A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease
<p>Hypertension represents a major health burden in both the developed and developing world. A significant component of hypertension is abnormal activation of the sympathetic nervous system, which is associated with a wide spectrum of serious co-morbidities. However, the molecular mechanisms b...
| Main Author: | |
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2021
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| Subjects: |
| _version_ | 1826314428791914496 |
|---|---|
| author | Davis, H |
| author2 | Paterson, D |
| author_facet | Paterson, D Davis, H |
| author_sort | Davis, H |
| collection | OXFORD |
| description | <p>Hypertension represents a major health burden in both the developed and
developing world. A significant component of hypertension is abnormal activation of
the sympathetic nervous system, which is associated with a wide spectrum of
serious co-morbidities. However, the molecular mechanisms behind this are poorly
understood, as are the biophysical properties underlying heightened cardiac
sympathetic activity in the prehypertensive state. This thesis utilised large-scale
transcriptomics, combined with patch-clamp electrophysiology and live-cell imaging
to investigate the molecular mechanisms behind the sympathetic hyperactivity
observed in hypertension.</p>
<p><b>Chapter 1</b> introduces the sympathetic nervous system in the context of arterial
blood pressure control. This chapter also introduces hypertension, the
contemporary pharmacopeia of hypertensive treatments and sympathetic
dysfunction in hypertension. Finally, ion channel biophysics is covered here to
enable further discussion.</p>
<p><b>Chapter 2</b> explains the methodologies used in the following data chapters.
Particular focus is given to whole-cell and perforated patch-clamp electrophysiology
which feature heavily throughout this thesis. The results provided a target discovery
framework for subsequent chapters.</p>
<p><b>Chapter 3</b> provides single-cell and bulk RNA-sequencing datasets describing the
transcriptomic profile of the cardiac innervating stellate ganglia from normotensive
and spontaneously hypertensive rats. This chapter also discusses the methodology
behind RNA-sequencing analysis.</p>
<p><b>Chapter 4</b>, with supporting data from chapter 3, highlighted a downregulation in Mcurrent subunit encoding KCNQ5 in stellate ganglia neurons from prehypertensive
rats. This chapter demonstrated that the decrease in KCNQ5 transcript expression
led to a functional decrease in M-Current, with the conclusion that it is likely to cause
the electrical hyperactivity observed in prehypertensive stellate ganglia neurons.
Further, these data suggested that selective inhibition of several Nav subunits was
sufficient to restore a normotensive electrical phenotype in prehypertensive
neurons.</p>
<p><b>Chapter 5</b> demonstrated that sympathetic stellate ganglia neurons could sense Na<sup>+</sup>
with a similar potency to central sodium sensing regions in the brain. This argued
that this may have important implications for the correlation between Na<sup>+</sup> sensitivity
and blood pressure control.</p>
<p><b>Chapter 6</b> investigated the ability for sympathetic stellate ganglia neurons to
respond to sensory signals via transient receptor potential channels or via G-protein
coupled receptors. These data revealed functional TRPV2 signalling in stellate
ganglia neurons, although they did not produce robust responses to any of the
inflammatory transmitters. Finally, this chapter investigated the ability for
cardiomyocytes to communicate with sympathetic neurons via retrograde signalling.
This study identified that prehypertensive neurons co-cultured with normotensive
cardiomyocytes exhibited a phenotype similar to that in normotensive neurons.</p>
<p><b>Chapter 7</b> is a concluding discussion which places these results into a physiological
context and suggests new molecular and intercellular mechanisms for the targeting
of the stellate ganglia neurons in states of sympathetic dysautonomia.</p> |
| first_indexed | 2024-03-07T03:16:48Z |
| format | Thesis |
| id | oxford-uuid:b60dcebe-eecc-40aa-ba41-54f9e33c608b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:32:22Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:b60dcebe-eecc-40aa-ba41-54f9e33c608b2024-08-29T07:46:24ZA transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and diseaseThesishttp://purl.org/coar/resource_type/c_db06uuid:b60dcebe-eecc-40aa-ba41-54f9e33c608bHypertensionSympathetic nervous systemPhysiology, ExperimentalElectrophysiologyPatch-clamp techniques (Electrophysiology)EnglishHyrax Deposit2021Davis, HPaterson, DHerring, N<p>Hypertension represents a major health burden in both the developed and developing world. A significant component of hypertension is abnormal activation of the sympathetic nervous system, which is associated with a wide spectrum of serious co-morbidities. However, the molecular mechanisms behind this are poorly understood, as are the biophysical properties underlying heightened cardiac sympathetic activity in the prehypertensive state. This thesis utilised large-scale transcriptomics, combined with patch-clamp electrophysiology and live-cell imaging to investigate the molecular mechanisms behind the sympathetic hyperactivity observed in hypertension.</p> <p><b>Chapter 1</b> introduces the sympathetic nervous system in the context of arterial blood pressure control. This chapter also introduces hypertension, the contemporary pharmacopeia of hypertensive treatments and sympathetic dysfunction in hypertension. Finally, ion channel biophysics is covered here to enable further discussion.</p> <p><b>Chapter 2</b> explains the methodologies used in the following data chapters. Particular focus is given to whole-cell and perforated patch-clamp electrophysiology which feature heavily throughout this thesis. The results provided a target discovery framework for subsequent chapters.</p> <p><b>Chapter 3</b> provides single-cell and bulk RNA-sequencing datasets describing the transcriptomic profile of the cardiac innervating stellate ganglia from normotensive and spontaneously hypertensive rats. This chapter also discusses the methodology behind RNA-sequencing analysis.</p> <p><b>Chapter 4</b>, with supporting data from chapter 3, highlighted a downregulation in Mcurrent subunit encoding KCNQ5 in stellate ganglia neurons from prehypertensive rats. This chapter demonstrated that the decrease in KCNQ5 transcript expression led to a functional decrease in M-Current, with the conclusion that it is likely to cause the electrical hyperactivity observed in prehypertensive stellate ganglia neurons. Further, these data suggested that selective inhibition of several Nav subunits was sufficient to restore a normotensive electrical phenotype in prehypertensive neurons.</p> <p><b>Chapter 5</b> demonstrated that sympathetic stellate ganglia neurons could sense Na<sup>+</sup> with a similar potency to central sodium sensing regions in the brain. This argued that this may have important implications for the correlation between Na<sup>+</sup> sensitivity and blood pressure control.</p> <p><b>Chapter 6</b> investigated the ability for sympathetic stellate ganglia neurons to respond to sensory signals via transient receptor potential channels or via G-protein coupled receptors. These data revealed functional TRPV2 signalling in stellate ganglia neurons, although they did not produce robust responses to any of the inflammatory transmitters. Finally, this chapter investigated the ability for cardiomyocytes to communicate with sympathetic neurons via retrograde signalling. This study identified that prehypertensive neurons co-cultured with normotensive cardiomyocytes exhibited a phenotype similar to that in normotensive neurons.</p> <p><b>Chapter 7</b> is a concluding discussion which places these results into a physiological context and suggests new molecular and intercellular mechanisms for the targeting of the stellate ganglia neurons in states of sympathetic dysautonomia.</p> |
| spellingShingle | Hypertension Sympathetic nervous system Physiology, Experimental Electrophysiology Patch-clamp techniques (Electrophysiology) Davis, H A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| title | A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| title_full | A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| title_fullStr | A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| title_full_unstemmed | A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| title_short | A transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| title_sort | transcriptomic and electrophysiological characterisation of the rat stellate ganglia in health and disease |
| topic | Hypertension Sympathetic nervous system Physiology, Experimental Electrophysiology Patch-clamp techniques (Electrophysiology) |
| work_keys_str_mv | AT davish atranscriptomicandelectrophysiologicalcharacterisationoftheratstellategangliainhealthanddisease AT davish transcriptomicandelectrophysiologicalcharacterisationoftheratstellategangliainhealthanddisease |