|Title:||Acetylcholine in Central Cardiorespiratory Regulation in Health and Depression|
|Publisher:||University of Sydney.|
Faculty of Medicine.
|Abstract:||Circulation and breathing movements that are essential for life are regulated by neurons in the hypothalamus and lower brainstem. Activity of these neurons is regulated by peripheral afferent and higher order inputs that release a diverse array of amino acids, amines and peptides. In this thesis we investigated the role of the neurotransmitter acetylcholine (ACh) and its receptors in regulation of cardiorespiratory homeostasis. Secondly, we determined whether or not genetic disturbances in regulation of acetylcholine receptor sensitivity affect central control of circulation, body temperature or respiration. The findings presented in Chapter 3 reveal a novel functional role of ACh and G-protein coupled muscarinic receptor (mAChR) activation in the rostral ventrolateral medulla (RVLM). We showed for the first time that some non-C1 RVLM neurons express mRNA for the M2 or M3 receptor; however, both C1 and enkephalinergic RVLM neurons were closely apposed by c holinergic terminals positive for the vesicular acetylcholine transporter (vAChT). Physiological studies demonstrated that activation of mAChR within the RVLM in anaesthetised rats increases arterial pressure and sympathetic nerve activity and has differential effects on major cardiorespiratory reflexes: RVLM mAChR activation resets the sympathetic baroreflex to higher arterial pressures and increases its gain and, concomitantly, attenuates excitatory reflexes evoked by peripheral chemoreceptor or somatic afferent stimulation. Retrograde tracing from the RVLM combined with vAChT immunoreactivity showed that neurons in the pedunculopontine tegmental nucleus (PPT) are the sole source of cholinergic input to the RVLM. The PPT-RVLM pathway appears to be part of a central command circuit concerned with adjusting circulatory function appropriate to increased muscle activity. These data support the notion that activation of specific neurotransmitter receptors in the RVLM encodes fu nctional specificity in control of sympathetic outflow and r! eflex fu nction. The extent to which genetic variations in central mAChR sensitivity influence autonomic function is unknown. Flinders Sensitive Line (FSL) rats were bred from Sprague Dawley (SD) rats for exaggerated behavioural and hypothermic responses to cholinesterase inhibitors and direct-acting mAChR agonists. A control genetic counterpart, the Flinders Resistant Line (FRL), was also bred in parallel for reduced responses to cholinergic agonists. The findings of Chapter 5 showed for the first time that FSL rats exhibit an increase in M2 and reduction in M3 receptor expression in the rostral medulla, suggesting that cholinergic signalling in this region may be altered. However, alterations of mAChR expression specific to FSL rats were restricted to this area and there were no changes in cerebellar expression of mAChR in any strain. Physiological studies showed that conscious or anaesthetised FSL rats were more sensitive to thermoregulatory responses to central mAChR a ctivation (ie hypothermia and increase in cutaneous blood flow); whereas pressor responses were reduced compared to SD and FRL rats. The increase in sympathetic activity and depression of respiration evoked by central mAChR activation was unchanged and attenuated, respectively, in FSL rats compared to control strains. These findings indicate that mAChR involved in control of different autonomic functions are regulated independently at the genetic and / or post-transcriptional level. The findings of Chapters 4 and 6 reveal a novel effect of breeding for cholinergic hypersensitivity in FSL rats on control of vagal and sympathetic outflow. Spectral analysis of blood pressure recordings in conscious FSL rats showed a reduction in total and high frequency power of heart rate variability (HRV), an increase in the LF/HF ratio and reduction in baroreflex sensitivity (BRS) compared to controls. These changes reflect a reduction in reflex vagal input and relative predominan ce of sympathetic input to the sinus node in FSL rats. Under! urethan e anaesthesia, FSL rats had a higher heart rate and exhibited lower gain of baroreflex control of splanchnic sympathetic nerve activity (SNA). Moreover, FSL rats were more susceptible to ventricular arrhythmias during infusion of the cardiac glycoside ouabain under anaesthesia compared to controls. These data indicate that FSL rats exhibit impaired reflex regulation of vagal and sympathetic outflow that could underlie increased vulnerability to arrhythmia seen in this strain. The precise brain regions and neurotransmitters that underlie autonomic disturbances seen in FSL rats are unclear. As well as muscarinic hypersensitivity, FSL rats also exhibit increased sensitivity to nicotine, serotonin and dopamine. Multiple chemical sensitivities in FSL rats may arise from functional interactions with mAChR or changes in common intracellular regulatory or signalling pathways. FSL rats exhibit a number of behavioural and somatic abnormalities consistent with clinical depre ssion, including reduced motivated behaviour and sleep and psychomotor disturbances. These symptoms are also alleviated by treatment with antidepressants, suggesting that similar neurochemical abnormalities may underlie behavioural disturbances seen in FSL rats and human depression. Symptoms of depression are an emerging risk factor in the development of cardiovascular disease and are associated with increased risk of dying from a cardiac-related event. A reduction in HRV and BRS in depressed patients has been widely reported and is considered to be a key substrate predisposing to arrhythmia in this patient group. In this thesis we demonstrate for the first time that FSL rats exhibit similar autonomic abnormalities to those reported in human depression and are more vulnerable to ouabain-induced ventricular arrhythmias. These findings suggest that biological factors predisposing to autonomic dysfunction and arrhythmia in FSL rats could also operate in human depression. This m ay involve altered neurotransmission in cardiovascular brain! regions , or inappropriate regulation of cardiovascular function by arousal or motor control pathways. Overall, this thesis provides novel insights into cholinergic mechanisms that regulate cardiorespiratory homeostasis. ACh is important in physiological regulation of circulation via activation of G-protein coupled mAChR in the RVLM. Selective breeding for cholinergic hypersensitivity in FSL and FRL rats results in region- and subtype-specific changes in mAChR expression in the lower brainstem and differentially influences muscarinic control of circulation and breathing. Variations in central mAChR sensitivity may contribute to impaired reflex control of vagal and sympathetic outflow and could hence predispose to cardiac complications including arrhythmias. Future studies may aim to further understand the relationship between endogenous sensitivity of metabotropic neurotransmitter receptors in the CNS and cardiovascular disturbances associated with depression.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (Open Access)|
|James_Padley_Thesis_2007.pdf||22.75 MB||Adobe PDF|
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