Multiple subsets of nociceptive, parasympathetic, and sympathetic nerves innervate human nasal mucosa. These play carefully coordinated roles in regulating glandular, vascular, and other processes. These functions are vital for cleaning and humidifying ambient air before it is inhaled into the lungs. The recent identification of distinct classes of nociceptive nerves with unique patterns of transient receptor potential sensory receptor ion channel proteins may account for the polymodal, chemo- and mechanicosensitivity of many trigeminal neurons. Modulation of these families of proteins, excitatory and inhibitory autoreceptors, and combinations of neurotransmitters introduces a new level of complexity and subtlety to nasal innervation. These findings may provide a rational basis for responses to air-temperature changes, culinary and botanical odorants (“aromatherapy”), and inhaled irritants in conditions as diverse as allergic and nonallergic rhinitis, occupational rhinitis, hyposmia, and multiple chemical sensitivity.
transient receptor potential; TRPV1; nociceptive axon response; nociception
Endogenous retroviruses (ERVs) are present in the genome of all vertebrates and have coevolved with their hosts for millions of years. Some ERVs play a critical role in placental development, contribute to genome plasticity, and protect the host against infection of related pathogenic and exogenous retroviruses, thus some ERVs have been positively selected and maintained in the host genome. The sheep genome contains 27 endogenous retroviruses (en-JSRVs) related to the pathogenic Jaagsiekte sheep retrovirus (JSRV), the causative agent of a transmissible lung cancer in sheep. en-JSRVs are able to protect their host against JSRV infection by blocking different steps of the viral replication cycle. In addition, en-JSRVs are absolutely required for sheep placental development. Thus, en-JSRVs-JSRV provides a unique and interesting model to study the symbiotic relationship and interplay between host ERVs and evolution. This review will provide some examples of the biological functions of ERVs. In particular, the role of ERVs in reproductive biology and in protecting the host against pathogenic retrovirus infections will be emphasized using en-JSRVs/JSRV and the sheep as a model.
JSRV; en-JSRVs; placenta; endogenous retroviruses; virus evolution; virus–host coevolution
Dietary restriction is one manipulation that delays aging in every species in which it has been applied, including man. The mechanisms are not yet known. This symposium was designed to bring to ISOT 2008 leading scientists in the field of molecular mechanisms of aging/longevity to stimulate interest in novel research that may bridge the burgeoning interface between chemical senses and longevity. Speakers presented provocative research into the mechanisms underlying longevity that suggest that life span is regulated by both gene modification and environmental cues and that chemosensory perception of food-related environmental cues can modulate lifespan.
chemosensory aging; longevity; olfactory impairment; gustatory; taste; smell; olfactory; odor; aging; c. elegans
The rate of discovery of new microbes and of new associations of microbes with health and disease is accelerating. Many factors contribute to this phenomenon including those that favor the true emergence of new pathogens as well as new technologies and paradigms that enable their detection and characterization. This chapter reviews recent progress in the field of pathogen surveillance and discovery with a focus on viral hemorrhagic fevers.
Intestinal injury from ionizing radiation is a clinically important entity, as enteritis symptoms occur commonly after radiotherapy for pelvic malignancies. Preventative or therapeutic options for radiation enteritis are mostly unsatisfactory; however, available data suggests that probiotic bacteria—those which confer health benefit—may have therapeutic value. Previous reports from both human trials and animal models have evaluated various end points for probiotic usage in limiting radiation-associated intestinal damage. Newer data suggests that particular probiotics and/or their secreted or derived bacterial products may have unique radioprotective properties. We will review the area with a focus on new developments surrounding probiotic therapy in radiation-induced intestinal injury and repair.
probiotics; radiation; enteritis; lactobacillus rhamnosus GG; LGG; COX-2
Rocky Mountain Spotted Fever cases in the notorious Bitterroot Valley outbreak of the early 20th century were peculiarly distributed, with virtually all reported from the west side of the valley. Such a distribution remained unexplained until Burgdorfer et al (1981) reported that endosymbiotic rickettsiae were prevalent in wood ticks on the east side of the Bitterroot River valley but not on the west side. The “east side agent” was said to prevent the transovarial transmission of Rickettsia rickettsii, thereby severely limiting the prevalence of the latter. This hypothesis has been considered one of the most innovative explanations for an epidemiological conundrum, and indeed, has generally been accepted as a fact in the medical entomology literature. I review the evidence for the interference hypothesis, and suggest that the distribution of the Bitterroot Valley RMSF outbreak might actually have its basis in habitat or microclimate-related factors as opposed to reflecting interspecific competition by closely related rickettsiae.
Rocky Mountain spotted fever; rickettsia; Rickettsia rickettsii; ticks; Dermacentor; Rickettsia peacockii; interference; transovarial transmission; Bitterroot Valley
The ability to inhibit expression of a mutant allele while retaining expression of wild-type protein might provide a useful approach to treating Huntington’s Disease (HD) and other inherited pathologies. The mutant form of huntingtin (HTT), the protein responsible for HD, is encoded by an mRNA containing an expanded CAG repeat. We demonstrate that peptide nucleic acid (PNA) conjugates and locked nucleic acids (LNAs) complementary to the CAG repeat selectively block expression of mutant HTT. The selectivity of inhibition is at least as good as that shown by an siRNA targeted to a deletion polymorphism. Our data suggest that antisense oligomers are promising subject for further development as an anti-HD therapeutic strategy.
Huntington’s disease; huntingtin; allele selectivity; peptide nucleic acid; PNA; locked nucleic acid; LNA; siRNA; trinucleotide repeat; CAG repeat
Tick-borne pathogens in the genus Ehrlichia cause emerging zoonoses. Although laboratory mice are susceptible to Ehrlichia infections, many isolates do not cause clinical illness. In contrast, the Ixodes ovatus Ehrlichia-like agent (IOE) causes disease and immune responses in mice comparable to the human illness caused by Ehrlichia chaffeensis. No culture system had been developed for IOE, however, which limited studies of this pathogen. We reasoned that endothelial and tick cell lines could potentially serve as host cells, since the IOE is found in ticks and in endothelial cells in mice. Infected spleen cells from RAG-deficient mice were overlaid onto ISE6 and RF/6A cultures, and colonies typical of Ehrlichia were noted in RF/6A cells within 2 weeks. Infection of ISE6 cells was established after transfer of IOE from RF/6A cells. Electron microscopy revealed densely packed inclusions in infected RF/6A and ISE6 cells; these inclusions contained copious amounts of filamentous structures, apparently originating from Ehrlichial cells. In particular, within RF/6A cells the structures assumed an ordered morphology of finely combed hair. IOE from RF/6A cells, when inoculated into C57BL/6 and RAG-deficient mice, induced fatal disease. These data reveal unique structural features of IOE that may contribute to the pathogen's high virulence.
Ehrlichia; tick cell; endothelial cell; bacterial infection; ultrastructure
The mammalian olfactory system recognizes a wide range of chemical stimuli. The majority of cells in the main olfactory epithelium (MOE) use a cAMP-mediated signaling system to transduce odor signals. However, a subset of MOE neurons instead expresses components of a cGMP signaling cascade, including the receptor guanylyl cyclase GC-D and the cyclic nucleotide-gated channel subunit CNGA3. We used a combination of molecular biological, physiological and imaging approaches to characterize this neuronal population. Neurons expressing GC-D show excitatory responses to the natriuretic peptide hormones uroguanylin and guanylin, as well as to stimuli present in urine, that are dependent on both GC-D and CNGA3. Though all GC-D-expressing neurons are highly sensitive to these stimuli, individual cells are differentially tuned to either one or both of the peptides. Together, these findings suggest that neurons expressing GC-D are part of a specialized olfactory subsystem that is responsive to semiochemicals.
semiochemical; cGMP; necklace glomeruli; natriuretic peptides; GC-D; PDE2
In women, the corpus luteum is the source of circulating relaxin. No previous studies have addressed whether the corpus luteum is also a relaxin target organ. We determined relaxin receptor LGR7 mRNA expression in human term pregnancy corpora lutea and non-human primate corpora lutea obtained during the menstrual cycle. Real-time RT-PCR demonstrated the expression of LGR 7 mRNA in both human and rhesus monkey corpora lutea. Rhesus monkey corpora lutea were obtained from naturally cycling animals following documented LH surges at early, mid, mid-late and late luteal phases. Luteal expression of LGR7 mRNA did not show temporal variation. Since the primate corpus luteum is LH dependent, we assessed LGR7 mRNA expression in corpora lutea from rhesus monkeys treated with a GnRH antagonist which significantly suppressed pituitary LH levels. GnRH antagonist treatment, which also inhibits both progesterone and relaxin production, resulted in a five fold increase in luteal LGR7 mRNA expression. These data suggest that luteal LGR7 mRNA expression may be regulated by relaxin and/or LH, and that the primate corpus luteum is a target organ for relaxin.
RXFP1; LGR7; rhesus monkey; relaxin; corpus luteum; relaxin receptor
Relaxin has beneficial effects upon the endometrium which are responsible for establishment of pregnancy. We have demonstrated that relaxin stimulates endometrial decidualization, the structural and biochemical changes in endometrial parenchymal cells, and the accompanying angiogenesis, modulation of matrix metalloproteinase activity and increased concentration in local immune cells which are required for implantation Our recent data also demonstrate that either too much or too little relaxin can be detrimental. Elevated circulating maternal relaxin concentrations (hyperrelaxinemia) are associated with premature birth. This is likely due to the effects of relaxin at the level of the cervix, via upsetting the balance in the maintenance of cervical connective tissue architecture. In addition, the absence of circulating relaxin during pregnancy in women may have negative consequences upon glucose metabolism.
relaxin; rhesus monkey; endometrium; human pregnancy; preterm birth
Synapses between dendrites are at the core of mechanisms for processing odor stimuli, as well as for processing in many other brain systems. A perspective on the development of our understanding of these mechanisms may therefore be of interest. Studies of the olfactory bulb leading to the discovery of dendrodendritic synapses began in 1959. They involved a multidisciplinary approach that included Golgi cell morphology, electrophysiology, a microcircuit wiring diagram, membrane biophysics, theory of field potentials, cable theory, dendritic electrotonus theory, computational models of mitral and granule cells, prediction by the models of dendrodendritic synaptic interactions, confirmation with electron microscopy using single sections and serial sections, and final integration in the reports of feedback and lateral inhibitory interactions in 1966 and 1968. Following the discovery of glomerular odor maps in the 1970s, the functional significance of the dendrodendritic inhibition in processing the maps has been increasingly documented. Recent experimental and computational studies are revealing how these synapses are organized into distributed systems for processing the odor maps. Future studies need to situate dendrodendritic mechanisms in these distributed systems and correlate them with the tight functional loops between olfactory bulb and olfactory cortex. Studies in awake behaving animals will be increasingly important. The relations of dendritic mechanisms to perception, memory, and the pathogenesis of disorders such as Alzheimer’s will be rich fields for study. Dendrites and their synapses should continue to provide ideal models for the study of basic mechanisms of cortical integration and the neural basis of smell.
dendrodendritic synapses; reciprocal synapses; mitral cells; granule cells; dendritic spines; active dendrites; cortical columns; lateral inhibition; olfactory discrimination; cortical microcircuits; computational modeling; multidisciplinary research
Social neuroscience offers a window onto the mental origins of empathy. People must appreciate another mind, in order to empathize. People first categorize the other as human, assuming a mind, and then differentiate among social categories according to universal dimensions of perceived traits: warmth and competence. The least warm and competent groups (poor people, homeless, drug addicts) may even be denied humanity and a meaningful mind, according to both neural and behavioral responses to allegedly disgusting outcasts. Other groups may be instead envied and viewed as tools or automatons, that is, objectified. The patterns can reverse when perceivers must consider the other’s preferences, that is, appreciate the other’s mind.
social cognition; social neuroscience; empathy; dehumanization; objectification; mPFC; amygdala; prejudice; mind
The critical epidemiological data for estimating the prevalence of chemosensory disorders in the US are lacking. Several reasons for this will be discussed, including the time-consuming nature of many existing tests, stimulus delivery in a large-scale study, and the rationale for inclusion in a large-scale epidemiological study. The opportunity to include measures of chemosensory function in ongoing population-based studies has greatly facilitated the collection of recent data that establishes the high prevalence of olfactory impairment in older adults in the US population and the inability of self-report measures to capture this impairment. Epidemiological studies of the complete range of the population that involve chemosensory testing pose considerable challenges, but are critical to establishing prevalence rates. These studies have the potential to suggest prevention or intervention strategies for chemosensory impairment. Key issues, including cross-cultural issues in stimulus design, testing of special populations, cohort effects and optimal analyses of population-based chemosensory data, are considered.
olfaction; olfactory impairment; smell; odor; prevalence; epidemiology; population studies
The integrity of the tight junction barrier in epithelial and endothelial cells is critical to human health, but we still lack a detailed mechanistic knowledge of how the barrier is formed during development or responds to pathological and pharmacological insults. This limits our understanding of barrier dysfunction in disease and slows the development of therapeutic strategies. Recent studies confirm the long-maintained but previously unsupported view that the zonula occludens (ZO) proteins ZO-1 and ZO-2 are critical determinants of barrier formation. However, ZO proteins can also be components of adherens junctions, and recent studies suggest that ZO proteins may also promote the assembly and function of these junctions during epithelial morphogenesis. We review these studies and outline several recent observations that suggest that one role of ZO proteins is to regulate cytoskeletal dynamics at cell junctions. Finally, we propose a model by which the functional activities of ZO proteins in the adherens junction and tight junction are differentiated by a novel regulatory motif known as the U6 or acidic motif.
tight junction; adherens junction; zonula occludens; ZO-1; ZO-2; E-cadherin; cytoskeleton; MAGUK; PDZ; scaffold; permeability; epithelia; morphogenesis
As the second synapse in the central gustatory pathway of the rodent, the parabrachial nucleus of the pons (PbN) receives information about taste stimuli directly from the nucleus of the solitary tract (NTS). Data show that NTS cells amplify taste responses before transmitting taste-related signals to the PbN. NTS cells of varied response profiles send converging input to PbN cells, though input from NTS cells with similar profiles is more effective at driving PbN responses. PbN cells follow NTS input for the first 3 s of taste stimulation for NaCl, HCl, and quinine, but are driven in cyclic bursts throughout the response interval for sucrose. Analyses of the temporal characteristics of NTS and PbN responses show that both structures use temporal coding with equal effectiveness to identify taste quality. Thus, the NTS input to the PbN is comprehensive, in that PbN cells receive NTS input that could support broad sensitivity, systematic, in that the time course of PbN firing patterns depend reliably on the tastant, and efficient, in that information from the NTS is preserved as it is communicated across structures. Comparisons of NTS and PbN taste responses in rats form the basis for our speculation that in primates, where the central gustatory pathway does not synapse in the PbN, the function of the PbN in taste processing may have been incorporated into that of the NTS.
taste; parabrachial pons; temporal coding
Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating taste sensitivity are poorly understood. Using immunohistochemical, biochemical and behavioral approaches, we found that the peptide hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) are expressed in mammalian taste buds. Furthermore, we found that GLP-1 signaling plays an important role in the modulation of taste sensitivity: GLP-1R knockout mice exhibit a dramatic reduction in sweet taste sensitivity as well as an enhanced sensitivity to umami-tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals.
glucagon-like peptide-1; hormone; sweet; umami; glutamate
Neuroscientists are now coming to appreciate that a significant degree of information processing occurs in the peripheral sensory organs of taste prior to signals propagating to the brain. Gustatory stimulation causes taste bud cells to secrete neurotransmitters that act on adjacent taste bud cells (paracrine transmitters) as well as on primary sensory afferent fibers (neurocrine transmitters). Paracrine transmission, representing cell-cell communication within the taste bud, has the potential to shape the final signal output that taste buds transmit to the brain. The following paragraphs summarize current thinking about how taste signals generally, and umami taste in particular, are processed in taste buds.
taste; neurotransmitters; serotonin; ATP; norepinephrine; synaptic transmission
Splenectomized mice express progressively increased numbers of platelets in the blood and reduced numbers of megakaryocytes in the marrow with age. The megakaryocytes in the marrow of these animals express reduced levels of Gata1, a transcription factor necessary for their maturation. In addition, the marrow from these animals expresses greater levels of cytokines (TGF-β, PDGF-α, and VEGF) known to be produced at high levels by megakaryocytes expressing reduced levels of Gata1. This high level of cytokine expression is in turn associated with active osteoblast proliferation localized to areas of the femur, where megakaryocytes expressing reduced Gata1 levels are also found. These results confirm the role of megakaryocytes as regulator of bone formation in mice and suggest that a cross-talk between the spleen and marrow may regulate the total numbers of hemopoietic niches present in an animal.
spleen; megakaryocytes; Gata1; bone formation
Research and outcomes with cochlear implants (CIs) have revealed a dichotomy in the cues necessary for speech and music recognition. CI devices typically transmit 16–22 spectral channels, each modulated slowly in time. This coarse representation provides enough information to support speech understanding in quiet and rhythmic perception in music, but not enough to support speech understanding in noise or melody recognition. Melody recognition requires some capacity for complex pitch perception, which in turn depends strongly on access to spectral fine structure cues. Thus, temporal envelope cues are adequate for speech perception under optimal listening conditions, while spectral fine structure cues are needed for music perception. In this paper, we present recent experiments that directly measure CI users’ melodic pitch perception using a melodic contour identification (MCI) task. While normal-hearing (NH) listeners’ performance was consistently high across experiments, MCI performance was highly variable across CI users. CI users’ MCI performance was significantly affected by instrument timbre, as well as by the presence of a competing instrument. In general, CI users had great difficulty extracting melodic pitch from complex stimuli. However, musically-experienced CI users often performed as well as NH listeners, and MCI training in less experienced subjects greatly improved performance. With fixed constraints on spectral resolution, such as it occurs with hearing loss or an auditory prosthesis, training and experience can provide a considerable improvements in music perception and appreciation.
cochlear implant; music perception; melodic contour identification
Recently the function of the sirtuin family, named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), has received a lot of attention, as their beneficial impact on longevity was linked to their effects on metabolic control. All sirtuins require nicotinamide adenine dinucleotide (NAD+) for their deacetylase or ADP-ribosyl transferase activity, linking their function tightly to cellular energy levels. SIRT1, the founding member of the sirtuin family, modulates many aspects of glucose and lipid homeostasis in almost all key metabolic tissues. Other members including SIRT2, SIRT3, and SIRT4 are also implicated in various metabolic processes. Here, we review the recent data related to the role of sirtuins in the control of metabolic homeostasis and possible underlying molecular mechanisms.
sirtuin; NAD+; deacetylase; ADP-ribosyl transferase; metabolic homeostasis; metabolic disorders
Cumulative evidence in rats suggests that the pontine parabrachial nucleus (PBN) is necessary for assigning hedonic value to taste stimuli. In a series of studies, our laboratory has investigated the parabrachial coding of sapid sucrose in normal and obese rats. First, using chronic microdialysis, we demonstrated that sucrose intake increases dopamine release in the nucleus accumbens, an effect that is dependent on oral stimulation and on concentration. The dopamine response was independent of the thalamocortical gustatory system, but was blunted substantially by lesions of the PBN. Similar lesions of the PBN but not the thalamic taste relay diminished cFos activation by sucrose ingestion in the nucleus accumbens. Recent single neuron recording studies demonstrated that processing of sucrose-evoked activity in the PBN is altered in the Otsuka Long Evans Tokushima Fatty (OLETF) rats that develop obesity due to chronic overeating and express increased avidity to sweet. Compared with lean controls, taste neurons in OLETF rats had reduced overall sensitivity to sucrose and altered concentration responses: decreased responses to lower and augmented responses to higher concentrations. The decreased sensitivity to sucrose was specific to NaCl-best neurons that also responded to sucrose, but the concentration effects were carried by the sucrose-specific neurons. Collectively, these findings support the hypothesis that the PBN enables taste stimuli to engage the reward system and, in doing so, influences food intake and body weight regulation. Obesity, in turn, may further alter the gustatory code via forebrain connections to the taste relays or hormonal changes consequent to weight gain.
taste; gustatory plasticity; pons; dopamine; appetite; obesity; diabetes
Though iron and oxygen are required to sustain essential biological processes, an excess of either can result in oxidative stress. Therefore, mammals tightly regulate cellular and systemic iron and oxygen homeostasis. At the cellular level, the hypoxia-inducible transcription factors (HIFs) are key mediators of oxygen homeostasis through their regulation of genes involved in anaerobic metabolism and oxygen delivery, among others. Iron regulatory proteins (IRPs) largely govern cellular iron homeostasis through their effects on the translation and stability of mRNAs involved in iron uptake, utilization, export, and storage. Here, we describe regulatory factors for each pathway that sense both iron and oxygen availability and coordinate the maintenance of mammalian iron and oxygen homeostasis at both the cellular and systemic levels.
iron; oxygen; hypoxia; iron regulatory protein (IRP); hypoxia-inducible factor (HIF); FBXL5; iron- and 2-oxoglutarate-dependent dioxygenase; hemerythrin
In birds as in other vertebrates, estrogens produced in the brain by aromatization of testosterone have widespread effects on behavior. Research conducted with male Japanese quail demonstrates that effects of brain estrogens on all aspects of sexual behavior, including appetitive and consummatory components as well as learned aspects, can be divided in two main classes based on their time-course. First, estrogens via binding to estrogen receptors regulate the transcription of a variety of genes involved primarily in neurotransmission. These neurochemical effects ultimately result in the activation of male copulatory behavior after a latency of a few days. Correlatively, testosterone and its aromatized metabolites increase the transcription of the aromatase mRNA resulting in an increased concentration and activity of the enzyme that actually precedes behavioral activation. Second, recent studies with quail demonstrate that brain aromatase activity (AA) can also be modulated within minutes by phosphorylation processes regulated by changes in intracellular calcium concentration such as those associated with glutamatergic neurotransmission. The rapid up or down-regulations of brain estrogen concentration presumably resulting from these changes in AA affect, by non-genomic mechanisms with relatively short latencies (frequency increases or decreases respectively within 10–15 min), the expression of male sexual behavior in quail and also in rodents. Brain estrogens thus affect behavior on different time-scales by genomic and non-genomic mechanisms similar to those of a hormone or a neurotransmitter.
copulatory behavior; appetitive sexual behavior; sexual learning; rhythmic contractions of the cloacal gland sphincter; medial preoptic area; non genomic effects of steroids; aromatase; Japanese quail - estrogens