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.

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.

No description available.

Electrical stimulation of the vagus nerve attenuates tumor necrosis factor (TNF) synthesis by macrophages and reduces the systemic inflammatory response. Current evidence suggests that the α7 nicotinic acetylcholine receptor present in the celiac/superior mesenteric ganglia is a key component in vagus nerve signaling to the spleen; however, there is currently no direct anatomical evidence that the α7 receptor is present in the murine celiac/superior mesenteric ganglia. Our study addresses this deficiency by providing anatomical evidence that the α7 receptor is expressed within the celiac/superior mesenteric ganglia and splenic nerve fibers using immunohistochemistry and quantitative polymerase chain reaction (qPCR). α7 receptor mRNA is highly expressed in the celiac/superior mesenteric ganglia and at low levels in the spleen compared to the brain. Double-labeling for α7 and tyrosine hydroxylase shows that α7 receptor protein is present on noradrenergic neurons within the ganglia and prejunctionally on noradrenergic nerve fibers within the spleen. The α7 receptor in the ganglia provides a possible location for the action of α7-selective agonists, while prejunctional α7 receptor expressed on splenic nerves may induce an increase in norepinephrine release in a positive feedback system enhanced by lymphocyte-derived acetylcholine.

While prolonged nearwork is considered to be an environmental risk factor associated with myopia development, an underlying genetic susceptibility to nearwork-induced accommodative adaptation may be one possible mechanism for human myopia development. As the control of accommodation by the autonomic system may be one such genetically predetermined system, this research sought to investigate whether an anomaly of the autonomic control of accommodation may be responsible for myopia development and progression. The emphasis of this work was determining the effect of altering the sympathetic input to the ciliary muscle on accommodation responses such as tonic accommodation and nearwork-induced accommodative adaptation in myopes and non-myopes. The first study of the thesis was based on observations of Gilmartin and Winfield (1995) which suggested that a deficit in the sympathetic inputs to the ciliary muscle may be associated with a propensity for myopia development. The effect of ß-antagonism with timolol application on accommodation characteristics was studied in different refractive error groups. Our results support the previous findings that a deficit of sympathetic facility during nearwork was not a feature of late-onset myopia. However it was found that classifying myopes according to stability of their myopia and their ethnic background was important and this allowed differentiation between accommodation responses and characteristics of the ciliary muscle autonomic inputs, with the greatest difference observed between Caucasian stable myopes and Asian progressing myopes. Progressing myopes, particularly those with an Asian background, demonstrated enhanced susceptibility to nearwork-induced accommodative adaptation and this was suggested to result from a possible parasympathetic dominance and a relative sympathetic deficit to the ciliary muscle. In contrast, stable myopes, particularly those with an Asian background, demonstrated minimal accommodation changes following nearwork (counter-adaptation in some cases), and increased accommodative adaptation with ß-antagonism, suggesting sympathetic dominance as the possible autonomic accommodation control profile. As ethnic background was found to be an important factor, a similar study was also conducted in a group of Hong Kong Chinese children to investigate if enhanced susceptibility to nearwork-induced changes in accommodation may explain in part the high prevalence of myopia in Hong Kong. Despite some minor differences in methodology between the two studies, the Hong Kong stable myopic children demonstrated counter-adaptive changes and greater accommodative adaptation with timolol, findings that were consistent with those of the adult Asian stable myopes. Both Asian progressing myopic children and adults also showed greater accommodative adaptation than the stable myopes and similar response profiles following ß-adrenergic antagonism. Thus a combination of genetically predetermined accommodation profiles that confer high susceptibility and extreme environmental pressures is a likely explanation for the increase in myopia over the past decades in Asian countries. The hypothesis that a sympathetic deficit is linked to myopia was also investigated by comparing the effect of â-stimulation with salbutamol, a ß-agonist, on accommodation with that of ß-antagonism using timolol. It was hypothesized that salbutamol would have the opposite effect of timolol, and that it would have a greater effect on subjects who demonstrated greater accommodative adaptation effects, i.e. the progressing myopes, compared to those who showed minimal changes in accommodation following nearwork. Consistent with the hypothesis, the effect of sympathetic stimulation with salbutamol application was only evident in the progressing myopes whom we hypothesized may have a parasympathetic dominance and a relative sympathetic deficit type of autonomic imbalance while it did not further enhance the rapid accommodative regression profile demonstrated by the stable myopes. Characteristics of the convergence system and the interaction between accommodation and convergence were also investigated in the Hong Kong children. No significant differences in response AC/A ratios between the emmetropic, stable and progressing myopic children were found and it was concluded that elevated AC/A ratios were not associated with higher myopic progression rate in this sample of Hong Kong children. However, ß-adrenergic antagonism with timolol application produced a greater effect on accommodative convergence (AC) in stable myopic children who presumably have a more adequate, robust sympathetic input to the ciliary muscle, but had little effect on AC of progressing myopic children. This finding again points to the possibility that the autonomic control of the accommodation and convergence systems may be different between stable and progressing myopia. The primary contribution of this study to the understanding of myopia development is that differences in the autonomic control of the ciliary muscle may be responsible for producing anomalous accommodation responses. This could have significant impact on retinal image quality and thus results in myopia development. This knowledge may be incorporated into computer models of accommodation and myopia development and provides scope for further investigation of the therapeutic benefits of autonomic agents for myopia control.

Indiana University-Purdue University Indianapolis (IUPUI) / Autonomic innervation of the heart begins in utero and continues during the neonatal phase of life. A balance between the sympathetic and parasympathetic arms of the autonomic nervous system is required to regulate heart rate as well as the force of each contraction. Our lab studies the development of sympathetic innervation of the early postnatal heart in a conditional knockout (cKO) of Src homology protein tyrosine phosphatase 2 (Shp2). Shp2 is a ubiquitously expressed non-receptor phosphatase involved in a variety of cellular functions including survival, proliferation, and differentiation. We targeted Shp2 in post-migratory neural crest (NC) lineages using our novel Periostin-Cre. This resulted in a fully penetrant mouse model of diminished cardiac sympathetic innervation and concomitant bradycardia that progressively worsen. Shp2 is thought to mediate its basic cellular functions through a plethora of signaling cascades including extracellular signal-regulated kinases (ERK) 1 and 2. We hypothesize that abrogation of downstream ERK1/2 signaling in NC lineages is primarily responsible for the failed sympathetic innervation phenotype observed in our mouse model. Shp2 cKOs are indistinguishable from control littermates at birth and exhibit no gross structural cardiac anomalies; however, in vivo electrocardiogram (ECG) characterization revealed sinus bradycardia that develops as the Shp2 cKO ages. Significantly, 100% of Shp2 cKOs die within 3 weeks after birth. Characterization of the expression pattern of the sympathetic nerve marker tyrosine hydroxylase (TH) revealed a loss of functional sympathetic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Shp2 cKOs exhibit lineage-specific suppression of activated pERK1/2 signaling, but not of other downstream targets of Shp2 such as pAKT (phosphorylated-Protein kinase B). Interestingly, restoration of pERK signaling via lineage-specific expression of constitutively active MEK1 (Mitogen-activated protein kinase kinase1) rescued TH-positive cardiac innervation as well as heart rate. These data suggest that the diminished sympathetic cardiac innervation and the resulting ECG abnormalities are a result of decreased pERK signaling in post-migratory NC lineages.