Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the rat central nervous system, notably in areas involved in control of autonomic and neuroendocrine functions. The aim of this study was to evaluate the effects of CART peptide fragment 55-102, referred to herein as CARTp, by intrathecal injection on blood pressure (BP) and heart rate (HR) before and after intrathecal glutamate in urethane-anesthetized male Sprague-Dawley rats. CARTp (0.1-10 nmol) administered intrathecally caused no or a small, statistically insignificant increase of blood pressure and heart rate, except at the concentration of 10 nmol, which caused a significant increase of blood pressure and heart rate. Intrathecal glutamate (0.1-10 nmol) produced a dose-dependent increase in arterial pressure and heart rate. Pretreatment with CARTp dose-dependently potentiated the pressor effects of glutamate (1 nmol), which by itself elicited a moderate increase of blood pressure and heart rate. Further, CARTp significantly potentiated the tachycardic effect of glutamate at 1 and 5 nmol, but attenuated the response at 10 nmol. The effect of CARTp was long-lasting, as it enhanced glutamatergic responses up to 90 min after administration. Prior injection of CARTp antiserum (1:500) but not normal rabbit serum nullified the potentiating effect of CARTp on glutamatergic responses. The result suggests that CARTp, whose immunoreactivity is detectable in sympathetic preganglionic neurons as well as in fibers projecting into the intermediolateral cell column, augments spinal sympathetic outflow elicited by glutamate at lower concentrations and may directly excite neurons in the intermediolateral cell column at higher concentrations.

Hypertension (HTN) is a critical public health issue estimated to contribute to 10% of deaths worldwide. Additionally, the salt sensitivity of blood pressure, an exaggerated pressor response to elevated dietary sodium intake, is estimated to be present in approximately 50% of the hypertensive population and 25% of the normotensive population. This is a critical problem as the average American consumes roughly three times the daily sodium intake recommended by the American Heart Association. Our laboratory has previously identified a critical role of Hypothalamic Paraventricular Nucleus (PVN) Gαi2 proteins in the maintenance of salt resistance and normotension in the rat. Salt resistant rats such as the Sprague-Dawley (SD) rat site- specifically upregulate these proteins in response to elevated dietary sodium intake to facilitate sympathoinhibition, natriuresis, and normotension. In contrast, in the Dahl Salt Sensitive (DSS) rat, and in salt resistant rats in which this protein is experimentally downregulated, our laboratory has identified the development of renal nerve-dependent sympathoexcitation and salt-sensitive hypertension (ssHTN). However, the neural mechanisms whereby PVN Gαi2 proteins facilitate salt resistance are unclear. In addition, there is a robust literature in other rat models of HTN suggesting that both neuroinflammation in the PVN as well as an imbalance between PVN inhibitory GABAergic and excitatory glutamatergic signaling contribute to elevations in sympathetic outflow to promote HTN. In this study, SD rats infused chronically with either targeted Gαi2 oligodeoxynucleotides (ODNs) or control scrambled (SCR) ODNs and challenged with either normal (0.6% NaCl) or high-salt (4% NaCl) diets were used to demonstrate that 1) PVN microglial activation and associated pro-inflammatory cytokine production contribute to the development of Gαi2 protein dependent ssHTN, 2) sex-dependent PVN microglial-mediated neuroinflammation precedes and likely drives the development of sympathoexcitation following high dietary sodium administration in male but not female Gαi2 protein dependent ssHTN, and 3) PVN GABAergic and glutamatergic signaling is disrupted and imbalanced, favoring excitation over inhibition, following elevated dietary sodium intake in Gαi2 protein dependent ssHTN. Together, these findings shed light on the pathological neural processes that occur in the absence of PVN Gαi2 protein upregulation and reveal potential mechanistic targets in the management of ssHTN.

No description available.

No description available.

No description available.

Central mechanisms involving aldosterone - mineralocorticoid receptor (MR) activation mediate the increase in sympathetic tone after myocardial infarction (MI). We hypothesized that an increase in cardiac sympathetic activity (CSA) post MI facilitates cardiac sympathetic axonal sprouting, and that central MR blockade attenuates CSA and reduces cardiac sympathetic hyperinnervation post MI. Western blotting and qRT-PCR were used to assess protein and gene expression, and fluorescent immunohistochemistry was used to study changes in sympathetic innervation. Tyrosine hydroxylase (TH) and Norepinephrine transporter protein content in the non-infarcted base of the heart remained unaltered. In contrast, protein gene product (PGP 9.5) protein was significantly increased 2 fold in the base of the heart, and 6 fold in the peri-infarct area at 1 wk post MI, and associated with increased ubiquitin expression. Cardiac myocytes rather than sympathetic axons were identified as the main source of elevated PGP 9.5 expression. At the infarct border sympathetic hyperinnervation was observed with a 4 fold increase in growth associated protein 43 (GAP 43), a 2 fold increase in TH and a 50% increase in PGP 9.5 positive fibers when compared to the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone at 5 ug/day for 9 days post MI markedly attenuated the increase in TH, GAP 43 and PGP 9.5 nerve densities at the infarct border. Central MR blockade may attenuate sympathetic hyperinnervation by several mechanisms, including decreasing CSA post MI, or affecting expression or function of nerve growth factor protein. Marked PGP 9.5 expression occurs in cardiomyocytes early post MI, which may contribute to the increase in ubiquitin and the early cardiac remodeling post MI.

Abstract The purpose of this study was to explore the development and course of social phobia by analysing qualitatively all the textual material obtained about the persons with treatment-resistant social phobia who, during the years 1995-2000, underwent a surgical procedure called endoscopic sympathetic block (ESB) to alleviate their phobic symptoms. In the other part of this study, the effect of this surgical procedure on social phobia was assessed quantitatively. The qualitative part of the study was based on the phenomenologic-existential philosophy and the principles of grounded theory. The qualitative analysis revealed four kinds of parenthood in the families of socially phobic persons: a violent, alcoholic type, a dominant type with high demands, a negligent type and a good enough type. A "vicious circle of social phobia" was formulated as a substantial category. The quantitative part of the study was an open, prospective follow-up study, where 169 patients operated on for social phobia during the years 1995–2000 were followed up for 5 years, and the changes in their symptoms were estimated using a modified version of Davidson's brief social phobia scale and the Liebowitz quality of life scale. The quantitative and qualitative parts of the study were linked together by investigating each person's family background with a semi-structured interview. According to variation analysis of the results, all symptoms of social phobia seemed to be alleviated highly significantly by ESB, and the results remained similar throughout the follow-up. Reflex sweating of the trunk was the only significant side effect. Overall satisfaction with the operation was estimated to be 3.5 on a five-point scale, representing the description "some help of the operation". Thus, ESB can be regarded as an additional treatment method for social phobia if traditional treatment with medication and psychotherapy has not provided any help for the patient.

Central mechanisms involving aldosterone - mineralocorticoid receptor (MR) activation mediate the increase in sympathetic tone after myocardial infarction (MI). We hypothesized that an increase in cardiac sympathetic activity (CSA) post MI facilitates cardiac sympathetic axonal sprouting, and that central MR blockade attenuates CSA and reduces cardiac sympathetic hyperinnervation post MI. Western blotting and qRT-PCR were used to assess protein and gene expression, and fluorescent immunohistochemistry was used to study changes in sympathetic innervation. Tyrosine hydroxylase (TH) and Norepinephrine transporter protein content in the non-infarcted base of the heart remained unaltered. In contrast, protein gene product (PGP 9.5) protein was significantly increased 2 fold in the base of the heart, and 6 fold in the peri-infarct area at 1 wk post MI, and associated with increased ubiquitin expression. Cardiac myocytes rather than sympathetic axons were identified as the main source of elevated PGP 9.5 expression. At the infarct border sympathetic hyperinnervation was observed with a 4 fold increase in growth associated protein 43 (GAP 43), a 2 fold increase in TH and a 50% increase in PGP 9.5 positive fibers when compared to the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone at 5 ug/day for 9 days post MI markedly attenuated the increase in TH, GAP 43 and PGP 9.5 nerve densities at the infarct border. Central MR blockade may attenuate sympathetic hyperinnervation by several mechanisms, including decreasing CSA post MI, or affecting expression or function of nerve growth factor protein. Marked PGP 9.5 expression occurs in cardiomyocytes early post MI, which may contribute to the increase in ubiquitin and the early cardiac remodeling post MI.

The physiological significance of noradrenergic sympathohabenular ingrowth following medial septal lesions was investigated. Following septal lesions, sympathetic fibers originating in the superior cervical ganglia are known to sprout into the medial habenular nuclei, and into the hippocampal formation. Previous work involving sympathohippocampal ingrowth showed that firing rates in septal animals with no ingrowth showed that firing rates in septal animals with no ingrowth were higher than rates of septal animals with ingrowth and controls. Those results suggested that sympathetic ingrowth in the hippocampus had some functional capability in a modulatory manner. The primary aim of the present study was to determine if the peripheral sympathetic ingrowth into the medial habenular nuclei following a septal lesion is functionally significant. The results showed that firing rates of neurons of the medial habenulae in animals receiving septal lesions were significantly higher than rates of control animals and septal lesioned + ganglionectomized animals.

The central nervous system is largely responsible for receiving sensory information from the environment and determining motor output. Yet, centrally-derived behavior and sensation depends on the optimal maintenance of the cells, tissues, and organs that feed and support these functions. Most of visceral regulation occurs without conscious oversight, making the spinal cord a key site for integration and control. How the spinal cord modulates output to our organs, or sensory information from them, is poorly understood. The overall aim of this dissertation was to better understand spinal processing of both visceral sensory information to and sympathetic output from the spinal cord. I first established and validated a HB9-GFP transgenic mouse model that unambiguously identified sympathetic preganglionic neurons (SPNs), the spinal output neurons for the sympathetic nervous system. Using this model, I investigated the electrophysiological similarities and diversity of SPNs, and compared their active and passive membrane properties to those in other animal models. My results indicate that while many of the same characteristics are shared, SPNs are a heterogeneous group that can be differentiated based on their electrophysiological properties. Since descending monoaminergic pathways have particularly dense projections to sympathetic regions of the spinal cord, I next examined the modulatory role that the monoamines have on spinal sympathetic output. While each neuromodulator tested had a unique signature of action, serotonin and norepinephrine appeared to increase the excitability of individual SPNs, while dopamine had more mixed actions. Since many autonomic reflexes are integrated by the spinal cord, I also questioned whether these reflexes would be similarly modulated. I therefore developed a novel in vitro spinal cord and sympathetic chain preparation, which allowed for the investigation of visceral afferent-mediated reflexes and their neuromodulation by monoamines. This preparation exposed a dichotomy of action, where sympathetic and somatic motor output is generally enhanced by the monoamines, but reflexes mediated by visceral input are depressed. Utilizing the spinal cord and sympathetic chain preparation, I also investigated how the spinal cord modulates visceral sensory information. One of the most powerful means of selectively inhibiting afferent information from reaching the spinal cord is presynaptic inhibition. I hypothesized that both spinal visceral afferents and descending monoaminergic systems would depress transmission of visceral afferents to the spinal cord. My results demonstrated that activity in spinal visceral afferents can lead to spinally generated presynaptic inhibition, and that in addition to depressing synaptic transmission to the spinal cord, the monoamines also depress the intrinsic circuitry that generates this activity-dependent presynaptic inhibition. Taken together, my results indicate that descending monoaminergic pathways act to limit the amount of visceral sensory information reaching the central nervous system and increase sympathetic output, resulting in an uncoupling of output from visceral sensory input and transitioning to a feed-forward, sympathetically dominant control strategy. This combination offers complex modulatory strategies for descending systems.