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1.
Science ; 381(6661): 952, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37651507

RESUMO

A compelling new play revisits the discovery that drastically reduced maternal mortality.

2.
Science ; 381(6656): 380, 2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37499026

RESUMO

The man who discovered that whales sing.


Assuntos
Vocalização Animal , Baleias , Animais
3.
Nat Neurosci ; 25(9): 1119, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35902651
4.
Cell ; 185(6): 1052-1064.e12, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35180380

RESUMO

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.


Assuntos
Anosmia , COVID-19 , Animais , Cricetinae , Regulação para Baixo , Humanos , Receptores Odorantes , SARS-CoV-2 , Olfato
5.
bioRxiv ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33594368

RESUMO

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.

6.
Science ; 368(6487)2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32273438

RESUMO

Olfactory responses to single odors have been well characterized but in reality we are continually presented with complex mixtures of odors. We performed high-throughput analysis of single-cell responses to odor blends using Swept Confocally Aligned Planar Excitation (SCAPE) microscopy of intact mouse olfactory epithelium, imaging ~10,000 olfactory sensory neurons in parallel. In large numbers of responding cells, mixtures of odors did not elicit a simple sum of the responses to individual components of the blend. Instead, many neurons exhibited either antagonism or enhancement of their response in the presence of another odor. All eight odors tested acted as both agonists and antagonists at different receptors. We propose that this peripheral modulation of responses increases the capacity of the olfactory system to distinguish complex odor mixtures.


Assuntos
Odorantes/análise , Neurônios Receptores Olfatórios/fisiologia , Olfato/fisiologia , Acetofenonas/análise , Monoterpenos Acíclicos/análise , Animais , Compostos de Benzil/análise , Camundongos , Camundongos Mutantes , Microscopia Confocal , Mucosa Olfatória/inervação , Análise de Célula Única
7.
Sci Adv ; 4(2): eaao6086, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29487905

RESUMO

Crucial for any hypothesis about odor coding is the classification and prediction of sensory qualities in chemical compounds. The relationship between perceptual quality and molecular structure has occupied olfactory scientists throughout the 20th century, but details of the mechanism remain elusive. Odor molecules are typically organic compounds of low molecular weight that may be aliphatic or aromatic, may be saturated or unsaturated, and may have diverse functional polar groups. However, many molecules conforming to these characteristics are odorless. One approach recently used to solve this problem was to apply machine learning strategies to a large set of odors and human classifiers in an attempt to find common and unique chemical features that would predict a chemical's odor. We use an alternative method that relies more on the biological responses of olfactory sensory neurons and then applies the principles of medicinal chemistry, a technique widely used in drug discovery. We demonstrate the effectiveness of this strategy through a classification for esters, an important odorant for the creation of flavor in wine. Our findings indicate that computational approaches that do not account for biological responses will be plagued by both false positives and false negatives and fail to provide meaningful mechanistic data. However, the two approaches used in tandem could resolve many of the paradoxes in odor perception.


Assuntos
Química Farmacêutica/métodos , Odorantes/análise , Animais , Comportamento Animal , Ésteres/química , Humanos , Camundongos , Neurônios Receptores Olfatórios/fisiologia , Olfato/fisiologia
8.
Sci Rep ; 6: 35215, 2016 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-27739476

RESUMO

Olfactory receptors (ORs) are G protein-coupled receptors which serve important sensory functions beyond their role as odorant detectors in the olfactory epithelium. Here we describe a novel role for one of these ORs, Olfr1393, as a regulator of renal glucose handling. Olfr1393 is specifically expressed in the kidney proximal tubule, which is the site of renal glucose reabsorption. Olfr1393 knockout mice exhibit urinary glucose wasting and improved glucose tolerance, despite euglycemia and normal insulin levels. Consistent with this phenotype, Olfr1393 knockout mice have a significant decrease in luminal expression of Sglt1, a key renal glucose transporter, uncovering a novel regulatory pathway involving Olfr1393 and Sglt1. In addition, by utilizing a large scale screen of over 1400 chemicals we reveal the ligand profile of Olfr1393 for the first time, offering new insight into potential pathways of physiological regulation for this novel signaling pathway.


Assuntos
Glucose/metabolismo , Túbulos Renais Proximais/metabolismo , Neurônios Receptores Olfatórios/metabolismo , Animais , Linhagem Celular , Cães , Células HEK293 , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Olfatória/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Odorantes/metabolismo , Transdução de Sinais/fisiologia , Transportador 1 de Glucose-Sódio/metabolismo
9.
Nat Commun ; 7: 11157, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27040654

RESUMO

Associating an odorant's chemical structure with its percept is a long-standing challenge. One hindrance may come from the adoption of the organic chemistry scheme of molecular description and classification. Chemists classify molecules according to characteristics that are useful in synthesis or isolation, but which may be of little importance to a biological sensory system. Accordingly, we look to medicinal chemistry, which emphasizes biological function over chemical form, in an attempt to discern which among the many molecular features are most important for odour discrimination. Here we use medicinal chemistry concepts to assemble a panel of molecules to test how heteroaromatic ring substitution of the benzene ring will change the odour percept of acetophenone. This work allows us to describe an extensive rule in odorant detection by mammalian olfactory receptors. Whereas organic chemistry would have predicted the ring size and composition to be key features, our work reveals that the topological polar surface area is the key feature for the discrimination of these odorants.


Assuntos
Acetofenonas/química , Discriminação Psicológica/fisiologia , Odorantes , Receptores Odorantes/fisiologia , Animais , Camundongos , Estrutura Molecular , Receptores Odorantes/química , Estimulação Química
11.
Front Neurosci ; 9: 367, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26500487

RESUMO

While the capacity of the olfactory epithelium (OE) to generate sensory neurons continues into middle age in mice, it is presumed that this regenerative potential is present throughout all developmental stages. However, little experimental evidence exists to support the idea that this regenerative capacity remains in late adulthood, and questions about the functionality of neurons born at these late stages remain unanswered. Here, we extend our previous work in the VNO to investigate basal rates of proliferation in the OE, as well as after olfactory bulbectomy (OBX), a commonly used surgical lesion. In addition, we show that the neural stem cell retains its capacity to generate mature olfactory sensory neurons in aged animals. Finally, we demonstrate that regardless of age, a stem cell in the OE, the horizontal basal cell (HBC), exhibits a morphological switch from a flattened, quiescent phenotype to a pyramidal, proliferative phenotype following chemical lesion in aged animals. These findings provide new insights into determining whether an HBC is active or quiescent based on a structural feature as opposed to a biochemical one. More importantly, it suggests that neural stem cells in aged mice are responsive to the same signals triggering proliferation as those observed in young mice.

12.
Proc Natl Acad Sci U S A ; 111(47): 16931-6, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25385630

RESUMO

The piriform cortex (PCX) is the largest component of the olfactory cortex and is hypothesized to be the locus of odor object formation. The distributed odorant representation found in PCX contrasts sharply with the topographical representation seen in other primary sensory cortices, making it difficult to test this view. Recent work in PCX has focused on functional characteristics of these distributed afferent and association fiber systems. However, information regarding the efferent projections of PCX and how those may be involved in odor representation and object recognition has been largely ignored. To investigate this aspect of PCX, we have used the efferent pathway from mouse PCX to the orbitofrontal cortex (OFC). Using double fluorescent retrograde tracing, we identified the output neurons (OPNs) of the PCX that project to two subdivisions of the OFC, the agranular insula and the lateral orbitofrontal cortex (AI-OPNs and LO-OPNs, respectively). We found that both AI-OPNs and LO-OPNs showed a distinct spatial topography within the PCX and fewer than 10% projected to both the AI and the LO as judged by double-labeling. These data revealed that the efferent component of the PCX may be topographically organized. Further, these data suggest a model for functional organization of the PCX in which the OPNs are grouped into parallel output circuits that provide olfactory information to different higher centers. The distributed afferent input from the olfactory bulb and the local PCX association circuits would then ensure a complete olfactory representation, pattern recognition capability, and neuroplasticity in each efferent circuit.


Assuntos
Córtex Piriforme/anatomia & histologia , Células Receptoras Sensoriais/citologia , Animais , Camundongos , Córtex Piriforme/citologia
13.
ACS Chem Biol ; 9(11): 2563-71, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25181321

RESUMO

The mammalian odorant receptors (ORs) form a chemical-detecting interface between the atmosphere and the nervous system. This large gene family is composed of hundreds of membrane proteins predicted to form as many unique small molecule binding niches within their G-protein coupled receptor (GPCR) framework, but very little is known about the molecular recognition strategies they use to bind and discriminate between small molecule odorants. Using rationally designed synthetic analogs of a typical aliphatic aldehyde, we report evidence that among the ORs showing specificity for the aldehyde functional group, a significant percentage detect the aldehyde through its ability to react with water to form a 1,1-geminal (gem)-diol. Evidence is presented indicating that the rat OR-I7, an often-studied and modeled OR known to require the aldehyde function of octanal for activation, is likely one of the gem-diol activated receptors. A homology model based on an activated GPCR X-ray structure provides a structural hypothesis for activation of OR-I7 by the gem-diol of octanal.


Assuntos
Aldeídos/metabolismo , Receptores Odorantes/metabolismo , Animais , Ratos
14.
Front Neurosci ; 8: 182, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25018692

RESUMO

Neurogenesis continues well beyond embryonic and early postnatal ages in three areas of the nervous system. The subgranular zone supplies new neurons to the dentate gyrus of the hippocampus. The subventricular zone supplies new interneurons to the olfactory bulb, and the olfactory neuroepithelia generate new excitatory sensory neurons that send their axons to the olfactory bulb. The latter two areas are of particular interest as they contribute new neurons to both ends of a first-level circuit governing olfactory perception. The vomeronasal organ and the main olfactory epithelium comprise the primary peripheral olfactory epithelia. These anatomically distinct areas share common features, as each exhibits extensive neurogenesis well beyond the juvenile phase of development. Here we will discuss the effect of age on the structural and functional significance of neurogenesis in the vomeronasal and olfactory epithelia, from juvenile to advanced adult ages, in several common model systems. We will next discuss how age affects the regenerative capacity of these neural stem cells in response to injury. Finally, we will consider the integration of newborn neurons into an existing circuit as it is modified by the age of the animal.

15.
J Gen Physiol ; 143(5): 527-42, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24733839

RESUMO

The odorant receptors (ORs) provide our main gateway to sensing the world of volatile chemicals. This involves a complex encoding process in which multiple ORs, each of which detects its own set of odorants, work as an ensemble to produce a distributed activation code that is presumably unique to each odorant. One marked challenge to decoding the olfactory code is OR deorphanization, the identification of a set of activating odorants for a particular receptor. Here, we survey various methods used to try to express defined ORs of interest. We also suggest strategies for selecting odorants for test panels to evaluate the functional expression of an OR. Integrating these tools, while retaining awareness of their idiosyncratic limitations, can provide a multi-tiered approach to OR deorphanization, spanning the initial discovery of a ligand to vetting that ligand in a physiologically relevant setting.


Assuntos
Clonagem Molecular/métodos , Ensaios de Triagem em Larga Escala/métodos , Receptores Odorantes/metabolismo , Animais , Humanos , Ligantes , Ligação Proteica , Receptores Odorantes/agonistas , Receptores Odorantes/antagonistas & inibidores , Receptores Odorantes/genética
16.
Proc Natl Acad Sci U S A ; 110(11): 4410-5, 2013 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-23401498

RESUMO

Olfactory receptors are G protein-coupled receptors that mediate olfactory chemosensation and serve as chemosensors in other tissues. We find that Olfr78, an olfactory receptor expressed in the kidney, responds to short chain fatty acids (SCFAs). Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs. In addition, both Olfr78 and G protein-coupled receptor 41 (Gpr41), another SCFA receptor, are expressed in smooth muscle cells of small resistance vessels. Propionate, a SCFA shown to induce vasodilation ex vivo, produces an acute hypotensive response in wild-type mice. This effect is differentially modulated by disruption of Olfr78 and Gpr41 expression. SCFAs are end products of fermentation by the gut microbiota and are absorbed into the circulation. Antibiotic treatment reduces the biomass of the gut microbiota and elevates blood pressure in Olfr78 knockout mice. We conclude that SCFAs produced by the gut microbiota modulate blood pressure via Olfr78 and Gpr41.


Assuntos
Pressão Sanguínea/fisiologia , Intestinos/microbiologia , Rim/metabolismo , Metagenoma/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Odorantes/metabolismo , Renina/metabolismo , Transdução de Sinais/fisiologia , Animais , Biomassa , Pressão Sanguínea/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/microbiologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Knockout , Propionatos/metabolismo , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/genética , Receptores Odorantes/genética , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
17.
Neurobiol Aging ; 34(7): 1873-81, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23419702

RESUMO

Throughout life the subventricular zone (SVZ) is a source of new olfactory bulb (OB) interneurons. From the SVZ, neuroblasts migrate tangentially through the rostral migratory stream (RMS), a restricted route approximately 5 mm long in mice, reaching the OB within 10-14 days. Within the OB, neuroblasts migrate radially to the granule and glomerular layers where they differentiate into granule and periglomerular (PG) cells and integrate into existing synaptic circuits. SVZ neurogenesis decreases with age, and might be a factor in age-related olfactory deficits. However, the effect of aging on the RMS and on the differentiation of interneuron subpopulations remains poorly understood. Here, we examine RMS cytoarchitecture, neuroblast proliferation and clearance from the RMS, and PG cell subpopulations at 6, 12, 18, and 23 months of age. We find that aging affects the area occupied by newly generated cells within the RMS and regional proliferation, and the clearance of neuroblasts from the RMS and PG cell subpopulations and distribution remain stable.


Assuntos
Envelhecimento/fisiologia , Movimento Celular/fisiologia , Ventrículos Cerebrais/fisiologia , Neurogênese/fisiologia , Bulbo Olfatório/fisiologia , Animais , Proliferação de Células , Ventrículos Cerebrais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Bulbo Olfatório/citologia
18.
Sci Am ; 306(4): 10, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22486102
19.
Nat Methods ; 8(8): 684-90, 2011 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-21725301

RESUMO

Membrane proteins are a large, diverse group of proteins, serving a multitude of cellular functions. They are difficult to study because of their requirement of a lipid membrane for function. Here we show that two-photon polarization microscopy can take advantage of the cell membrane requirement to yield insights into membrane protein structure and function, in living cells and organisms. The technique allows sensitive imaging of G-protein activation, changes in intracellular calcium concentration and other processes, and is not limited to membrane proteins. Conveniently, many suitable probes for two-photon polarization microscopy already exist.


Assuntos
Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Proteínas de Membrana/metabolismo , Proteínas de Membrana/ultraestrutura , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Microscopia de Polarização/métodos , Conformação Proteica , Relação Estrutura-Atividade
20.
J Comp Neurol ; 519(18): 3713-26, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21674486

RESUMO

Neural connections in the adult nervous system are established with a high degree of precision. Several examples throughout the nervous system indicate that this precision is achieved by first establishing an initial exuberant immature pattern of connectivity that is then sculpted into the adult pattern via pruning. This often emerges as an activity-dependent process. In the olfactory system, sensory axons from neurons expressing the same odorant receptor project with high precision to specific glomerular structures in the olfactory bulb. This process undergoes maturation-dependent refinements that are not fully understood. Due to technical impediments that have made it difficult to focus on single axons, it is unknown whether olfactory sensory projections are established in an exuberant fashion. Here we developed a novel technique of electroporation that allowed us to simultaneously label single olfactory sensory neuron (OSN) axonal arbors and their presynaptic specializations. Using this method we were able to incorporate plasmids into OSNs at an immature stage, thereby allowing a time-course study of axonal arbor development and synapse formation in single olfactory sensory axons. We observed that the number of branch points, the total branch length, and the number and density of presynaptic specializations peaked at postnatal day 8 and decreased afterwards. Our data demonstrate that olfactory sensory axons develop in an exuberant way, both in terms of branch growth and synaptic composition. We hypothesize that exuberant branches and synapses are eliminated to achieve the mature pattern in a process likely to be regulated by neural activity.


Assuntos
Axônios/fisiologia , Plasticidade Neuronal/fisiologia , Condutos Olfatórios/crescimento & desenvolvimento , Neurônios Receptores Olfatórios/fisiologia , Sinapses/fisiologia , Animais , Animais Recém-Nascidos , Eletroporação/métodos , Camundongos , Camundongos da Linhagem 129 , Técnicas de Rastreamento Neuroanatômico/métodos , Neurópilo/citologia , Neurópilo/fisiologia , Bulbo Olfatório/citologia , Bulbo Olfatório/crescimento & desenvolvimento , Mucosa Olfatória/citologia , Nervo Olfatório/citologia , Nervo Olfatório/crescimento & desenvolvimento , Condutos Olfatórios/citologia , Neurônios Receptores Olfatórios/citologia , Plasmídeos/administração & dosagem
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