bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the water quality in the Guadarrama river at the section of Las Rozas‐Madrid, Spain
Authors: Vicente J. , Colmenarejo M. F. , Sánchez E. , Rubio A. , García M. G. , Borja R. , Jimenez A. M.
Published: July 2009

The variation of the water quality of the Guadarrama river and its tributaries in a section of Las Rozas‐Madrid, Spain, was studied during the time period between January 2003 and January 2008. The parameter water quality index (WQI) was used to determine the water quality based on the conventional parameters of pollution. It was found that the WQI was slightly affected in the section evaluated. The value of the WQI was in the range of 56–64, which corresponded to the classification of ‘good quality’. It was determined that 64.3% of the organic matter present in the river was removed in the section of Las Rozas‐Madrid. The river acted as a plug flow reactor and a first‐order kinetics governed the ultimate biological oxygen demand (BOD5) (BODU) decay. The value of the first‐order constant demonstrated the river's high self‐purification capacity. In addition, a high linear relationship was found between the WQI and the dissolved oxygen deficit (D). Therefore, a quick determination of WQI may be carried out if the values of D are known. These are easily obtainable by field measurements.
Functional Expression of Chemoreceptors with the Help of a Guanine Nucleotide Exchange Factor
Authors: Malnic Bettina , Gonzalez‐Kristeller Daniela C.
Published: July 2009

Odorant receptors and other chemoreceptors are usually poorly expressed in the plasma membrane of heterologous cells. A key point of regulation in G protein–mediated signaling is the interconversion between the active GTP‐bound and inactive GDP‐bound states of the Gα subunit, which regulatory proteins, such as guanine nucleotide exchange factors (GEFs), can control. GEFs stimulate formation of the GTP‐bound state of Gα and therefore are considered to work as positive regulators of G protein–coupled receptor signaling. Ric‐8B, a GEF that is specifically expressed in olfactory sensory neurons, promotes functional expression of odorant receptors in HEK293T cells because it amplifies the initially low receptor signaling through Gαolf. This same strategy could be used to functionally express other types of chemoreceptors.
Olfactory Receptor Interactions with Other Receptors
Authors: Hall Randy A.
Published: July 2009

Olfactory receptors expressed in heterologous cells often suffer from retention in the endoplasmic reticulum and poor trafficking to the plasma membrane. Interactions of the olfactory receptor M71 with several subtypes of adrenergic and purinergic receptors can alleviate M71 trafficking deficits in heterologous cells and allow for robust M71 plasma membrane expression. Furthermore, the signaling pathway to which M71 couples upon agonist stimulation can be strongly influenced by the partner receptor's driving M71 trafficking to the plasma membrane. These studies provide evidence that olfactory receptors can interact with other G protein–coupled receptors and that these interactions can promote olfactory receptor surface expression and functionality in heterologous cells.
Molecular Basis of Odor Detection in Insects
Authors: Benton Richard
Published: July 2009

Olfactory systems are evolutionarily ancient, underlying the common requirement for all animals to sense and respond to diverse volatile chemical signals in their environment. Odor detection is mediated by odorant receptors (ORs) that, in most olfactory systems, comprise large families of divergent G protein–coupled receptors. Here, I discuss our and others’ recent investigations of ORs in the fruit fly, Drosophila melanogaster, which have revealed insights into the distinct evolutionary origin and molecular function of insect ORs. I also describe a bioinformatics strategy that we developed to identify molecules that function with these insect‐specific receptors in odor detection.
GABAa Receptor Heterogeneity Modulates Dendrodendritic Inhibition
Authors: Sassoè‐Pognetto Marco , Panzanelli Patrizia , Lagier Samuel , Fritschy Jean‐Marc , Lledo Pierre‐Marie
Published: July 2009

In the olfactory bulb, mitral and tufted cells receive GABAergic inhibition at dendrodendritic synapses with granule cells. Recent studies have revealed a remarkable variability in the subunit composition of GABAa receptors in dendrodendritic microcircuits, with differential expression patterns of the α1 and α3 subunits in different subtypes of mitral and tufted cells. In particular, all mitral cells express the α1 subunit, whereas GABAaα3 is restricted to a subgroup of mitral cells, as well as to several subtypes of tufted cells. To assess the functional relevance of this heterogeneity, we investigated a mouse strain carrying a genetic deletion of the α1 subunit. Elimination of GABAaα1 was partially compensated for in mitral cells by receptors containing the α3 subunit, substantially decreasing the frequency of spontaneous inhibitory postsynaptic currents, as well as prolonging their decay time. Evoked inhibition between granule and mitral cells was slower to rise and decay and had smaller amplitude in α1 mutants. Remarkably, these changes in synaptic inhibition were accompanied by a significant reduction in the frequency of field oscillations. Therefore, the subunit composition of GABAa receptors strongly influences rhythmic activities in the olfactory bulb network. Together, these data indicate that dendrodendritic circuits in the external plexiform layer segregate into parallel pathways involving distinct GABAa receptors that are expressed by different subtypes of mitral and tufted cells.
Risk is in the Air
Authors: Prediger Rui D. S. , Rial Daniel , Medeiros Rodrigo , Figueiredo Cláudia P. , Doty Richard L. , Takahashi Reinaldo N.
Published: July 2009

The presence of smell loss and the early pathological involvement of the olfactory pathways in the early stages of some neurodegenerative disorders are in accord with the tenants of the olfactory vector hypothesis. This hypothesis postulates that some such diseases may be caused or catalyzed by agents that enter the brain via the olfactory mucosa. In this study, rats infused intranasally (i.n.) with a low concentration of the proneurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) subsequently suffered olfactory, cognitive, and motor function impairments conceivably analogous to those observed during different stages of the development of Parkinson's disease (PD). Such infusion decreased the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra by means of apoptotic mechanisms, reducing dopamine levels in different brain structures, such as the olfactory bulb, striatum, and prefrontal cortex. These findings reinforce the suggestion that the olfactory system may be a particularly sensitive route for the penetration of xenobiotic agents into the central nervous system and that the i.n. MPTP rat model may provide insight into the underlying mechanisms of PD pathogenesis, potentially leading to the development of new therapeutic strategies for this devastating disease.
Olfactory Navigation in Homing Pigeons
Authors: Gagliardo Anna , Ioalè Paolo , Savini Maria , Wild J. Martin
Published: July 2009

The olfactory navigation hypothesis of pigeon homing was recently challenged by the discovery in the upper beak of putative magnetoreceptors innervated by the ophthalmic branch of the trigeminal nerve. To assess whether the nature of the cues used for navigation is determined by the kind of stimuli to which the birds are preferentially exposed during development, we tested the navigational performance of pigeons subjected when young to section of either the ophthalmic branch of the trigeminal nerve (V1) or the olfactory nerve and then subjected to training flights after the surgery. Section of V1 had no effect on homing performance, but olfactory cues are needed for development of the navigational map.
Shaping of Drosophila Male Courtship Posture by a Gustatory Pheromone
Authors: Koganezawa Masayuki , Matsuo Takashi , Kimura Ken‐ichi , Yamamoto Daisuke
Published: July 2009

Drosophila melanogaster males display stereotypical courtship ritual in courting potential mates. The fruitless (fru) gene plays a pivotal role in the generation of male‐typical courtship behavior by instructing the formation of the central circuitry underlying this behavior during development. The fru gene expression can be monitored by a reporter, fruNP21, that labels approximately 800 neurons in the adult male brain. Among these fru‐expressing neurons, a male‐specific neural cluster called P1 initiated male‐typical courtship behavior; when the P1 cluster was ectopically produced in the female brain, many such females displayed male‐typical courtship behavior toward a target female. To further elucidate the central circuitry for courtship behavior, we examined central projections of sensory neurons that appear to perceive sex pheromones sensed in the foreleg gustatory receptors. The central terminals of these sensory neurons are located near dendrites of the fru‐expressing interneurons named mAL. These results suggest that different subsets of fru‐expressing neurons are involved in both the sensory integration of sexual cues and the activation of motor centers that generate motor outputs for courtship behavior in the Drosophila brain.
Metabotropic Glutamate Receptors and Dendrodendritic Synapses in the Main Olfactory Bulb
Authors: Dong Hong‐Wei , Heinbockel Thomas , Hamilton Kathryn A. , Hayar Abdallah , Ennis Matthew
Published: July 2009

The main olfactory bulb (MOB) is the first site of synaptic processing in the central nervous system for odor information that is relayed from olfactory receptor neurons in the nasal cavity via the olfactory nerve (ON). Glutamate and ionotropic glutamate receptors (iGluRs) play a dominant role at ON synapses. Similarly, glutamate and iGluRs mediate dendrodendritic transmission between several populations of neurons within the MOB network. Neuroanatomical studies demonstrate that metabotropic glutamate receptors (mGluRs) are densely expressed through the MOB network, and they are particularly abundant at dendrodendritic synapses. Until recently, the physiological roles of mGluRs in the MOB were poorly understood. Over the past several years, mGluRs have been shown to play surprisingly powerful neuromodulatory roles at ON synapses and in dendrodendritic neurotransmission in the MOB. This chapter focuses on recent advances in our understanding of mGluR‐mediated signaling components at dendrodendritic synapses.
Molecular and Cellular Mechanisms of Trigeminal Chemosensation
Authors: Gerhold Kristin A. , Bautista Diana M.
Published: July 2009

Three sensory systems, olfaction, taste, and somatosensation, are dedicated to the detection of chemicals in the environment. Trigeminal somatosensory neurons enable us to detect a wide range of environmental stimuli, including pressure, temperature, and chemical irritants, within the oral and nasal mucosa. Natural plant‐derived irritants have served as powerful pharmacological tools for identifying receptors underlying somatosensation. This is illustrated by the use of capsaicin, menthol, and wasabi to identify the heat‐sensitive ion channel TRPV1, the cold‐sensitive ion channel TRPM8, and the irritant receptor TRPA1, respectively. In addition to TRP channels, members of the two‐pore potassium channel family have also been implicated in trigeminal chemosensation. KCNK18 was recently identified as a target for hydroxy‐α‐sanshool, the tingling and numbing compound produced in Schezuan peppers and other members of the Xanthoxylum genus. The role of these channels in trigeminal thermosensation and pain will be discussed.
The Olfactory Pathway of Adult and Larval Drosophila
Authors: Stocker Reinhard F.
Published: July 2009

Tracing of olfactory projections based on odorant receptor expression has led to an almost complete receptor‐to‐glomerulus map in adult Drosophila. While most of the glomeruli may be involved in processing of food odors, others appear to be more specialized, for example, responding to CO2 or to pheromonal cues. Recent studies have shed light on signal processing in the antennal lobe and in higher centers. Newly detected cholinergic excitatory local interneurons in the antennal lobe appear to provide substrates for the broad odor tuning properties of projection neurons. In the mushroom bodies, projection neurons establish an intricate divergence‐convergence network with their target cells, allowing complex modes of signal transfer. In the lateral horn, projection neurons innervating candidate pheromone glomeruli appear to segregate from those innervating “normal” glomeruli. Hence, pheromone and food information may be handled by separate channels, consistent with discrete behavioral meanings of the two kinds of signals. The olfactory pathway of the larva shares the general layout of its adult counterpart, with a number of simplifications. The presence of only 21 glomeruli suggests a reduction of primary olfactory “dimensions” compared to adults. The existence of a pheromone‐sensing subsystem is unlikely. Larval glomeruli are targets of single, unique sensory neurons rather than being sites of convergence as in the adult. Projection neuron outputs are restricted to single glomeruli in the mushroom body. Their target cells either innervate one or several of them creating substrates for elementary odor coding and coincidence detection. In conclusion, olfactory discrimination capacities of the larva are very likely reduced, consistent with the requirements of a substrate feeder.
Clinical Trial of Glutamate for the Improvement of Nutrition and Health in the Elderly
Authors: Tomoe Miki , Inoue Yuki , Sanbe Akiko , Toyama Kenji , Yamamoto Shigeru , Komatsu Tatsushi
Published: July 2009

Dietary free‐glutamate (Glu) improves taste and palatability. In our previous study, we found that Glu intake by hospitalized elderly was low and supplementation of monosodium l‐glutamate (MSG) to their staple diet improved their behavior. To confirm such findings, we conducted a double‐blind and placebo‐controlled trial in hospitalized elderly. The study consisted of a 1‐month lead‐in period, a 3‐month intervention period, and a 1‐month follow‐up period. In the intervention group, 0.5% (w/w) MSG was added to every staple diet, 150 g of rice gruel (the MSG group). Fourteen subjects in the MSG group (average age 83.0 ± 8.9 years) and 15 in the control group (average age 84.3 ± 9.6 years) completed the study. The subjects of both groups took most of the given foods based on the energy requirement of each subject's metabolic rate, body weight, and activity. In the last week of each period, nurses assessed the dementia score and daily performance of both groups. The daily performance was improved by dietary MSG. Behavior during mealtime was video‐recorded for 5 min in the lead‐in period and after 3 months in the intervention period. Significant improvement in the mealtime behavior was observed only in the MSG group. Furthermore, although serum albumin itself did not increase, the ratio of reduced‐form albumin to total albumin increased only in the MSG group. In conclusion, supplementation of 0.5% MSG to rice gruel three times a day for 3 months improved behaviors and the nutritional status of hospitalized elderly.
Effect of Free Dietary Glutamate on Gastric Secretion in Dogs
Authors: Zolotarev Vasiliy , Khropycheva Raisa , Uneyama Hisayuki , Torii Kunio
Published: July 2009

The amino acid, l‐glutamate, which is abundant in many foodstuffs, is a potent stimulator of gastric vagal afferents. The aim of the study was to evaluate a role of dietary glutamate in neuroendocrine control of gastric secretion of acid, pepsinogen, and fluid. In mongrel dogs with small gastric pouches surgically prepared according to Pavlov (vagally innervated) or Heidenhain (vagally decentralized), secretion in a pouch was induced by infusion into the main stomach of an amino acid‐rich diet lacking glutamate (Elental) or the same diet supplemented with monosodium glutamate (MSG). Having no effect alone, MSG (100 mM) potentiated secretion induced by Elental both in Pavlov and Heidenhain models. In the Pavlov pouch, the effect of MSG was markedly reduced after i.v. injection of granisetron, an antagonist of 5‐HT3 receptors. In the Heidenhain model, MSG enhanced the stimulatory effect of pentagastrin (1 μg/kg, s.c.). In conclusion, dietary glutamate at doses not exceeding its common concentrations in foods substantially potentiates gastric phase secretion induced by stimulation of gastric mucosa with an amino acid‐rich diet or by administration of pentagastrin. The effect of glutamate is partially mediated via serotonin secretion and stimulation of 5‐HT3 receptors.
Avian Chemoreception
Authors: McKeegan Dorothy E. F.
Published: July 2009

The first detailed physiological evidence for olfactory and trigeminal chemoreception in an avian species is provided by a series of investigations in the chicken (Gallus domesticus). Initial work indicated that the activity of avian olfactory bulb neurones closely resembles that of other vertebrates, exhibiting variable spontaneous temporal firing patterns with mean firing rates between those reported for mammals and reptiles. Application of odors directly to the olfactory epithelium showed that like mammals, avian olfactory bulb neurones respond in the form of inhibition and excitation with accompanying changes in temporal firing pattern. When exposed to a range of concentrations of a single odor, all responsive neurones exhibited an ability to discriminate small step‐changes in concentration producing clear stimulus response relationships. Avian trigeminal chemoreception was also investigated by examining the responses of single mucosal receptors in the nasal cavity and palate. Slowly and rapidly adapting nasal mechanoreceptors were identified, some of which exhibited chemical sensitivity when exposed to ammonia gas, acetic acid vapor or carbon dioxide. These results demonstrate that polymodal nociceptors are present in avian nasal mucosa and represent the first attempt in any species to quantify the responses of single trigeminal receptors to a range of concentrations of noxious airborne chemicals. Collectively, the findings demonstrate how an electrophysiological approach can improve our understanding of the underlying sensory physiology relating to avian perception of the chemical environment.
Different Prion Conformers Target the Olfactory Pathway in Sporadic Creutzfeldt–Jakob Disease
Authors: Zanusso Gianluigi , Ferrari Sergio , Benedetti Diego , Sbriccoli Marco , Rizzuto Nicola , Monaco Salvatore
Published: July 2009

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are mammalian neurodegenerative diseases that occur as sporadic, inherited, or iatrogenic forms. Human TSEs exhibit a wide spectrum of phenotypic variability, which is influenced by (1) the conformation of the pathologic prion protein, or PrPSc; (2) the polymorphic codon 129 of the prion protein gene (PRNP), involving synonymous or nonsynonymous expression of Met or Val; and (3) the site of formation or entry of the self‐replicating PrPSc. Brain deposition of PrPSc occurs in a phenotype‐specific regional pattern, either as extracellular amyloid plaques and plaque‐like aggregates, or as fine granular immunoreactivity at intracellular sites and presynaptic and postsynaptic locations, including dendrites. We previously demonstrated PrPSc deposition in ciliated dendrites of olfactory sensory neurons in sporadic Creutzfeldt–Jakob disease (sCJD), the most common human prion disease. PrPSc immunoreactivity was not limited to the olfactory neuroepithelium. But additionally involved the central olfactory pathway. More recently, we have found that the pathology of the olfactory pathway occurs early in the disease course, either in the myoclonic or classic sCJD or in the ataxic variant. Intriguingly, in the ataxic or cerebellar variant, mainly observed in patients with the Met/Val polymorphism (2) carrying PrPSc type 2, olfactory involvement is accompanied by pathologic changes in the dorsal motor nucleus of the vagus and other brainstem nuclei. These findings suggest that different molecular events and distinct routes of PrPSc spread contribute to the prominent heterogeneity of sCJD, conceivably providing support to the olfactory pathogenesis theory of neurodegenerative diseases.
Central Processing of Trigeminal Activation in Humans
Authors: Hummel T. , Iannilli E. , Frasnelli J. , Boyle J. , Gerber J.
Published: July 2009

Although numerous fMRI studies have been performed on the processing of olfactory information, the intranasal trigeminal system so far has not received much attention. In a pilot study stimulants were presented within a constantly flowing airstream birhinally to activate the olfactory (phenylethyl alcohol, H2S) or the trigeminal (CO2) nerves. Both olfactory and trigeminal stimulation activated the ventral insular cortex. Intranasal trigeminal stimulation additionally led to an activation of the midbrain, superior temporal gyrus, anterior caudate nucleus, and the dorsolateral orbitofrontal cortex. Cerebellar activation was reduced relative to odorous stimuli. For all stimuli, right‐sided activity was more pronounced. These results suggested that processing of intranasal activation follows a pattern which is, at least to some degree, similar for both trigeminal and olfactory stimulation. This and results from several other studies emphasize the fact that there is a high degree of interaction between the different aspects of the chemical senses, also in the sense that chemosensory‐induced activation in the nasal cavity is processed in similar cortical networks. Interactions between the olfactory and trigeminal system can also be seen in patients with acquired olfactory loss, who exhibit reduced trigeminal sensitivity, possibly due to the lack of a central‐nervous interaction. Both the orbitofrontal cortex and the rostral insula appear to be of significance in the amplification of trigeminal input, which is missing in patients with olfactory loss.
Gustatory and Homeostatic Functions of the Rodent Parabrachial Nucleus
Authors: De Araujo Ivan E.
Published: July 2009

Previous studies demonstrate that lesions to the rodent parabrachial nucleus (PBN) disrupt the formation of gustatory‐postingestive associations, while preserving gustatory and viscerosensory functions. This suggests that the rodent PBN functions essentially as an integrative circuit, supporting the conditioning of tastants to postingestive factors. In the case of primates, however, anatomical studies have failed to demonstrate gustatory projections from medullary nuclei to PBN. It should therefore be inferred that the primate PBN lacks the associative functions assigned to its rodent counterpart. Moreover, the ability of rodent midbrain dopaminergic systems to respond to the activation of palatable tastants depends on the integrity of the gustatory PBN. However, recent studies demonstrate that caloric palatable compounds do not require taste signaling to produce elevated brain dopamine levels. This raises the possibility that, in rodents, PBN neurons are important for the detection of postingestive effects of nutrients that occur independently of gustatory input. If confirmed, such function would assign non‐associative roles to the rodent PBN, approximating its functional organization to its primate counterpart. We are currently testing this possibility by monitoring the behavioral responses to caloric glucose solutions in sweet‐blind mice having sustained bilateral lesions to the PBN. Preliminary results indicate that the rodent PBN regulates nutrient intake even when no gustatory inputs are involved. This favors the assignment of non‐gustatory, homeostatic functions to the rodent PBN during feeding, a concept that brings an additional perspective on the rodent versus primate functional discrepancy associated with the anatomy of this pontine nucleus.
Parabrachial Coding of Sapid Sucrose:
Authors: Hajnal Andras , Norgren Ralph , Kovacs Peter
Published: July 2009

Cumulative evidence in rats suggests that the pontine parabrachial nuclei (PBN) are 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 in the nucleus accumbens caused by sucrose ingestion. Recent single‐neuron recording studies have demonstrated that processing of sucrose‐evoked activity in the PBN is altered in Otsuka Long Evans Tokushima Fatty (OLETF) rats, which 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, with decreased responses to lower concentrations 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.
Genetic Tracing of the Gustatory Neural Pathway Originating from T1R3‐expressing Sweet/Umami Taste Receptor Cells
Authors: Matsumoto Ichiro , Ohmoto Makoto , Yasuoka Akihito , Yoshihara Yoshihiro , Abe Keiko
Published: July 2009

Neural pathways conveying taste information from the tongue to the brain underlie gustatory information coding and processing. To visualize the gustatory neural pathways, we established transgenic mouse lines in which a transneuronal tracer, wheat germ agglutinin (WGA), was faithfully and robustly expressed in sweet/umami taste receptor cells (TRCs) under the control of mouse T1R3 gene promoter/enhancer. WGA protein was transferred not laterally to the cells with synaptic structure, but directly to a subset of neurons in the geniculate and nodose/petrosal ganglia, and further conveyed to a subpopulation of neurons in the rostro‐central region of the nucleus of the solitary tract. However, no WGA immunoreactivity was observed in more central gustatory relay nuclei even in the parabrachial nucleus. These results imply that sweet/umami information from TRCs can be directly transmitted to the gustatory neurons that innervate the sweet/umami TRCs, and this study uncovered a precise map of the sweet/umami information pathway from TRCs to the nucleus of solitary tract in the brain stem.
Behavioral and Cellular Level Changes in the Aging Somatosensory System
Authors: Wang Shuying , Albers Kathryn M.
Published: July 2009

A study of the peripheral sensory system of young and aged Blk6 mice obtained from the National Institutes on Aging mouse colony is described. Behavioral assays showed male and female aged mice had decreased sensitivity to thermal stimuli. The receptor for the growth factor artemin (Artn), GFRα3, and the ion channel TRPV1, which is expressed by 95–99% of GFRα3‐positive primary sensory neurons, was also decreased. Calcium imaging of isolated dorsal root ganglia neurons grown with nerve growth factor was used to test the in vitro effects of Artn on TRPV1 activation by capsaicin in young and old neurons. Artn potentiated initial TRPV1 responses to capsaicin in young and old neurons, but the percent of capsaicin responders following repeated exposure to capsaicin increased only in young neurons. The lack of change in aged neurons suggests that differences in TRPV1 responses occur with aging in the somatosensory system.
Pattern Separation and Completion in Olfaction
Authors: Wilson Donald A.
Published: July 2009

The nervous system must provide a mechanism for very precise discrimination of differing patterns of activity, yet at the same time, there must be a mechanism for generalization to prevent all experiences from being independent and novel. Pattern separation and completion by cortical circuits contribute to these processes, respectively. Based on theoretical and computational models of the piriform cortex and experimental designs developed for hippocampal spatial memory, we provide evidence for pattern separation and completion in the olfactory system and demonstrate the predictive power of these two processes for behavioral odor perception.
AMP‐activated Protein Kinase and FoxO Transcription Factors in Dietary Restriction–induced Longevity
Authors: Greer Eric L. , Banko Max R. , Brunet Anne
Published: July 2009

Aging is regulated by modifications in single genes and by simple changes in the environment. The signaling pathway connecting insulin to FoxO transcription factors integrates environmental stimuli to regulate lifespan. FoxO transcription factors are directly phosphorylated in response to insulin/growth factor signaling by the protein kinase Akt, thereby causing their sequestration in the cytoplasm. In the absence of insulin/growth factors, FoxO factors translocate to the nucleus where they trigger a range of cellular responses, including resistance to oxidative stress—a phenotype highly coupled with lifespan extension. Our recent results indicate that FoxO transcription factors are also regulated in response to nutrient deprivation by the AMP‐activated protein kinase (AMPK) pathway. The energy‐sensing AMPK directly phosphorylates FoxO transcription factors at six regulatory sites. AMPK phosphorylation enhances FoxO transcriptional activity, leading to the expression of specific target genes involved in stress resistance and changes in energy metabolism. The AMPK–FoxO pathway plays a crucial role in the ability of a dietary restriction regimen to extend lifespan in Caenorhabditis elegans. Understanding the intricate signaling networks that translate environmental conditions like dietary restriction into changes in gene expression that extend lifespan will be of critical importance to identify ways to delay the onset of aging and age‐dependent diseases.
Visual Motion Processing in Aging and Alzheimer's Disease
Authors: Duffy Charles J.
Published: July 2009

Aging and Alzheimer's disease (AD) are accompanied by impairments of autonomous navigation and spatial orientation that commonly demand the abandonment of driving and independent living. We have studied the neuronal mechanisms of navigation using single neurons in monkey cerebral cortex, finding a specific population of cells that processes the visual motion patterns of optic flow that provide important cues about self‐movement. We have found that AD patients show pronounced deficits in the perceptual processing of optic flow, with different patterns of less severe impairment in mild cognitive impairment and cognitive aging. These perceptual deficits occur in subjects who show difficulties in real‐world navigation that can be linked to visual associative processing impairments. Human neurophysiological recordings reveal a robust link between navigational capacity and cortical information processing in aging and AD. We conclude that visual information processing is progressively impaired in aging and AD. We speculate that these behavioral impairments reflect the progress of mechanistically linked cortical pathophysiologies that are manifestations of the fateful transition from cognitive aging to AD.
dOr83b—Receptor or Ion Channel?
Authors: Wicher Dieter , Schäfer Ronny , Bauernfeind René , Stensmyr Marcus C. , Heller Regine , Heinemann Stefan H. , Hansson Bill S.
Published: July 2009

Odorant signals are detected by binding of odor molecules to odorant receptors. These belong to the G protein‐coupled receptor family. They in turn couple to G proteins, most of which induce cAMP production. This second messenger activates ion channels to depolarize the olfactory sensory neuron, thus providing a signal for further neuronal processing. Recent findings challenge this concept of olfactory signal transduction in insects, since their odorant receptors, which lack any sequence similarity to other G protein‐coupled receptors, are composed of conventional odorant receptors (e.g., Or22a), dimerized with a ubiquitously expressed chaperone protein, such as Or83b in Drosophila. Or83b has a structure similar to G protein‐coupled receptors, but has an inverted orientation in the plasma membrane. Still, G proteins are expressed in insect olfactory receptor neurons, and olfactory perception is modified by mutations affecting the cAMP transduction pathway. In our experiments we demonstrated that application of odorants to mammalian cells co‐expressing Or22a and Or83b results in nonselective cation currents activated via both an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca2+ concentration. Expression of Or83b alone leads to functional ion channels not directly responding to odorants, but directly activated by intracellular cAMP or cGMP. Insect odorant receptors thus form ligand‐gated channels as well as complexes of odorant‐sensing units and cyclic nucleotide–activated nonselective cation channels.
Functional Analysis of the Guanylyl Cyclase Type D Signaling System in the Olfactory Epithelium
Authors: Cockerham Renee E. , Leinders‐Zufall Trese , Munger Steven D. , Zufall Frank
Published: July 2009

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.
Linking Cell Cycle Reentry and DNA Damage in Neurodegeneration
Authors: Kim Dohoon , Tsai Li‐Huei
Published: July 2009

Aberrant cell cycle activity and DNA damage have been observed in neurons in association with various neurodegenerative conditions. While there is strong evidence for a causative role for these events in neurotoxicity, it is unclear how they are triggered and why they are toxic. Here, we introduce a brief background of the current view on cell cycle activity and DNA damage in neurons and speculate on their relevance to neuronal survival. Furthermore, we suggest that the two events may be triggered in common by deregulation of fundamental processes, such as chromatin modulation, which are required for maintaining both DNA integrity and proper regulation of cell cycle gene expression.
Receptors and Transduction of Umami Taste Stimuli
Authors: Kinnamon Sue C. , Vandenbeuch Aurelie
Published: July 2009

L‐glutamate and 5′‐ribonucleotides, such as GMP and IMP, elicit the “umami” taste, also known as the fifth taste. This review will highlight recent advancements in our understanding of umami taste receptors and their downstream signaling effectors in taste receptor cells. Several G protein‐coupled receptors that bind umami stimuli have been identified in taste buds, including the heterodimer T1R1/T1R3, truncated and brain forms of mGluR4 and mGluR1, brain mGluR2, and brain mGluR3. Further, ionotropic glutamate receptors are expressed in taste cells and may play a role in glutamate transduction or signaling between taste cells and/or nerve fibers. Knockout of T1R1 or T1R3 reduces, but does not eliminate, responses to umami stimuli, suggesting that multiple receptors contribute to umami taste. The signaling effectors downstream of umami G protein‐coupled receptors involve Gβγ activation of PLCβ2 to elicit Ca2+ release from intracellular stores and activation of a cation channel, TRPM5. In fungiform and palatal taste buds, T1R1/T1R3 is co‐expressed with Gα gustducin and transducin, but the Gα proteins involved in circumvallate taste buds have not been identified. In most taste fields, however, cAMP antagonizes responses to umami stimuli, suggesting that the Gα subunit serves to modulate umami taste sensitivity.
Neural Basis of Olfactory Perception
Authors: Gelperin Alan , Ghatpande Ambarish
Published: July 2009

The neural basis of olfactory information processing and olfactory percept formation is a topic of intense investigation as new genetic, optical, and psychophysical tools are brought to bear to identify the sites and interaction modes of cortical areas involved in the central processing of olfactory information. New methods for recording cellular interactions and network events in the awake, behaving brain during olfactory processing and odor‐based decision making have shown remarkable new properties of neuromodulation and synaptic interactions distinct from those observed in anesthetized brains. Psychophysical, imaging, and computational studies point to the orbitofrontal cortex as the likely locus of odor percept formation in mammals, but further work is needed to identify a causal link between perceptual and neural events in this area.
The Alarm Reaction in Fishes—Odorants, Modulations of Responses, Neural Pathways
Authors: Døving Kjell B. , Lastein Stine
Published: July 2009

In 1938, von Frisch discovered the alarm reaction (“schreck reaktion”) in fishes. He found that substances stored in the skin are released upon injury and detected by the olfactory organ. Several agonists that induce alarm reactions have been identified since then, but the true nature of the alarm substances remains veiled. Behavioral experiments have demonstrated that skin extract of conspecifics is more potent than that of heterospecifics. During development, the alarm reaction is seen in the larval stages in several cyprinid species; the threshold for eliciting the reaction decreases with age. Further, in crucian carp the alarm reaction was shown to be suppressed in the majority of females during the spawning period. The anatomy of the olfactory organ of this species is advantageous for studying underlying mechanisms of olfactory‐induced behaviors. Crucian carp have been applied as a model organism in our lab for identification of the neural pathway of the alarm reaction, mainly in primary and secondary olfactory neurons. In the olfactory bulb, there is a distinct region that responds specifically to skin extract. The neural basis for discrimination between extracts of skin from different species has been investigated, suggesting that identification of conspecifics may be based on activation of specific subsets of neurons.
Onset of Odorant Receptors
Authors: Rodriguez‐Gil Diego J. , Treloar Helen B. , Miller Alexandra , Two Aimee , Iwema Carrie , Greer Charles A.
Published: July 2009

Odorant receptors are thought to be critical determinants of olfactory sensory neuron axon targeting and organization. Nonetheless, a systematic characterization of the onset of odorant receptor expression has not yet been done in the main olfactory epithelium. Here, we briefly review our current understanding regarding the onset of odorant receptor expression in the main olfactory epithelium and identify some of those questions which we believe must be of high priority for future study.
WNT5a in Tongue and Fungiform Papilla Development
Authors: Liu Hong‐Xiang , Grosse Ann M. Staubach , Walton Katherine D. , Saims Daniel A. , Gumucio Deborah L. , Mistretta Charlotte M.
Published: July 2009

Fungiform papillae are complex taste organs that develop in a pattern on anterior tongue in rodent embryos. Several intrinsic secreted molecules are important for papilla development and patterning, including sonic hedgehog, bone morphogenetic proteins, Noggin, epidermal growth factor, and WNTs. Recent data about roles of WNTs in regulation of tongue and fungiform papilla development lead to new insights about the importance of tissue and timing contexts when studying the effects of morphogenetic proteins. WNT/β‐catenin signaling is required for formation of fungiform papillae, but not for determining tongue size and shape. In contrast, WNT5a apparently is important for tongue outgrowth, but not papilla development. Preliminary data from WNT5a mutant mice separate genetic programs for papilla number from those for tongue shape and size.
Activity‐dependent Extrinsic Regulation of Adult Olfactory Bulb and Hippocampal Neurogenesis
Authors: Ma Dengke K. , Kim Woon Ryoung , Ming Guo‐li , Song Hongjun
Published: July 2009

The adult mammalian brain continuously generates new neurons in the olfactory bulb and hippocampus throughout life. Adult neurogenesis, a highly dynamic process, has been shown to be exquisitely modulated by neuronal circuit activity at different stages, from proliferation of adult neural progenitors, to differentiation, maturation, integration, and survival of newborn neurons in the adult brain. Strategic activity‐dependent addition of new neurons into the existing neuronal circuitry represents a prominent form of structural plasticity and may contribute to specific brain functions, such as learning, memory, and mood modulation. Here we review extrinsic mechanisms through which adult neurogenesis is regulated by environmental cues, physiological learning‐related stimuli, and neuronal activities.
Heterologous Expression of Olfactory Receptors for Targeted Chemosensing
Authors: Dhanasekaran Danny N. , Radhika Venkat , Proikas‐Cezanne Tassula , Jayaraman Muralidharan , Ha Jihee
Published: July 2009

With the broad objective of developing a heterologous expression system for the mammalian olfactory signaling pathway, we have engineered yeast cells in which the mammalian olfactory signaling pathway is genetically integrated. Our results demonstrate that the prototypic “olfactory yeast” strain WIF‐1α can sense and report the presence of defined chemical agents through the engineered mammalian olfactory system. In this heterologous Saccharomyces cerevisiae‐based expression system, the primary components of the mammalian olfactory signaling pathway have been engineered, and signaling by the rat olfactory receptor is coupled to the expression of green fluorescent protein. By shuttling a library of olfactory receptor ligand‐binding pockets into the pre‐engineered signaling units of WIF‐1 yeast cells, we further demonstrate the ability of these olfactory yeast cells to detect 2,4‐dinitrotoluene. Using this approach, our results have identified the novel rat olfactory receptor Olfr226 as a 2,4‐dinitrotoluene‐responsive receptor. Genetic integration of a highly discriminatory olfactory system into biologically stable and biochip‐adaptable yeast cells, as presented here, can provide an ideal targeted chemosensing platform for detecting diverse chemical molecules. In addition to their potential use in deorphanizing the superfamily of olfactory receptors, the engineered olfactory yeast cells should be amenable for high‐throughput screening to identify receptor‐specific molecular targets.
Neuroregulation of Human Nasal Mucosa
Authors: Baraniuk James N. , Merck Samantha J.
Published: July 2009

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.
Epidemiological Studies of Smell
Authors: Smith Wendy , Murphy Claire
Published: July 2009

The critical epidemiological data for estimating the prevalence of chemosensory disorders in the United States 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 establish the high prevalence of olfactory impairment in older adults in the U.S. 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.
T1r3 and α‐Gustducin in Gut Regulate Secretion of Glucagon‐like Peptide‐1
Authors: Kokrashvili Zaza , Mosinger Bedrich , Margolskee Robert F.
Published: July 2009

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that underlies the augmented insulin release from the pancreas in response to glucose in the gut lumen more than to intravenous injected glucose (the “incretin effect”). GLP‐1, found in enteroendocrine L cells of the gut, regulates appetite and gut motility and is released from L cells in response to glucose. GLP‐1‐expressing duodenal L cells also express T1r taste receptors, α‐gustducin, and many other taste transduction elements. Knockout mice lacking α‐gustducin or T1r3 have deficiencies in secretion of GLP‐1 and in the regulation of plasma levels of insulin and glucose. Gut‐expressed taste‐signaling elements underlie multiple chemosensory functions of the gut including the incretin effect. Modulating hormone secretion from gut “taste cells” may provide novel treatments for obesity, diabetes, and malabsorption.