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1.
bioRxiv ; 2023 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-37293074

RESUMEN

Neurodegenerative tauopathies are hypothesized to propagate via brain networks. This is uncertain because we have lacked precise network resolution of pathology. We therefore developed whole-brain staining methods with anti-p-tau nanobodies and imaged in 3D PS19 tauopathy mice, which have pan-neuronal expression of full-length human tau containing the P301S mutation. We analyzed patterns of p-tau deposition across established brain networks at multiple ages, testing the relationship between structural connectivity and patterns of progressive pathology. We identified core regions with early tau deposition, and used network propagation modeling to determine the link between tau pathology and connectivity strength. We discovered a bias towards retrograde network-based propagation of tau. This novel approach establishes a fundamental role for brain networks in tau propagation, with implications for human disease.

2.
J Neurosci ; 43(7): 1178-1190, 2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36623874

RESUMEN

The accessory olfactory system (AOS) is critical for the development and expression of social behavior. The first dedicated circuit in the AOS, the accessory olfactory bulb (AOB), exhibits cellular and network plasticity in male and female mice after social experience. In the AOB, interneurons called internal granule cells (IGCs) express the plasticity-associated immediate-early gene Arc following intermale aggression or mating. Here, we sought to better understand how Arc-expressing IGCs shape AOB information processing and social behavior in the context of territorial aggression. We used "ArcTRAP" (Arc-CreERT2) transgenic mice to selectively and permanently label Arc-expressing IGCs following male-male resident-intruder interactions. Using whole-cell patch-clamp electrophysiology, we found that Arc-expressing IGCs display increased intrinsic excitability for several days after a single resident-intruder interaction. Further, we found that Arc-expressing IGCs maintain this increased excitability across repeated resident-intruder interactions, during which resident mice increase or "ramp" their aggression. We tested the hypothesis that Arc-expressing IGCs participate in ramping aggression. Using a combination of ArcTRAP mice and chemogenetics (Cre-dependent hM4D(Gi)-mCherry AAV injections), we found that disruption of Arc-expressing IGC activity during repeated resident-intruder interactions abolishes the ramping aggression exhibited by resident male mice. This work shows that Arc-expressing AOB IGC ensembles are activated by specific chemosensory environments, and play an integral role in the establishment and expression of sex-typical social behavior. These studies identify a population of plastic interneurons in an early chemosensory circuit that display physiological features consistent with simple memory formation, increasing our understanding of central chemosensory processing and mammalian social behavior.SIGNIFICANCE STATEMENT The accessory olfactory system plays a vital role in rodent chemosensory social behavior. We studied experience-dependent plasticity in the accessory olfactory bulb and found that internal granule cells expressing the immediate-early gene Arc after the resident-intruder paradigm increase their excitability for several days. We investigated the roles of these Arc-expressing internal granule cells on chemosensory social behavior by chemogenetically manipulating their excitability during repeated social interactions. We found that inhibiting these cells eliminated intermale aggressive ramping behavior. These studies identify a population of plastic interneurons in an early chemosensory circuit that display physiological features consistent with simple memory formation, increasing our understanding of central chemosensory processing and mammalian social behavior.


Asunto(s)
Interneuronas , Bulbo Olfatorio , Ratones , Masculino , Femenino , Animales , Bulbo Olfatorio/fisiología , Interneuronas/fisiología , Neuronas , Conducta Social , Agresión , Ratones Transgénicos , Mamíferos
3.
eNeuro ; 10(1)2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36564214

RESUMEN

Accurate and efficient quantification of animal behavior facilitates the understanding of the brain. An emerging approach within machine learning (ML) field is to combine multiple ML-based algorithms to quantify animal behavior. These so-called hybrid models have emerged because of limitations associated with supervised [e.g., random forest (RF)] and unsupervised [e.g., hidden Markov model (HMM)] ML models. For example, RF models lack temporal information across video frames, and HMM latent states are often difficult to interpret. We sought to develop a hybrid model, and did so in the context of a study of mouse risk assessment behavior. We used DeepLabCut to estimate the positions of mouse body parts. Positional features were calculated using DeepLabCut outputs and were used to train RF and HMM models with equal number of states, separately. The per-frame predictions from RF and HMM models were then passed to a second HMM model layer ("reHMM"). The outputs of the reHMM layer showed improved interpretability over the initial HMM output. Finally, we combined predictions from RF and HMM models with selected positional features to train a third HMM model ("reHMM+"). This reHMM+ layered hybrid model unveiled distinctive temporal and human-interpretable behavioral patterns. We applied this workflow to investigate risk assessment to trimethylthiazoline and snake feces odor, finding unique behavioral patterns to each that were separable from attractive and neutral stimuli. We conclude that this layered, hybrid ML workflow represents a balanced approach for improving the depth and reliability of ML classifiers in chemosensory and other behavioral contexts.


Asunto(s)
Algoritmos , Aprendizaje Automático , Animales , Ratones , Cadenas de Markov , Reproducibilidad de los Resultados , Medición de Riesgo , Flujo de Trabajo
5.
Sci Adv ; 6(22): eaaz6868, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32523992

RESUMEN

The mouse accessory olfactory system (AOS) supports social and reproductive behavior through the sensation of environmental chemosignals. A growing number of excreted steroids have been shown to be potent AOS cues, including bile acids (BAs) found in feces. As is still the case with most AOS ligands, the specific receptors used by vomeronasal sensory neurons (VSNs) to detect BAs remain unknown. To identify VSN BA receptors, we first performed a deep analysis of VSN BA tuning using volumetric GCaMP6f/s Ca2+ imaging. These experiments revealed multiple populations of BA-receptive VSNs with submicromolar sensitivities. We then developed a new physiology-forward approach for identifying AOS ligand-receptor interactions, which we call Fluorescence Live Imaging for Cell Capture and RNA sequencing, or FLICCR-seq. FLICCR-seq analysis revealed five specific V1R family receptors enriched in BA-sensitive VSNs. These studies introduce a powerful new approach for ligand-receptor matching and reveal biological mechanisms underlying mammalian BA chemosensation.

6.
J Neurosci ; 40(27): 5247-5263, 2020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32503886

RESUMEN

The accessory olfactory bulb (AOB), the first neural circuit in the mouse accessory olfactory system, is critical for interpreting social chemosignals. Despite its importance, AOB information processing is poorly understood compared with the main olfactory bulb (MOB). Here, we sought to fill gaps in the understanding of AOB interneuron function. We used 2-photon GCaMP6f Ca2+ imaging in an ex vivo preparation to study chemosensory tuning in AOB external granule cells (EGCs), interneurons hypothesized to broadly inhibit activity in excitatory mitral cells (MCs). In ex vivo preparations from mice of both sexes, we measured MC and EGC tuning to natural chemosignal blends and monomolecular ligands, finding that EGC tuning was sparser, not broader, than upstream MCs. Simultaneous electrophysiological recording and Ca2+ imaging showed no differences in GCaMP6f-to-spiking relationships in these cell types during simulated sensory stimulation, suggesting that measured EGC sparseness was not due to cell type-dependent variability in GCaMP6f performance. Ex vivo patch-clamp recordings revealed that EGC subthreshold responsivity was far broader than indicated by GCaMP6f Ca2+ imaging, and that monomolecular ligands rarely elicited EGC spiking. These results indicate that EGCs are selectively engaged by chemosensory blends, suggesting different roles for EGCs than analogous interneurons in the MOB.SIGNIFICANCE STATEMENT The mouse accessory olfactory system (AOS) interprets social chemosignals, but we poorly understand AOS information processing. Here, we investigate the functional properties of external granule cells (EGCs), a major class of interneurons in the accessory olfactory bulb (AOB). We hypothesized that EGCs, which are densely innervated by excitatory mitral cells (MCs), would show broad chemosensory tuning, suggesting a role in divisive normalization. Using ex vivo GCaMP6f imaging, we found that EGCs were instead more sparsely tuned than MCs. This was not due to weaker GCaMP6f signaling in EGCs than in MCs. Instead, we found that many MC-activating chemosignals caused only subthreshold EGC responses. This indicates a different role for AOB EGCs compared with analogous cells in the main olfactory bulb.


Asunto(s)
Bulbo Olfatorio/citología , Bulbo Olfatorio/fisiología , Olfato/fisiología , Animales , Calcio/fisiología , Gránulos Citoplasmáticos , Fenómenos Electrofisiológicos/fisiología , Femenino , Interneuronas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroimagen , Odorantes , Técnicas de Placa-Clamp , Órgano Vomeronasal/citología , Órgano Vomeronasal/fisiología
7.
Proc Natl Acad Sci U S A ; 117(9): 4983-4993, 2020 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-32051245

RESUMEN

Lymphocytes infiltrate the stroke core and penumbra and often exacerbate cellular injury. B cells, however, are lymphocytes that do not contribute to acute pathology but can support recovery. B cell adoptive transfer to mice reduced infarct volumes 3 and 7 d after transient middle cerebral artery occlusion (tMCAo), independent of changing immune populations in recipient mice. Testing a direct neurotrophic effect, B cells cocultured with mixed cortical cells protected neurons and maintained dendritic arborization after oxygen-glucose deprivation. Whole-brain volumetric serial two-photon tomography (STPT) and a custom-developed image analysis pipeline visualized and quantified poststroke B cell diapedesis throughout the brain, including remote areas supporting functional recovery. Stroke induced significant bilateral B cell diapedesis into remote brain regions regulating motor and cognitive functions and neurogenesis (e.g., dentate gyrus, hypothalamus, olfactory areas, cerebellum) in the whole-brain datasets. To confirm a mechanistic role for B cells in functional recovery, rituximab was given to human CD20+ (hCD20+) transgenic mice to continuously deplete hCD20+-expressing B cells following tMCAo. These mice experienced delayed motor recovery, impaired spatial memory, and increased anxiety through 8 wk poststroke compared to wild type (WT) littermates also receiving rituximab. B cell depletion reduced stroke-induced hippocampal neurogenesis and cell survival. Thus, B cell diapedesis occurred in areas remote to the infarct that mediated motor and cognitive recovery. Understanding the role of B cells in neuronal health and disease-based plasticity is critical for developing effective immune-based therapies for protection against diseases that involve recruitment of peripheral immune cells into the injured brain.


Asunto(s)
Encéfalo/metabolismo , Movimiento Celular/fisiología , Neurogénesis/fisiología , Recuperación de la Función/fisiología , Accidente Cerebrovascular/metabolismo , Inmunidad Adaptativa , Animales , Linfocitos B/metabolismo , Encéfalo/patología , Cognición , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Humanos , Infarto de la Arteria Cerebral Media , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal , Neuronas/metabolismo
8.
Nat Methods ; 16(11): 1109-1113, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31673159

RESUMEN

We present cleared-tissue axially swept light-sheet microscopy (ctASLM), which enables isotropic, subcellular resolution imaging with high optical sectioning capability and a large field of view over a broad range of immersion media. ctASLM can image live, expanded, and both aqueous and non-aqueous chemically cleared tissue preparations. Depending on the optical configuration, ctASLM provides up to 260 nm of axial resolution, a three to tenfold improvement over confocal and other reported cleared-tissue light-sheet microscopes. We imaged millimeter-scale cleared tissues with subcellular three-dimensional resolution, which enabled automated detection of multicellular tissue architectures, individual cells, synaptic spines and rare cell-cell interactions.


Asunto(s)
Microscopía Fluorescente/métodos , Animales , Ratones , Pez Cebra
9.
Front Neurosci ; 13: 1055, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31636534

RESUMEN

Whole-brain volumetric microscopy techniques such as serial two-photon tomography (STPT) can provide detailed information on the roles of neuroinflammation and neuroplasticity throughout the whole brain post-stroke. STPT automatically generates high-resolution images of coronal sections of the entire mouse brain that can be readily visualized in three dimensions. We developed a pipeline for whole brain image analysis that includes supervised machine learning (pixel-wise random forest models via the "ilastik" software package) followed by registration to a standardized 3-D atlas of the adult mouse brain (Common Coordinate Framework v3.0; Allen Institute for Brain Science). These procedures allow the detection of cellular fluorescent signals throughout the brain in an unbiased manner. To illustrate our imaging techniques and automated image quantification, we examined long-term post-stroke motor circuit connectivity in mice that received a motor cortex photothrombotic stroke. Two weeks post-stroke, mice received intramuscular injections of pseudorabies virus (PRV-152), a trans-synaptic retrograde herpes virus driving expression of green fluorescent protein (GFP), into the affected contralesional forelimb to label neurons in descending tracts to the forelimb musculature. Mice were sacrificed 3 weeks post-stroke. We also quantified sub-acute neuroinflammation in the post-stroke brain in a separate cohort of mice following a 60 min transient middle cerebral artery occlusion (tMCAo). Naive e450+-labeled splenic CD8+ cytotoxic T cells were intravenously injected at 7, 24, 48, and 72 h post-tMCAo. Mice were sacrificed 4 days after stroke. Detailed quantification of post-stroke neural connectivity and neuroinflammation indicates a role for remote brain regions in stroke pathology and recovery. The workflow described herein, incorporating STPT and automated quantification of fluorescently labeled features of interest, provides a framework by which one can objectively evaluate labeled neuronal or lymphocyte populations in healthy and injured brains. The results provide region-specific quantification of neural connectivity and neuroinflammation, which could be a critical tool for investigating mechanisms of not only stroke recovery, but also a wide variety of brain injuries or diseases.

10.
eNeuro ; 6(4)2019.
Artículo en Inglés | MEDLINE | ID: mdl-31358509

RESUMEN

In the mouse accessory olfactory bulb (AOB), inhibitory interneurons play an essential role in gating behaviors elicited by sensory exposure to social odors. Several morphological classes have been described, but the full complement of interneurons remains incomplete. In order to develop a more comprehensive view of interneuron function in the AOB, we performed targeted patch clamp recordings from partially overlapping subsets of genetically labeled and morphologically defined interneuron types. Gad2 (GAD65), Calb2 (calretinin), and Cort (cortistatin)-cre mouse lines were used to drive selective expression of tdTomato in AOB interneurons. Gad2 and Calb2-labeled interneurons were found in the internal, external, and glomerular (GL) layers, whereas Cort-labeled interneurons were enriched within the lateral olfactory tract (LOT) and external cellular layer (ECL). We found that external granule cells (EGCs) from all genetically labeled subpopulations possessed intrinsic functional differences that allowed them to be readily distinguished from internal granule cells (IGCs). EGCs showed stronger voltage-gated Na+ and non-inactivating voltage-gated K+ currents, decreased IH currents, and robust excitatory synaptic input. These specific intrinsic properties did not correspond to any genetically labeled type, suggesting that transcriptional heterogeneity among EGCs and IGCs is not correlated with expression of these particular marker genes. Intrinsic heterogeneity was also seen among AOB juxtaglomerular cells (JGCs), with a major subset of Calb2-labeled JGCs exhibiting spontaneous and depolarization-evoked plateau potentials. These data identify specific physiological features of AOB interneurons types that will assist in future studies of AOB function.


Asunto(s)
Interneuronas/fisiología , Bulbo Olfatorio/fisiología , Animales , Calbindina 2/metabolismo , Femenino , Glutamato Descarboxilasa/metabolismo , Interneuronas/citología , Interneuronas/metabolismo , Masculino , Ratones Transgénicos , Bulbo Olfatorio/citología , Bulbo Olfatorio/metabolismo , Potenciales Sinápticos
11.
eNeuro ; 5(4)2018.
Artículo en Inglés | MEDLINE | ID: mdl-30105301

RESUMEN

Sensory adaptation is a source of experience-dependent feedback that impacts responses to environmental cues. In the mammalian main olfactory system (MOS), adaptation influences sensory coding at its earliest processing stages. Sensory adaptation in the accessory olfactory system (AOS) remains incompletely explored, leaving many aspects of the phenomenon unclear. We investigated sensory adaptation in vomeronasal sensory neurons (VSNs) using a combination of in situ Ca2+ imaging and electrophysiology. Parallel studies revealed prominent short-term sensory adaptation in VSNs upon repeated stimulation with mouse urine and monomolecular bile acid ligands at interstimulus intervals (ISIs) less than 30 s. In such conditions, Ca2+ signals and spike rates were often reduced by more than 50%, leading to dramatically reduced chemosensory sensitivity. Short-term adaptation was reversible over the course of minutes. Population Ca2+ imaging experiments revealed the presence of a slower form of VSN adaptation that accumulated over dozens of stimulus presentations delivered over tens of minutes. Most VSNs showed strong adaptation, but in a substantial VSN subpopulation adaptation was diminished or absent. Investigation of same- and opposite-sex urine responses in male and female VSNs revealed that adaptation to same-sex cues occurred at ISIs up to 180 s, conditions that did not induce adaptation to opposite-sex cues. This result suggests that VSN sensory adaptation can be modulated by sensory experience. These studies comprehensively establish the presence of VSN sensory adaptation and provide a foundation for future inquiries into the molecular and cellular mechanisms of this phenomenon and its impact on mammalian behavior.


Asunto(s)
Adaptación Fisiológica/fisiología , Células Receptoras Sensoriales/fisiología , Olfato/fisiología , Órgano Vomeronasal/fisiología , Animales , Calcio/metabolismo , Fenómenos Electrofisiológicos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal
12.
Nat Commun ; 9(1): 2041, 2018 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-29795268

RESUMEN

Innate behaviors are genetically encoded, but their underlying molecular mechanisms remain largely unknown. Predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) are believed to activate specific odorant receptors to elicit innate fear/defensive behaviors in naive mice. Here, we conduct a large-scale recessive genetics screen of ethylnitrosourea (ENU)-mutagenized mice. We find that loss of Trpa1, a pungency/irritancy receptor, diminishes TMT/2MT and snake skin-evoked innate fear/defensive responses. Accordingly, Trpa1 -/- mice fail to effectively activate known fear/stress brain centers upon 2MT exposure, despite their apparent ability to smell and learn to fear 2MT. Moreover, Trpa1 acts as a chemosensor for 2MT/TMT and Trpa1-expressing trigeminal ganglion neurons contribute critically to 2MT-evoked freezing. Our results indicate that Trpa1-mediated nociception plays a crucial role in predator odor-evoked innate fear/defensive behaviors. The work establishes the first forward genetics screen to uncover the molecular mechanism of innate fear, a basic emotion and evolutionarily conserved survival mechanism.


Asunto(s)
Conducta Animal/fisiología , Miedo/fisiología , Instinto , Olfato/fisiología , Canal Catiónico TRPA1/fisiología , Animales , Femenino , Técnicas de Genotipaje , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutagénesis , Neuronas/fisiología , Nocicepción/fisiología , Odorantes , Tiazoles/química , Ganglio del Trigémino/citología , Ganglio del Trigémino/fisiología
13.
J Neurosci ; 38(14): 3377-3387, 2018 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-29519850

RESUMEN

Steroids play vital roles in animal physiology across species, and the production of specific steroids is associated with particular internal biological functions. The internal functions of steroids are, in most cases, quite clear. However, an important feature of many steroids (their chemical stability) allows these molecules to play secondary, external roles as chemical messengers after their excretion via urine, feces, or other shed substances. The presence of steroids in animal excretions has long been appreciated, but their capacity to serve as chemosignals has not received as much attention. In theory, the blend of steroids excreted by an animal contains a readout of its own biological state. Initial mechanistic evidence for external steroid chemosensation arose from studies of many species of fish. In sea lampreys and ray-finned fishes, bile salts were identified as potent olfactory cues and later found to serve as pheromones. Recently, we and others have discovered that neurons in amphibian and mammalian olfactory systems are also highly sensitive to excreted glucocorticoids, sex steroids, and bile acids, and some of these molecules have been confirmed as mammalian pheromones. Steroid chemosensation in olfactory systems, unlike steroid detection in most tissues, is performed by plasma membrane receptors, but the details remain largely unclear. In this review, we present a broad view of steroid detection by vertebrate olfactory systems, focusing on recent research in fishes, amphibians, and mammals. We review confirmed and hypothesized mechanisms of steroid chemosensation in each group and discuss potential impacts on vertebrate social communication.


Asunto(s)
Comunicación Animal , Comunicación no Verbal , Conducta Social , Esteroides/metabolismo , Animales , Células Quimiorreceptoras/fisiología , Humanos , Feromonas Humanas/química , Feromonas Humanas/metabolismo , Esteroides/química
14.
J Neurosci ; 37(30): 7240-7252, 2017 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-28659282

RESUMEN

Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC-interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate-early gene Arc after male-male social experience. Following the resident-intruder paradigm, Arc-expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc-expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated IH currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident-intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc-expressing interneurons.SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male-male social chemosensory encounters. We show that the plasticity-associated immediate-early gene Arc is selectively expressed in IGCs from resident males following the resident-intruder assay. After behavior, Arc-expressing IGCs are more strongly excited by sensory input stimulation and MC activation is suppressed. Arc-expressing IGCs do not show increased excitatory synaptic drive but instead show increased intrinsic excitability. These data indicate that MC-IGC plasticity is induced after male-male social chemosensory encounters, resulting in enhanced MC suppression by Arc-expressing IGCs.


Asunto(s)
Agresión/fisiología , Interneuronas/fisiología , Aprendizaje/fisiología , Plasticidad Neuronal/fisiología , Bulbo Olfatorio/fisiología , Conducta Social , Animales , Conducta Animal/fisiología , Proteínas del Citoesqueleto/metabolismo , Relaciones Interpersonales , Masculino , Ratones Endogámicos C57BL , Red Nerviosa/fisiología , Proteínas del Tejido Nervioso/metabolismo , Transmisión Sináptica/fisiología
15.
J Neurophysiol ; 117(3): 1342-1351, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28053247

RESUMEN

Norepinephrine (NE) release has been linked to experience-dependent plasticity in many model systems and brain regions. Among these is the rodent accessory olfactory system (AOS), which is crucial for detecting and processing socially relevant environmental cues. The accessory olfactory bulb (AOB), the first site of chemosensory information processing in the AOS, receives dense centrifugal innervation by noradrenergic fibers originating in the locus coeruleus. Although NE release has been linked to behavioral plasticity through its actions in the AOB, the impacts of noradrenergic modulation on AOB information processing have not been thoroughly studied. We made extracellular single-unit recordings of AOB principal neurons in ex vivo preparations of the early AOS taken from adult male mice. We analyzed the impacts of bath-applied NE (10 µM) on spontaneous and stimulus-driven activity. In the presence of NE, we observed overall suppression of stimulus-driven neuronal activity with limited impact on spontaneous activity. NE-associated response suppression in the AOB came in two forms: one that was strong and immediate (21%) and one other that involved gradual, stimulus-dependent monotonic response suppression (47%). NE-associated changes in spontaneous activity were more modest, with an overall increase in spontaneous spike frequency observed in 25% of neurons. Neurons with increased spontaneous activity demonstrated a net decrease in chemosensory discriminability. These results reveal that noradrenergic signaling in the AOB causes cell-specific changes in chemosensory tuning, even among similar projection neurons.NEW & NOTEWORTHY Norepinephrine (NE) is released throughout the brain in many behavioral contexts, but its impacts on information processing are not well understood. We studied the impact of NE on chemosensory tuning in the mouse accessory olfactory bulb (AOB). Electrophysiological recordings from AOB neurons in ex vivo preparations revealed that NE, on balance, inhibited mitral cell responses to chemosensory cues. However, NE's effects were heterogeneous, indicating that NE signaling reshapes AOB output in a cell- and stimulus-specific manner.


Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Neuronas/efectos de los fármacos , Norepinefrina/farmacología , Bulbo Olfatorio/citología , Bulbo Olfatorio/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Discriminación en Psicología , Femenino , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos BALB C , Norepinefrina/metabolismo , Caracteres Sexuales , Transducción de Señal/efectos de los fármacos , Estadísticas no Paramétricas , Orina
16.
Nat Commun ; 7: 11936, 2016 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-27324439

RESUMEN

The accessory olfactory system (AOS) guides behaviours that are important for survival and reproduction, but understanding of AOS function is limited by a lack of identified natural ligands. Here we report that mouse faeces are a robust source of AOS chemosignals and identify bile acids as a class of natural AOS ligands. Single-unit electrophysiological recordings from accessory olfactory bulb neurons in ex vivo preparations show that AOS neurons are strongly and selectively activated by peripheral stimulation with mouse faecal extracts. Faecal extracts contain several unconjugated bile acids that cause concentration-dependent neuronal activity in the AOS. Many AOS neurons respond selectively to bile acids that are variably excreted in male and female mouse faeces, and others respond to bile acids absent in mouse faeces. These results identify faeces as a natural source of AOS information, and suggest that bile acids may be mammalian pheromones and kairomones.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Ácidos y Sales Biliares/farmacología , Heces/química , Neuronas/efectos de los fármacos , Bulbo Olfatorio/efectos de los fármacos , Feromonas/orina , Potenciales de Acción/fisiología , Animales , Ácidos y Sales Biliares/química , Ácidos y Sales Biliares/aislamiento & purificación , Femenino , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Neuronas/fisiología , Bulbo Olfatorio/fisiología , Feromonas/farmacología , Factores Sexuales , Análisis de la Célula Individual , Técnicas de Cultivo de Tejidos
17.
J Vis Exp ; (90): e51813, 2014 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-25145699

RESUMEN

The mouse accessory olfactory system (AOS) is a specialized sensory pathway for detecting nonvolatile social odors, pheromones, and kairomones. The first neural circuit in the AOS pathway, called the accessory olfactory bulb (AOB), plays an important role in establishing sex-typical behaviors such as territorial aggression and mating. This small (<1 mm(3)) circuit possesses the capacity to distinguish unique behavioral states, such as sex, strain, and stress from chemosensory cues in the secretions and excretions of conspecifics. While the compact organization of this system presents unique opportunities for recording from large portions of the circuit simultaneously, investigation of sensory processing in the AOB remains challenging, largely due to its experimentally disadvantageous location in the brain. Here, we demonstrate a multi-stage dissection that removes the intact AOB inside a single hemisphere of the anterior mouse skull, leaving connections to both the peripheral vomeronasal sensory neurons (VSNs) and local neuronal circuitry intact. The procedure exposes the AOB surface to direct visual inspection, facilitating electrophysiological and optical recordings from AOB circuit elements in the absence of anesthetics. Upon inserting a thin cannula into the vomeronasal organ (VNO), which houses the VSNs, one can directly expose the periphery to social odors and pheromones while recording downstream activity in the AOB. This procedure enables controlled inquiries into AOS information processing, which can shed light on mechanisms linking pheromone exposure to changes in behavior.


Asunto(s)
Bulbo Olfatorio/anatomía & histología , Bulbo Olfatorio/fisiología , Órgano Vomeronasal/anatomía & histología , Órgano Vomeronasal/fisiología , Animales , Fenómenos Electrofisiológicos , Femenino , Ratones , Ratones Endogámicos BALB C , Odorantes , Bulbo Olfatorio/cirugía , Feromonas/fisiología , Órgano Vomeronasal/cirugía
18.
Nat Neurosci ; 17(7): 953-61, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24880215

RESUMEN

The mammalian accessory olfactory system extracts information about species, sex and individual identity from social odors, but its functional organization remains unclear. We imaged presynaptic Ca(2+) signals in vomeronasal inputs to the accessory olfactory bulb (AOB) during peripheral stimulation using light sheet microscopy. Urine- and steroid-responsive glomeruli densely innervated the anterior AOB. Glomerular activity maps for sexually mature female mouse urine overlapped maps for juvenile and/or gonadectomized urine of both sexes, whereas maps for sexually mature male urine were highly distinct. Further spatial analysis revealed a complicated organization involving selective juxtaposition and dispersal of functionally grouped glomerular classes. Glomeruli that were similarly tuned to urines were often closely associated, whereas more disparately tuned glomeruli were selectively dispersed. Maps to a panel of sulfated steroid odorants identified tightly juxtaposed groups that were disparately tuned and dispersed groups that were similarly tuned. These results reveal a modular, nonchemotopic spatial organization in the AOB.


Asunto(s)
Bulbo Olfatorio/fisiología , Envejecimiento/fisiología , Animales , Mapeo Encefálico , Señalización del Calcio , Proteína Quinasa Dependiente de GMP Cíclico Tipo II/genética , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuroimagen , Odorantes , Bulbo Olfatorio/anatomía & histología , Vías Olfatorias/fisiología , Caracteres Sexuales , Olfato/genética , Olfato/fisiología , Esteroides/farmacología , Estimulación Química , Orina/química
19.
Methods Mol Biol ; 1068: 237-46, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24014366

RESUMEN

Electrical recordings from individual accessory olfactory bulb neurons allow exploration of the functional properties of this important pheromonal processing circuit. Several approaches to performing such recordings have been used. Here, we describe ex vivo methods that we have found useful for recording from accessory olfactory bulb neurons using simple extracellular glass electrodes.


Asunto(s)
Fenómenos Electrofisiológicos , Bulbo Olfatorio/fisiología , Órgano Vomeronasal/inervación , Órgano Vomeronasal/fisiología , Animales , Impedancia Eléctrica , Neuronas/fisiología , Bulbo Olfatorio/metabolismo , Feromonas/fisiología , Órgano Vomeronasal/química
20.
Nat Neurosci ; 13(6): 723-30, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20453853

RESUMEN

In mice, nonvolatile social cues are detected and analyzed by the accessory olfactory system (AOS). Here we provide a first view of information processing in the AOS with respect to individual chemical cues. 12 sulfated steroids, recently discovered mouse AOS ligands, caused widespread activity among vomeronasal sensory neurons (VSNs), yet VSN responses clustered into a small number of repeated functional patterns or processing streams. Downstream neurons in the accessory olfactory bulb (AOB) responded to these ligands with enhanced signal/noise compared to VSNs. Although the dendritic connectivity of AOB mitral cells suggests the capacity for broad integration, most sulfated steroid responses were well-modeled by linear excitatory drive from just one VSN processing stream. However, a substantial minority demonstrated multi-stream integration. Most VSN excitation patterns were also observed in the AOB, but excitation by estradiol sulfate processing streams was rare, suggesting AOB circuit organization is specific to the biological relevance of sensed cues.


Asunto(s)
Bulbo Olfatorio/fisiología , Percepción Olfatoria/fisiología , Células Receptoras Sensoriales/fisiología , Órgano Vomeronasal/fisiología , Potenciales de Acción , Animales , Análisis por Conglomerados , Señales (Psicología) , Dendritas/fisiología , Estradiol , Técnicas In Vitro , Modelos Lineales , Masculino , Ratones , Microelectrodos , Modelos Neurológicos , Estimulación Física , Percepción Social , Esteroides , Sulfatos , Orina
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