Stuart Firestein

We performed comprehensive data mining to explore the vomeronasal receptor (V1R and V2R) repertoires in mouse and rat using the mm5 and rn3 genome, respectively. This bioinformatic analysis was followed by investigation of gene expression using a custom designed high-density oligonucleotide array containing all of these receptors and other selected genes of interest. This array enabled us to detect the specific expression of V1R and V2Rs which were previously identified solely based on computational prediction from gene sequence data, thereby establishing that these genes are indeed part of the vomeronasal system, especially the V2Rs...

During normal and diseased aging, it is thought the capacity for tissue regeneration and repair in neuronal tissues diminishes. In the peripheral olfactory system, stem cell reservoirs permit regeneration of olfactory and vomeronasal sensory neurons, a unique capacity among neurons. Following injury, a large number of new neurons can be regenerated in a young animal. However, it is unknown whether this capacity for renewal exists in aged proliferative populations. Here, we report that neuronal replacement-associated proliferation continues in the vomeronasal organ of aged (18-24 months) mice...

Olfactory sensory neuron (OSN) axons exit the olfactory epithelium (OE) and extend toward the olfactory bulb (OB) where they coalesce into glomeruli. Each OSN expresses only 1 of approximately 1,200 odor receptors (ORs). OSNs expressing the same OR are distributed in restricted zones of the OE. However, within a zone, the OSNs expressing a specific OR are not contiguous - distribution appears stochastic. Upon reaching the OB the OSN axons expressing the same OR reproducibly coalesce into two to three glomeruli...

As odorant receptors (ORs) are thought to be critical determinants of olfactory sensory neuron (OSN) axon targeting and organization, we examined the spatiotemporal onset of mice ORs expression from the differentiation of OSNs in the olfactory placode to an aging olfactory epithelium. ORs were first detected in the placode at embryonic day 9 (E9), at the onset of OSN differentiation but before axon extension. By E13, 22 of 23 ORs were expressed. Onset of individual OR expression was diverse; levels and patterns of expression were unique for each OR...

The discrimination of n-alkyl-saturated aldehydes during the early stage of odorant recognition by the rat I7 olfactory receptor (OR-I7) is investigated. The concentrations of odorants necessary for 50% activation (or inhibition) of the OR-I7 are measured by calcium imaging recordings of dissociated rat olfactory sensory neurons, expressing the recombinant OR-I7 from an adenoviral vector. These are correlated with the corresponding binding free energies computed for a homology structural model of the OR-I7 built from the crystal structure of bovine visual rhodopsin at 2...

Adult neurogenesis replenishes olfactory bulb (OB) interneurons throughout the life of most mammals, yet during this constant flux it remains unclear how the OB maintains a constant structure and function. In the mouse OB, we investigated the dynamics of turnover and its impact on olfactory function by ablating adult neurogenesis with an x-ray lesion to the sub-ventricular zone (SVZ). Regardless of the magnitude of the lesion to the SVZ, we found no change in the survival of young adult born granule cells (GCs) born after the lesion, and a gradual decrease in the population of GCs born before the lesion...

The response of olfactory sensory neurons to TNT and RDX as well as to some volatile organic compounds present in the vapors of antipersonnel landmines has been studied both in the pig and in the rat. GC/MS analyses of different plastic components of six different kinds of landmines were performed in order to identify the components of the "perfume" of mines. Studies on rat olfactory mucosa were carried out with electro-olfactogram and calcium imaging techniques, while changes in the cyclic adenosine monophosphate (cAMP) levels following exposure to odorants and explosives were used as a criterion to evaluate the interaction of TNT and RDX with olfactory receptors in a preparation of isolated pig olfactory cilia...

No abstract text is available yet for this article.

Differentiated olfactory sensory neurons express specific presynaptic proteins, including enzymes involved in neurotransmitter transport and proteins involved in the trafficking and release of synaptic vesicles. Studying the regulation of these presynaptic proteins will help to elucidate the presynaptic differentiation process that ultimately leads to synapse formation. It has been postulated that the formation of a synapse between the axons of the sensory neurons and the dendrites of second order neurons in the olfactory bulb is a critical step in the processes of sensory neuron maturation...

The nearly 2,000 glomeruli that cover the surface of the olfactory bulb are so distinctive that they were noted specifically in the earliest of Cajal's catalogues. They have variously been considered a functional unit, an organizational unit and a crucial component of the olfactory coding circuit. Despite their central position in olfactory processing, the development of the glomeruli has only recently begun to be investigated with new and powerful genetic tools. Some unexpected findings have been made that may lead to a new understanding of the processes involved in wiring sensory regions of the brain...

SRp38 is an atypical SR protein splicing regulator. To define the functions of SRp38 in vivo, we generated SRp38 null mice. The majority of homozygous mutants survived only until E15.5 and displayed multiple cardiac defects. Evaluation of gene expression profiles in the SRp38(-/-) embryonic heart revealed a defect in processing of the pre-mRNA encoding cardiac triadin, a protein that functions in regulation of Ca(2+) release from the sarcoplasmic reticulum during excitation-contraction coupling. This defect resulted in significantly reduced levels of triadin, as well as those of the interacting protein calsequestrin 2...

Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (G(olf)), are expressed in the kidney. AC3 and G(olf) colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3(-/-) mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD...

In many species, the sense of smell plays important roles in locating food, detecting predators, navigating, and communicating social information. The olfactory system has evolved complex repertoires of odor receptors (ORs) to fulfill these functions. Through computational data mining, OR repertoires of multiple species were identified, revealing a surprisingly large OR gene family in rodents and evolutionary fluctuation among different organisms. Characteristics of OR genes were explored through computational and experimental methods, showing a complicated gene structure and special genomic distribution...

Olfactory receptors (ORs) form a large family of G protein-coupled receptor proteins (GPCRs) responsible for sensing the ambient chemical environment. The molecular recognition strategies used by ORs to detect and distinguish odorant molecules are unclear. Here, we investigated the variable of odorant carbon chain conformation for an established odorant-OR pair: n-octanal and rat OR-I7. A series of conformationally restricted octanal mimics were tested on live olfactory sensory neurons (OSNs). Our results support a model in which unactivated OR-I7 binds aliphatic aldehydes indiscriminately, and then applies conformational and length filters to distinguish agonists from antagonists...

The prion protein PrP(C) is infamous for its role in disease, but its normal physiological function remains unknown. Here we found a previously unknown behavioral phenotype of Prnp(-/-) mice in an odor-guided task. This phenotype was manifest in three Prnp knockout lines on different genetic backgrounds, which provides strong evidence that the phenotype is caused by a lack of PrP(C) rather than by other genetic factors. Prnp(-/-) mice also showed altered behavior in a second olfactory task, suggesting that the phenotype is olfactory specific...

Contrast enhancement in sensory systems often relies on spatial filters implemented by lateral inhibition. However, in this issue of Neuron, Fantana et al. provide evidence that lateral inhibition in the olfactory bulb selectively acts between sparse populations of principal neurons without regard to spatial relations.

Olfactory sensory neurons (OSNs) represent a unique population of neurons in which death and regeneration are ongoing throughout adulthood, a feature that makes them an attractive model cell type for the investigation of neuronal death. However, the mechanism by which OSNs die remains elusive. Therefore, we developed a culture system for studying pathways involved in OSN death. Here, we show that inhibition of transcription or translation, by actinomycin D or cycloheximide, respectively, suppresses pathways leading to death, prolonging the survival of OSNs in culture...

No abstract text is available yet for this article.

The normal physiological function of the prion protein PrP(C) remains elusive despite its widespread expression, particularly throughout the nervous system. A critical step toward identifying its function is to precisely localize its pattern of expression. Historically, the immunolocalization of PrP(C) has proved to be notoriously difficult and nonconsensual. We have thus undertaken a detailed expression analysis by means of a combination of in situ hybridization, knockout mice, and immunohistochemistry, using recently generated highly specific antibodies...

Neurogenesis persists in the olfactory system throughout life. The mechanisms of how new neurons are generated, how they integrate into circuits, and their role in coding remain mysteries. Here we report a technique that will greatly facilitate research into these questions. We found that electroporation can be used to robustly and selectively label progenitors in the Subventicular Zone. The approach was performed postnatally, without surgery, and with near 100% success rates. Labeling was found in all classes of interneurons in the olfactory bulb, persisted to adulthood and had no adverse effects...