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Background: Limited treatment options exist for damaged nerves and despite impressive advances in tissue engineering, scientists and clinicians have yet to fully replicate nerve development and recruitment. Innervation is a critical feature for normal organ function. While most organs are innervated prior to birth, a rare example of postnatal nerve recruitment occurs in the natural development of secondary teeth during adolescence. Many animals undergo postnatal shedding of deciduous teeth with development and eruption of secondary teeth, a process requiring recruitment of nerve and vasculature to each tooth pulp for viability. Here, the investigators created a novel model for the study of postnatal innervation by exploiting the natural phenomenon of tooth-driven nerve recruitment., Methods: The investigators theorized that developing teeth possess a special capacity to induce innervation which could be harnessed in a clinical setting for nerve regeneration, and hyptothesized that a transplant model could be created to capture this phenomenon. In this descriptive study, a rat model of autologous tooth transplantation and de novo nerve recruitment was developed by surgically transferring whole developing molars to the autologous tibia., Results: Downstream histological analysis performed 6 to 14 weeks after surgery demonstrated integration of molar into tibia in 81% of postoperative rats, with progressive pulpal expression of nerve marker ß-tubulin III suggestive of neuronal recruitment., Conclusions: These findings provide a novel model for the study of organ transplantation and support the theory that developing dental tissues may retain nerve-inductive properties postnatally., (© 2024. The Author(s).)

Increased sugar intake and taste dysfunction have been reported in patients with inflammatory bowel disease (IBD), a chronic disorder characterized by diarrhea, pain, weight loss and fatigue. It was previously unknown whether taste function changes in mouse models of IBD. Mice consumed dextran sodium sulfate (DSS) during three 7-day cycles to induce chronic colitis. DSS-treated mice displayed signs of disease, including significant weight loss, diarrhea, loss of colon architecture, and inflammation of the colon. After the last DSS cycle we assessed taste function by recording electrophysiological responses from the chorda tympani (CT) nerve, which transmits activity from lingual taste buds to the brain. DSS treatment significantly reduced neural taste responses to natural and artificial sweeteners. Responses to carbohydrate, salt, sour or bitter tastants were unaffected in mice with colitis, but umami responses were modestly elevated. DSS treatment modulated the expression of receptor subunits that transduce sweet and umami stimuli in oral taste buds as a substrate for functional changes. Dysregulated systemic cytokine responses or dysbiosis that occurs during chronic colitis may be upstream from changes in oral taste buds. We demonstrate for the first time that colitis alters taste input to the brain, which could exacerbate malnutrition in IBD patients., (© 2023. The Author(s).)

Taste receptor cells are sensory specialists that detect chemicals in food and drink. An exciting new report in PLOS Biology suggests that some taste cells could also be involved in immune surveillance like counterparts in the intestine., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Heisey, McCluskey. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: As the coronavirus disease 2019 (COVID-19) pandemic continues, there has been a growing interest in the chronic sequelae of COVID-19. Neuropsychiatric symptoms are observed in the acute phase of infection, but there is a need for accurate characterization of how these symptoms evolve over time. Additionally, African American populations have been disproportionately affected by the COVID-19 pandemic. The COVID-19 Neurological and Molecular Prospective Cohort Study in Georgia (CONGA) was established to investigate the severity and chronicity of these neurologic findings over the five-year period following infection., Methods: The CONGA study aims to recruit COVID-19 positive adult patients in Georgia, United States from both the inpatient and outpatient setting, with 50% being African American. This paper reports our preliminary results from the baseline visits of the first 200 patients recruited who were on average 125 days since having a positive COVID-19 test. The demographics, self-reported symptoms, comorbidities, and quantitative measures of depression, anxiety, smell, taste, and cognition were analyzed. Cognitive measures were compared to demographically matched controls. Blood and mononuclear cells were drawn and stored for future analysis., Results: Fatigue was the most reported symptom in the study cohort (68.5%). Thirty percent of participants demonstrated hyposmia and 30% of participants demonstrated hypogeusia. Self-reported neurologic dysfunction did not correlate with dysfunction on quantitative neurologic testing. Additionally, self-reported symptoms and comorbidities were associated with depression and anxiety. The study cohort performed worse on cognitive measures compared to demographically matched controls, and African American patients scored lower compared to non-Hispanic White patients on all quantitative cognitive testing., Conclusion: Our results support the growing evidence that there are chronic neuropsychiatric symptoms following COVID-19 infection. Our results suggest that self-reported neurologic symptoms do not appear to correlate with associated quantitative dysfunction, emphasizing the importance of quantitative measurements in the complete assessment of deficits. Self-reported symptoms are associated with depression and anxiety. COVID-19 infection appears to be associated with worse performance on cognitive measures, though the disparity in score between African American patients and non-Hispanic White patients is likely largely due to psychosocial, physical health, and socioeconomic factors., Competing Interests: D.C.H. receives funding from the National Institute of Neurological Disorders and Stroke (NIH/NINDS R01NS112511-01A1S1 (Hess, D)). The remaining authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work in this paper. David Hess reports financial support was provided by 10.13039/100000065National Institute of Neurological Disorders and Stroke. David Hess reports financial support was provided by TR Reddy Family Fund., (© 2022 The Authors.)

Sensory cells that specialize in transducing olfactory and gustatory stimuli are renewed throughout life and can regenerate after injury unlike their counterparts in the mammalian retina and auditory epithelium. This uncommon capacity for regeneration offers an opportunity to understand mechanisms that promote the recovery of sensory function after taste and smell loss. Immune responses appear to influence degeneration and later regeneration of olfactory sensory neurons and taste receptor cells. Here we review surgical, chemical, and inflammatory injury models and evidence that immune responses promote or deter chemosensory cell regeneration. Macrophage and neutrophil responses to chemosensory receptor injury have been the most widely studied without consensus on their net effects on regeneration. We discuss possible technical and biological reasons for the discrepancy, such as the difference between peripheral and central structures, and suggest directions for progress in understanding immune regulation of chemosensory regeneration. Our mechanistic understanding of immune-chemosensory cell interactions must be expanded before therapies can be developed for recovering the sensation of taste and smell after head injury from traumatic nerve damage and infection. Chemosensory loss leads to decreased quality of life, depression, nutritional challenges, and exposure to environmental dangers highlighting the need for further studies in this area., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is strong evidence for gut-taste bud interactions that influence taste function, behavior and feeding. However, the effect of gut inflammation on this axis is unknown despite reports of taste changes in gastrointestinal (GI) inflammatory conditions. Lipopolysaccharide (LPS), an inflammatory stimulus derived from gram-negative bacteria, is present in the normal GI tract and levels increase during high-fat feeding and gut infection and inflammation. Recordings from the chorda tympani nerve (CT), which transmits taste information from taste buds on the anterior tongue to the brain, previously revealed a transient decrease in sucrose responses in mice that ingest LPS during a single overnight period. Here we test the effect of acute or chronic, weekly LPS gavage on licking behavior and CT responses. Using brief-access testing, rats treated with acute LPS and mice receiving acute or chronic LPS decreased licking responses to sucrose and saccharin and to NaCl in mice. In long-term (23 h) tests chronic LPS also reduced licking responses to saccharin, sucrose, and NaCl in mice. Neurophysiological recordings from the CT supported behavioral changes, demonstrating reduced responses to sucrose, saccharin, acesulfame potassium, glucose and NaCl in acute and chronic LPS groups compared to controls. Chronic LPS significantly elevated neutrophils in the small intestine and colon, but LPS was not detected in serum and mice did not display sickness behavior or lose weight. These results indicate that sweet and salt taste sensitivity could be reduced even in asymptomatic or mild localized gut inflammatory conditions such as inflammatory bowel disease.

Sugar-sweetened beverages are the major source of added calories in the Western diet and their prevalence is associated with obesity and metabolic disruption. Despite the critical role of the taste system in determining food selection and consumption, the effects of chronic sucrose consumption on the peripheral taste system in mammals have received limited attention. We offered female Sprague Dawley rats free access to water and one of three diets for up to 40 days: (1) sucrose-free chow or "NS" diet; (2) a high-sucrose dry diet or "HS"; or (3) 30% sucrose solution and the NS diet, designated "LiqS" diet. Sucrose consumption by LiqS rats gradually increased and by day 14 was equal to that of HS rats. Food intake decreased in LiqS rats, but their energy intake remained higher than for NS or HS rats. There was no significant difference in weight gain of the groups during the study. Recordings from the chorda tympani nerve (CT), which innervates taste buds on the anterior tongue, revealed decreased responses to 1 M sucrose in both LiqS and HS rats and to acesulfame K and salt tastants in LiqS rats after 40 days on diet. Umami, bitter, and acid response magnitudes were unchanged in both groups. These results demonstrate that chronic sucrose exposure inhibits taste responses to higher concentrations of sweet stimuli. More surprisingly, CT responses to NaCl and 0.5M NaAc were significantly reduced in rats on the LiqS diet. Thus, the physical form of the diet influences taste responsiveness to salt and sweet taste function. These data suggest that taste buds are previously unappreciated targets of chronic sucrose consumption., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lymphatic vessel networks can expand and regress, with consequences for interstitial fluid drainage and nutrient supply to tissues, inflammation, and tumor spread. A diet high in sodium stimulates hyperplasia of cutaneous lymphatic capillaries. We hypothesized that dietary sodium restriction would have the opposite effect, shrinking lymphatic capillaries in the tongue. Lingual lymphatic capillary density and size was significantly reduced in mice fed a low-sodium diet (0.03%) for 3 weeks compared with control-fed mice. Blood vessel density was unchanged. Despite lymphatic capillary shrinkage, lingual edema was not observed. The effect on lymphatic capillaries was reversible, as lymphatic density and size in the tongue were restored by 3 weeks on a control diet. Lymphatic hyperplasia induced by a high-sodium diet is dependent on infiltrating macrophages. However, lingual CD68+ macrophage density was unchanged by sodium deficiency, indicating that distinct mechanisms may mediate lymphatic regression. Further studies are needed to test whether dietary sodium restriction is an effective, non-invasive co-therapy for oral cancer.

Inflammation-mediated changes in taste perception can affect health outcomes in patients, but little is known about the underlying mechanisms. In the present work, we hypothesized that proinflammatory cytokines directly modulate Na(+) transport in taste buds. To test this, we measured acute changes in Na(+) flux in polarized fungiform taste buds loaded with a Na(+) indicator dye. IL-1β elicited an amiloride-sensitive increase in Na(+) transport in taste buds. In contrast, TNF-α dramatically and reversibly decreased Na(+) flux in polarized taste buds via amiloride-sensitive and amiloride-insensitive Na(+) transport systems. The speed and partial amiloride sensitivity of these changes in Na(+) flux indicate that IL-1β and TNF-α modulate epithelial Na(+) channel (ENaC) function. A portion of the TNF-mediated decrease in Na(+) flux is also blocked by the TRPV1 antagonist capsazepine, although TNF-α further reduced Na(+) transport independently of both amiloride and capsazepine. We also assessed taste function in vivo in a model of infection and inflammation that elevates these and additional cytokines. In rats administered systemic lipopolysaccharide (LPS), CT responses to Na(+) were significantly elevated between 1 and 2 h after LPS treatment. Low, normally preferred concentrations of NaCl and sodium acetate elicited high response magnitudes. Consistent with this outcome, codelivery of IL-1β and TNF-α enhanced Na(+) flux in polarized taste buds. These results demonstrate that inflammation elicits swift changes in Na(+) taste function, which may limit salt consumption during illness., (Copyright © 2016 the American Physiological Society.)

A fundamental role of the taste system is to discriminate between nutritive and toxic foods. However, it is unknown whether bacterial pathogens that might contaminate food and water modulate the transmission of taste input to the brain. We hypothesized that exogenous, bacterially-derived lipopolysaccharide (LPS), modulates neural responses to taste stimuli. Neurophysiological responses from the chorda tympani nerve, which innervates taste cells on the anterior tongue, were unchanged by acute exposure to LPS. Instead, neural responses to sucrose were selectively inhibited in mice that drank LPS during a single overnight period. Decreased sucrose sensitivity appeared 7days after LPS ingestion, in parallel with decreased lingual expression of Tas1r2 and Tas1r3 transcripts, which are translated to T1R2+T1R3 subunits forming the sweet taste receptor. Tas1r2 and Tas1r3 mRNA expression levels and neural responses to sucrose were restored by 14 days after LPS consumption. Ingestion of LPS, rather than contact with taste receptor cells, appears to be necessary to suppress sucrose responses. Furthermore, mice lacking the Toll-like receptor (TLR) 4 for LPS were resistant to neurophysiological changes following LPS consumption. These findings demonstrate that ingestion of LPS during a single period specifically and transiently inhibits neural responses to sucrose. We suggest that LPS drinking initiates TLR4-dependent hormonal signals that downregulate sweet taste receptor genes in taste buds. Delayed inhibition of sweet taste signaling may influence food selection and the complex interplay between gastrointestinal bacteria and obesity., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The peripheral taste system remains plastic during adulthood. Sectioning the chorda tympani (CT) nerve, which sends sensory information from the anterior tongue to the central nervous system, causes degeneration of distal fibers and target taste buds. However, taste function is restored after about 40 days in young adult rodents. We tested whether aging impacts the reappearance of neural responses after unilateral CT nerve injury. Taste bud regeneration was minimal at day 50-65 after denervation, and most aged animals died before functional recovery could be assessed. A subset (n=3/5) of old rats exhibited normal CT responses at day 85 postsectioning, suggesting the potential for efficient recovery. The aged taste system is fairly resilient to sensory receptor loss and major functional changes in normal aging. However, injury to the taste system reveals a surprising vulnerability in old rodents. The gustatory system provides an excellent model to study mechanisms underlying delayed recovery from peripheral nerve injury. Strategies to accelerate recovery and restore normal function will be of interest, as the elderly population continues to grow., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The peripheral taste system presents an excellent model for studying the consequences of neural injury, for the damaged nerve and sensory cells and the neighboring, intact neural cells. Sectioning a primary afferent nerve, the chorda tympani (CT), rapidly recruits neutrophils to both sides of the tongue. The bilateral neutrophil response induces transient functional deficits in the intact CT. Normal function is subsequently restored as macrophages respond to injury. We hypothesized that macrophages produce the proinflammatory cytokine interleukin (IL)-1, which contributes to the maintenance of normal taste function after nearby injury. We demonstrate that IL-1β protein levels are significantly increased on the injured side of the tongue at day 2 after injury. Dietary sodium deficiency, a manipulation that prevents macrophage recruitment, inhibits the elevation in IL-1β. IL-1β was expressed in several cell populations, including taste receptor cells and infiltrating neutrophils and macrophages. To test whether IL-1 modulates taste function after injury, we blocked signaling with an IL-1 receptor antagonist (IL-1 RA) and recorded taste responses from the intact CT. This treatment inhibited the bilateral macrophage response to injury and impaired taste responses in the intact CT. Cytokine actions in the taste system are largely unstudied. These results demonstrate that IL-1 has a beneficial effect on taste function after nearby injury, in contrast to its detrimental role in the injured central nervous system., (Copyright © 2012 Wiley Periodicals, Inc.)

The adult peripheral taste system is capable of extensive functional plasticity after injury. Sectioning the chorda tympani (CT), a primary sensory afferent nerve, elicits transient changes in the uninjured, contralateral population of taste receptor cells. Remarkably, the deficits are specific to the sodium transduction pathway. Normal function is quickly restored in the intact nerve, in parallel with an influx of macrophages to both the denervated and uninjured sides of the tongue. However, changing the dietary environment by restricting sodium blocks the macrophage response and prolongs functional alterations. Since the functional deficits occur before macrophages are present in the peripheral taste system, we hypothesized that neutrophils play a role in modulating neural responses in the intact CT. First, the dynamics of the neutrophil response to nerve injury were analyzed in control-fed and sodium-deficient rats. Nerve sectioning briefly increased the number of neutrophils on both the denervated and uninjured sides of the tongue. The low-sodium diet amplified and extended the bilateral neutrophil response to injury, in parallel with the persistent changes in sodium taste function. To test the impact of neutrophils on taste function, we depleted these cells prior to nerve sectioning and recorded neural responses from the intact CT. This treatment restored normal sodium responses in the uninjured nerve. Moreover, recruiting neutrophils to the tongue induced deficits in sodium taste function in both CT nerves. Neutrophils play a critical role in ongoing inflammatory responses in the oral cavity, and may induce changes in taste perception. We also suggest that balanced neutrophil and macrophage responses enable normal neural responses after neural injury., (Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Dietary sodium restriction coupled with axotomy of the rat chorda tympani nerve (CTX) results in selectively attenuated taste responses to sodium salts in the contralateral, intact chorda tympani nerve. Converging evidence indicates that sodium deficiency also diminishes the activated macrophage response to injury on both the sectioned and contralateral, intact sides of the tongue. Because a sodium-restricted diet causes a robust increase in circulating aldosterone, we tested the hypothesis that changes in neurophysiological and immune responses contralateral to the CTX could be mimicked by aldosterone administration instead of the low-sodium diet. Taste responses in rats with CTX and supplemental aldosterone for 4-6 days were similar to rats with CTX and dietary sodium restriction. Responses to sodium salts were as much as 50% lower compared with sham-operated and vehicle-supplemented rats. The group-related functional differences were eliminated with lingual application of amiloride, suggesting that a major transduction pathway affected was through epithelial sodium channels. Consistent with the functional results, few macrophages were observed on either side of the tongue in rats with CTX and aldosterone. In contrast, macrophages were elevated on both sides of the tongue in rats with CTX and the vehicle. These results show that sodium deficiency or administration of aldosterone suppresses the immune response to neural injury, resulting in attenuation of peripheral gustatory function. They also show a potential key link among downstream consequences of sodium imbalance, taste function, and immune activity.

The combination of dietary sodium depletion and unilateral chorda tympani (CT) nerve section decreases sodium taste function in the intact CT nerve. However, functional changes have not been examined prior to day 4 postsectioning, even though degenerative and inflammatory responses are robust during that period. Rats received unilateral CT section and/or dietary sodium depletion, accomplished by 2 injections of furosemide and a sodium-restricted diet, on day 0. Surgical controls received sham nerve sectioning. At days 1, 2, 3, or 4, taste responses were recorded from the intact nerve. Functional changes were rapid and unexpected. At day 1 postsectioning, neural responses from the uninjured CT of both control-fed and sodium-depleted animals were reduced. By day 2, however, normal function was restored in control-fed rats, whereas functional deficits persisted in depleted animals. Sodium depletion alone also induced a transient decrease in sodium responses at days 2-3 after furosemide injection. These results demonstrate that distant neural injury can elicit gustatory plasticity regardless of the dietary environment, but normal responses can be restored. We suggest that neutrophils mediate the initial postinjury deficits in taste function, whereas macrophages promote the recovery of normal function.

Macrophages are recruited to both sides of the tongue following unilateral chorda tympani (CT) nerve injury. The mechanisms responsible for recruiting these macrophages to the peripheral taste system are unknown. Neural degeneration in other systems leads to the upregulation of small molecules that function as chemoattractant cytokines, or chemokines. The chemokines monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha are important regulators of macrophage recruitment to sites of infection and injury. We hypothesized that CT nerve sectioning leads to a bilateral upregulation of MCP-1 and MIP-1alpha. We examined lingual protein levels of MCP-1 and MIP-1alpha by enzyme-linked immunosorbent assays (ELISA)s at several time points after unilateral CT section in rats. MCP-1 was significantly upregulated on the intact side of the tongue at 12 h after sectioning, and on the injured side at 24-48 h post-injury. However, MIP-1alpha expression did not significantly change following CT nerve sectioning. These data indicate that chemokines are differentially regulated following neural injury, and that MCP-1 may contribute to the bilateral macrophage response to neural injury. Furthermore, the increase in MCP-1 occurs even in uninjured, distant sites, and may be upstream from the deficits in neural responses from the contralateral CT after sectioning.

In the peripheral taste system, activated macrophages are recruited to both sides of the tongue after unilateral sectioning of the chorda tympani nerve (CT). Neural degeneration elicits macrophage entry in other systems by upregulating vascular adhesion molecules. We hypothesized that CT sectioning leads to a bilateral increase in intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression on lingual vessels. To test this hypothesis, rats were euthanized at time points from 6 hr to 7 days post-sectioning. Frozen sections of tongue were processed for immunohistochemical staining for ICAM-1 and VCAM-1. Tongue homogenates from additional rats were analyzed with ELISA. ICAM-1 expression increases first on the denervated side of the tongue at 24 hr post-section and then on the uninjured side at 48 hr post-section. ICAM-1 remains elevated through Day 7 post-sectioning on both sides of the tongue. Dietary sodium restriction, which prevents the macrophage response to nerve sectioning, had no effect on ICAM-1 levels. VCAM-1+ vessels are increased on the denervated side of the tongue at 24-48 hr post-section in control-fed rats. However, dietary sodium restriction prevents the increase. These results indicate that vascular adhesion molecules are differentially regulated by CT sectioning. We suggest that macrophage entry, migration, and modulation of taste function are downstream of dynamic expression of adhesion molecules.

Erectile dysfunction (ED) is estimated to affect more than 30 million American men and 152 million men worldwide. Therapeutic agents targeting the nitric oxide/cyclic GMP signaling pathway have successfully treated patients with ED; however, the efficacies of these treatments are significantly lower in specific populations such as patients with diabetes. The goal of this study was to discover and identify new endothelium-derived relaxing factors involved in the regulation of erectile function, providing alternative therapeutic targets for treatment of ED. Immunoblotting results showed that protein expressions of epoxygenases from cytochrome P450 (CYP)2B, 2C and 2J subfamilies, as well as NADPH CYP reductase were present in rat corpora cavernosa, which was confirmed by immunohistochemical analysis. Furthermore, CYP2C was localized in cavernosal endothelial cells using double immunolabeling. CYP epoxygenase activity was analyzed by reverse-phase high-pressure liquid chromatography; and the results showed that 11,12- epoxyeicosatrienoic acid (EET) was the major product metabolized by CYP epoxygenases in rat corpora cavernosa. Inhibition of EETs function by injection of an EETs antagonist into rat penis significantly decreased intracavernosal pressure-induced by electrical stimulation of the major pelvic ganglion in vivo. In conclusion, our results suggest that EETs, produced by CYP epoxygenases, in penile endothelial cells serve as vasodilators. Inhibition of this pathway attenuated erectile function, suggesting that EETs are required for normal erection.

Classically, nitric oxide (NO) formed by endothelial NO synthase (eNOS) freely diffuses from its generation site to smooth muscle cells where it activates soluble guanylyl cyclase (sGC), producing cGMP. Subsequently, cGMP activates both cGMP- and cAMP-dependent protein kinases [cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA), respectively], leading to smooth muscle relaxation. In endothelial cells, eNOS has been localized to caveolae, small invaginations of the plasma membrane rich in cholesterol. Membrane cholesterol depletion impairs acetylcholine (ACh)-induced relaxation due to alteration in caveolar structure. Given the nature of NO to be more soluble in a hydrophobic environment than in water, and assuming that colocalization of components in a signal transduction cascade seems to be a critical determinant of signaling efficiency by eNOS activation, we hypothesize that sGC, PKA, and PKG activation may occur at the plasma membrane caveolae. In endothelium-intact rat aortic rings, the relaxation induced by ACh, by the sGC activator 3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1), and by 8-bromo-cGMP was impaired in the presence of methyl-beta-cyclodextrin, a drug that disassembles caveolae by sequestering cholesterol from the membrane. sGC, PKG, and PKA were colocalized with caveolin-1 in aortic endothelium, and this colocalization was abolished by methyl-beta-cyclodextrin. Methyl-beta-cyclodextrin efficiently disassembled caveolae in endothelium. In summary, our results provide evidence of compartmentalization of sGC, PKG, and PKA in endothelial caveolae contributing to NO signaling cascade, giving new insights by which the endothelium mediates vascular smooth muscle relaxation.

Unilateral chorda tympani (CT) nerve section and maintenance on a sodium-restricted diet leads to a rapid decrease in neurophysiological taste responses to sodium in the contralateral, intact CT nerve. Up-regulation of immune function with lipopolysaccharide (LPS; 100 microg i.p.) induces a recovery of normal sodium taste responses, suggesting that the sodium-deficient diet is immunosuppressive. In fact, there is a bilateral increase in the number of lingual, activated macrophages in control-fed rats receiving CT nerve section that does not occur in sodium-deficient rats after sectioning. In the current study, we hypothesized that the LPS-induced recovery of normal taste function in sodium-deficient rats is based on an increase in the activated macrophage response to denervation. Rats receiving a unilateral CT nerve section, a sodium-restricted diet, and/or an injection of LPS (100 microg; i.p.) were overdosed with pentobarbital at day 2 postsectioning, and tongues were rapidly dissected and frozen. Cryosections were then immunohistochemically stained to determine the percentage of ED1 staining for activated macrophages or the number of alphabeta or gammadelta T cells. Activated macrophage levels were significantly increased in sodium-restricted rats that received LPS following unilateral CT nerve section, supporting our hypothesis. These novel findings suggest that LPS overcomes the immunosuppression induced by the sodium-restricted diet and also indicate that the immune system plays a role in regulating taste function after neural injury., ((c) 2005 Wiley-Liss, Inc.)

Dietary sodium restriction combined with unilateral chorda tympani nerve section leads to a rapid and specific decrease in neurophysiological taste responses to sodium in the contralateral, intact chorda tympani (Hill and Phillips [1994] J. Neurosci. 14:2904-2910). Previous work demonstrated that dietary sodium restriction may induce these early functional deficits by inhibiting immune activity after denervation (Phillips and Hill [1996] Am. J. Physiol. 271:R857-R862). However, little is known about the leukocyte response to denervation of taste buds in fungiform papillae. In the current study, it was hypothesized that T cells and macrophages are increased in the tongue after unilateral denervation in control-fed but not sodium-restricted animals. Adult, specified pathogen-free rats received unilateral chorda tympani nerve section or sham section followed by dietary sodium restriction or maintenance on control diet. At day 1, 2, 5, 7, or 50 postsectioning, immunostaining was used to detect the percentage of staining for activated macrophages, the number of alpha beta T cells, and the number of delta gamma epithelial T cells in the tongue. The number of lingual T cells did not significantly differ between treatment groups following denervation. However, there was a dramatic bilateral increase in ED1(+) staining for activated macrophages in control-fed rats that peaked at day 2 postsectioning. In contrast, sodium-restricted rats did not show an increase in activated macrophages above baseline at any time postsectioning. Further analysis of extralingual macrophages indicated that the deficit in immune activity in sodium-restricted rats is localized to the tongue and is not widespread. A model for immune modulation of taste receptor cell function is proposed based on these novel findings.

Unilateral chorda tympani nerve (CT) section combined with dietary sodium restriction leads to striking alterations in sodium taste function. The regenerated rat CT exhibits deficits in sodium sensitivity, and surprisingly, there are also functional alterations in the intact, contralateral nerve. The studies presented here describe the functional "sensitive periods" for these aberrations and the number of taste buds present during corresponding stages. The regenerated CT is sensitive to dietary sodium restriction during the first 2 wk after denervation, whereas the intact CT is sensitive to dietary manipulation during the first week postsection. Therefore, distinct mechanisms are responsible for the effects of sodium restriction combined with denervation, because separate sensitive periods exist for the regenerated and intact CT nerves. Identification of mature taste buds with an antibody directed at anti-keratin 19 revealed that there is a loss of ~85% of taste buds on the denervated side of the tongue under control and low-sodium diets within the first week postsection. Thus, sodium restriction does not differentially affect the loss of taste buds following denervation.

The response of parenchymal microglia to interferon-gamma (IFN-gamma) varies across the brain. To ask if local neurochemicals contribute to site-specific control, the influence of substance P (SP) and glutamate was evaluated in brainstem vs. hippocampus. In brainstem, stereotaxic injection of SP increased class II MHC upregulation by IFN-gamma, while a SP receptor antagonist (Spantide I) prevented it. In hippocampus, where the baseline response to IFN-gamma was lower, SP was ineffective, but blocking glutamate enhanced the response in a proportion of rats. Attempts to understand and control immune activity in the CNS should take the local neurochemical environment into account.

Although it is often described as "immunologically privileged," the brain can display vigorous immune activity, both clinically and experimentally. The underlying control mechanisms are under active study. Here we shift attention from the brain as a whole to its diverse microenvironments. We review evidence that immune regulation in the brain is site-specific, and that local neurochemicals contribute to the site-specific control. Key points are illustrated by recent work from a rat model in which local injection of the proinflammatory cytokine, IFN-gamma, was used to modulate 2 essential aspects of the cell-mediated immune response: T cell entry from the blood, and expression of the MHC proteins that are needed to present antigen to the newly entered T cells. A growing number of neurologic disorders are known to be exacerbated by the immune/inflammatory network. Understanding the factors that influence local immune function may help explain the distribution of localized CNS damage and, more importantly, may suggest new therapeutic approaches for both desirable and unwanted responses.