |
15 Nov 2016 14:14 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/19339 |
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