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Tissue changes and the enlargement of the prostate, whether benign or malignant, are among the most common groups of diseases that affect men and can have significant impacts on length and quality of life. The prevalence of benign prostatic hyperplasia (BPH) increases significantly with age and affects nearly all men as they grow older. Other than skin cancers, prostate cancer is the most common cancer among men in the United States. Imaging is an essential component in the diagnosis and management of these conditions. Multiple modalities are available for prostate imaging, including several novel imaging modalities that have changed the landscape of prostate imaging in recent years. This review will cover the data relating to commonly used standard-of-care prostate imaging modalities, advances in newer technologies, and newer standards that impact prostate gland imaging. [ABSTRACT FROM AUTHOR]

This essay examines the role of organizing strategies and the digital media revolution in social movements. It outlines the orthodoxies in the academic literature on the Internet and social mobilization and traces the role of the Internet in social and political movements in the U.S. and Western Europe. It explores the common characteristics of patterns of mobilization and suggests theoretical propositions related to the phenomena characterizing social movements.

A new class of cyclometalated tetradentate platinum complexes of the type Pt[N^C--O--LL'] was synthesized and characterized. N^C is a cyclometalating ligand such as phenyl-pyrazole (ppz), phenyl-methylimidazole (pmi), or phenyl-pyridine (ppy), and LL' is an ancillary ligand such as phenoxyl-pyridine (popy). The complexes in this series are highly luminescent, emitting blue to green light in solution with quantum efficiencies ranging from 0.39 to 0.64 and luminescent lifetimes from 2 to 9 µs. When doped in a poly(methyl methaoylate) (PMMA) thin film, measured quantum efficiencies increase to 0.81-0.97 with lifetimes ranging from 4.5-10.4 µs. One notable example, the metal complex PtOO3, emits green light with a luminescent quantum efficiency approaching 100% and achieves approximately 100% electron-to-photon conversion efficiency in device settings. [ABSTRACT FROM AUTHOR]

This article looks at the case of theGrillinimovement and its emergence on the Italian political scene, and discusses its contribution to the growing literature on the increasing opportunities offered by the Internet for social movement participation and mobilization. My findings are that the movement is successful in both mobilizing and promoting open debate and participation because of its policies and its use of multiple, and fairly open platforms for participation and horizontal decision-making. TheGrillinihave been able to conciliate the characteristics of newly emerging, Internet-based, ‘internetworked movements’ as well as the more conventional use of the Internet on behalf of well-established social and political movements. They have been able to do so by articulating issues and mobilizing on a national scale, with an increasingly large bureaucratic elite, while retaining a vibrant, partly online- and partly offline-based public sphere and decentralized organizational forms. My conclusion is that theGrillinimovement, with its peculiar structure and commitment to participation and inclusion, is a crucial example of how the Internet can be used to aggregate new political issues and foster continuous debate while consolidating a growing electorally driven organization, which is still mostly held accountable by the movement's public sphere. [ABSTRACT FROM PUBLISHER]

In order to investigate the ground state and excited state properties of Pt(N^C^N)X, we have prepared a series of Pt complexes, where N^C^N aromatic chelates are derivatives of m-di(2-pyridinyl)benzene (dpb) and X are monoanionic and monodentate ancillary ligands including halide and phenoxide. Facile synthesis of platinum m-di(2-pyridinyl)benzene chloride and its derivatives, using controlled microwave heating, was reported. This method not only shortened the reaction time but also improved the reaction yield for most of the Pt complexes. Two Pt(NCN)X complexes have been structurally characterized by X-ray crystallography. The change of functional group does not affect the structure of the core Pt(N^C^N)Cl fragment. Both molecules pack as head-to-tail dimers, each molecule of the dimer related to the other by a center of inversion. The electrochemical studies of all Pt complexes demonstrate that the oxidation process occurs on the metal-phenyl fragment and the reduction process is associated with the electron accepting groups like pyridinyl groups and their derivatives. The maximum emission wavelength of the Pt(N^C^N)X complexes ranges between 471 and 610 nm, crossing the spectrum of visible light. Most of the Pt complexes are strongly luminescent (Φ = 0.32-0.63) and have short luminescence lifetimes (τ = 4-7 μs) at room temperature. The lowest excited state of the Pt(NCN)X complexes is identified as a dominant ligand-centered ³π-π* state with some ¹MLCT/³MLCT character, which appears to have a larger ¹MLCT component than their bidentate and tridentate analogs. This results in a high radiative decay rate and high quantum yield for Pt(dpb)Cl and its analogs. However, the excited state properties of the Pt(N^C^N)X complexes are strongly dependent on the nature of the electron-accepting groups and substituents to the metal-phenyl fragment. A rational design will be needed to tune the emission energies of the Pt(N^C^N)X complexes over a wide range while maintaining their high luminescent efficiency. [ABSTRACT FROM AUTHOR]

In nematodes, the ETS-family transcription factor ast-1 regulates multiple genes comprising the dopamine (DA) neuron phenotype, including biosynthetic enzymes and transporters. ETS transcription factors are hypothesized to play a similar role in vertebrates, and based on its expression in the adult mouse midbrain, Etv5/ERM has been proposed as a regulator of DA gene expression in the substantia nigra (SN) and ventral tegmental area (VTA). Here we show that Etv5 expression is not detectable until postnatal stages in the midbrain, well after development of the DA system, and that Etv5 knock-out and control mice show comparable tyrosine hydroxylase and dopamine transporter expression in the embryonic and adult midbrain. Other known members of the ETS family do not have expression patterns that are consistent with a role in DA gene regulation in the SN/VTA. These findings suggest that the ETS factors, while required for the generation of the DA phenotype in nematodes, do not play such a role in the mouse midbrain. [ABSTRACT FROM AUTHOR]

Reports that the expression of the I-POU/tI-POU message inhibiting the POU-domain transcription factors, is maximal late in the embryonic phase of Drosophila development, with I-POU as the preferred splice variant. Developmental expression of the I-POU/tI-POU; Interaction of POU-IV class proteins with DNA.

Case: A 21-year-old, active duty male sustained an irreducible, complex Lisfranc fracture-dislocation with distal extrusion of his intermediate cuneiform. He was treated in a staged manner with external fixator placement, followed by an extended midfoot fusion with autograft bone. At 19 months, he could perform all activities of daily living independently with minimal pain using an Intrepid Dynamic Exoskeletal Orthosis. Conclusions: Complex Lisfranc injuries are severe and often result in chronic pain and disability after operative management. To our knowledge, this is the only case report describing a Lisfranc fracture-dislocation with a distally extruded intermediate cuneiform treated with a fusion. [ABSTRACT FROM AUTHOR]

Abstract: At different retinal locations, we measured the visual system's sensitivity to a number of artifacts that can be introduced in near‐eye display systems. One study examined the threshold level of downsampling that an image can sustain at different positions in the retina and found that temporally stable approaches, both blurred and aliased, were much less noticeable than temporally volatile approaches. Also, boundaries between zones of different resolution had low visibility in the periphery. We also examined the minimum duration needed for the visual system to detect a low‐resolution region in an actively tracked system and found that low‐resolution images presented for less than 40 ms before being replaced with a high‐resolution image are unlikely to be visibly degraded. We also found that the visual system shows a rapid falloff in its ability to detect chromatic aberration in the periphery. These findings can inform the design on high performance and computationally efficient near‐eye display systems. [ABSTRACT FROM AUTHOR]

Introduction: Sonography is an effective method of diagnosing and treating musculoskeletal conditions, and the use of ultrasound has been shown to improve the accuracy, safety, and efficacy of both therapeutic and diagnostic injections. In 2012, we established an injection clinic at our institution to address our growing need for diagnostic and therapeutic injections.Methods: We performed an analysis of value and utilization following the development of an orthopedic injection clinic. This included an evaluation of the cost of materials, equipment, and training required to develop and run the clinic, and an analysis of the services rendered and relative value units (RVUs) generated over 3 fiscal years (FYs).Results: The cost to develop the clinic was $42,498.30. The cost to run the clinic thereafter was $16.90 to $21.60 per injection. By the end of FY 2012, 60% of providers performed at least 1 injection under ultrasound guidance. Every successive year thereafter, 100% of providers were using ultrasound guidance. In FY 2012, we performed 738 injections, 5.4% used ultrasound guidance and generated a total of 1,786.36 RVUs. In FY 2013, we performed 1,814 injections, 17.6% used ultrasound guidance, and generated a total of 7,224.5 RVUs. In FY 2014, we performed 2,821 injections, 25.2% used ultrasound guidance, and generated 13,786.82 RVUs. RVUs generated solely from ultrasound guided injections were 463.2 (2012), 3,694 (2013), 8,221.8 (2014). Injection accuracy was at least 98%. Average time until injection was 0 days.Conclusion: The cost to start an injection clinic is modest, with the potential for large annual growth and early return on investment, and can generate significant revenue by recapturing RVUs that would otherwise be lost to outside referrals. Furthermore, it helps to increase clinic throughput, maximize services rendered during a single patient visit improving the overall quality of their encounter, expands the clinical practice of our midlevel providers, offloads clinical time for surgical providers, and can help expedite clinical decision making. [ABSTRACT FROM AUTHOR]

From a population health perspective, the mental health care system in the USA faces two fundamental challenges: (1) a lack of capacity and (2) an inequitable geographic distribution of services. Telepsychiatry can help address the equity problem, and if applied thoughtfully, can also help address the capacity problem. In this paper we describe how telepsychiatry can be used to address the capacity and equity challenges related to the delivery of mental health services in rural areas. Five models of telepsychiatry are described, including (1) the traditional telepsychiatry referral model, (2) The telepsychiatry collaborative care model, (3) the telepsychiatry behavioural health consultant model, (4) the telepsychiatry consultation–liaison model, and (5) the telepsychiatry curbside consultation model. The strong empirical evidence for the telepsychiatry collaborative care model is presented along with two case studies of telepsychiatry consultation in the context of the telepsychiatry collaborative care model. By placing telepsychiatrists and tele-therapists in consultation roles, telepsychiatry collaborative care has the potential to leverage scarce specialist mental health resources to reach more patients, thereby allowing these providers to have a greater population level impact compared to traditional referral models of care. Comparative effectiveness trials are needed to identify which models of telepsychiatry are the most appropriate for patients with complex psychiatric disorders. [ABSTRACT FROM PUBLISHER]

In order to develop organic light‐emitting diodes with improved optical properties, a series of phosphorescent complexes exhibiting narrow‐band emission spectra are prepared and color tuned to emit efficiently across the whole visible spectrum through a judicious molecular design. Devices employing a green narrow‐band phosphorescent emitter are fabricated and demonstrate an internal quantum efficiency of close to unity and impressive device operational lifetimes, estimate at over 70 000 h at a practical luminance of 100 cd m‐2. Additionally, a deep blue narrow‐band emitter is incorporated into a device setting that demonstrates a peak external quantum efficiency of 17.6% and CIE coordinates of (0.14, 0.09). [ABSTRACT FROM AUTHOR]

Deep‐blue emitters based on cyclometalated platinum(II) complexes were synthesized, characterized, and used in organic light‐emitting devices. The complexes with tetradentate ligands exhibited improved photophysical properties over iridium analogues, and one such compound achieved a peak external quantum efficiency (EQE) of 23.7 %. [ABSTRACT FROM AUTHOR]

Tiefblaue Strahler auf der Grundlage von cyclometallierten Platin(II) ‐ Komplexen wurden synthetisiert, charakterisiert und in organischen Leuchtdioden eingesetzt. Die Komplexe mit vierzähnigen Liganden verfügten über bessere photophysikalische Eigenschaften als ihre Iridiumanaloga, und eine Verbindung erreichte eine höchste externe Quanteneffizienz (EQE) von 23.7 %. [ABSTRACT FROM AUTHOR]

The trigeminal ganglia differentiate in part from specialized ectodermal structures in the embryonic head termed the trigeminal placodes. However, the signals which govern the migration of trigeminal precursors and the final morphology of the ganglia are poorly defined. Here, we show that notochord or floor plate tissue can induce the formation of ectopic sensory ganglia adjacent to the developing dorsal mesencephalon. Neurons within these ganglia coexpress the transcription factors Brn3a and Islet, which together characterize primary sensory neurons throughout the developing embryo. The ectopic ganglia originate from Pax3-expressing regions of the surface ectoderm that normally contribute to the ophthalmic trigeminal (op5), and can only be induced at developmental stages during which op5 precursors are present in the mesencephalic region. The migration of trigeminal precursors is also blocked by a local source of recombinant Shh, while in mouse embryos lacking Shh, these cells continue to migrate until they fuse into a single ganglion at the ventral midline. Together, these results suggest that Shh acts to arrest the migration of sensory precursors rather than to induce sensory neurons de novo. Consistent with this hypothesis, Shh induces the expression of the proteoglycan PG-M/versican in the cranial mesoderm, which has been previously implicated in the regulation of the movement of sensory neural precursors. [Copyright &y& Elsevier]

Fe:ZnSe and other transition metals have broad upper and lower energy manifolds that give rise to broad absorption and fluorescence bands in the mid-infrared spectral region. Energy transfer between Fe2 + ions via re-absorption of fluorescence (due to the spectral overlap of these bands) and phonon-assisted energy transfer (due to the lattice dynamics of ZnSe) becomes more probable with increasing Fe2 + concentration. Here, we treat these processes as additional terms in the rate equations that govern the spontaneous decay of the Fe2 + ion. This treatment gives insight into anomalous behavior seen in the thermal lifetime of the Fe:ZnSe system. We also apply the model to other transition metal-doped II–VI materials. [ABSTRACT FROM AUTHOR]

Cholinergic transmission shapes the maturation of glutamatergic circuits, yet the developmental sources of acetylcholine have not been systematically explored. Here, we have used Cre‐recombinase‐mediated genetic labeling to identify and map both mature and developing CNS neurons that express choline acetyltransferase (ChAT). Correction of a significant problem with a widely used ChatCre transgenic line ensures that this map does not contain expression artifacts. ChatCre marks all known cholinergic systems in the adult brain, but also identifies several brain areas not usually regarded as cholinergic, including specific thalamic and hypothalamic neurons, the subiculum, the lateral parabrachial nucleus, the cuneate/gracilis nuclei, and the pontocerebellar system. This ChatCre fate map suggests transient developmental expression of a cholinergic phenotype in areas important for cognition, motor control, and respiration. We therefore examined expression of ChAT and the vesicular acetylcholine transporter in the embryonic and early postnatal brain to determine the developmental timing of this transient cholinergic phenotype, and found that it mirrored the establishment of relevant glutamatergic projection pathways. We then used an intersectional genetic strategy combining ChatCre with Vglut2Flp to show that these neurons adopt a glutamatergic fate in the adult brain. The transient cholinergic phenotype of these glutamatergic neurons suggests a homosynaptic source of acetylcholine for the maturation of developing glutamatergic synapses. These findings thus define critical windows during which specific glutamatergic circuits may be vulnerable to disruption by nicotine in utero, and suggest new mechanisms for pediatric disorders associated with maternal smoking, such as sudden infant death syndrome. [ABSTRACT FROM AUTHOR]

Genetic studies have shown an association between smoking and variation at the CHRNA5/A3/B4 gene locus encoding the α5, α3, and β4 nicotinic receptor subunits. The α5 receptor has been specifically implicated because smoking-associated haplotypes contain a coding variant in the CHRNA5 gene. The Chrna5/a3/b4 locus is conserved in rodents and the restricted expression of these subunits suggests neural pathways through which the reinforcing and aversive properties of nicotine may be mediated. Here, we show that, in the interpeduncular nucleus (IP), the site of the highest Chrna5 mRNA expression in rodents, electrophysiological responses to nicotinic acetylcholine receptor stimulation are markedly reduced in α5-null mice. IP neurons differ markedly from their upstream ventral medial habenula cholinergic partners, which appear unaltered by loss of α5. To probe the functional role of α5-containing IP neurons, we used BAC recombineering to generate transgenic mice expressing Cre-recombinase from the Chrna5 locus. Reporter expression driven by Chrna5Cre demonstrates that transcription of Chrna5 is regulated independently from the Chrna3/b4 genes transcribed on the opposite strand. Chrna5-expressing IP neurons are GABAergic and project to distant targets in the mesopontine raphe and tegmentum rather than forming local circuits. Optogenetic stimulation of Chrna5-expressing IP neurons failed to elicit physical manifestations of withdrawal. However, after recent prior stimulation or exposure to nicotine, IP stimulation becomes aversive. These results using mice of both sexes support the idea that the risk allele of CHRNA5 may increase the drive to smoke via loss of IP-mediated nicotine aversion. [ABSTRACT FROM AUTHOR]

In nocturnal rodents, voluntary wheel-running activity (WRA) represents a self-reinforcing behavior. We have previously demonstrated that WRA is markedly reduced in mice with a region-specific deletion of the transcription factor Pou4f1 (Brn3a), which leads to an ablation of the dorsal medial habenula (dMHb). The decrease in WRA in these dMHb-lesioned (dMHbCKO) mice suggests that the dMHb constitutes a critical center for conveying reinforcement by exercise. However, WRA also represents a prominent output of the circadian system, and the possibility remains that the dMHb is a source of input to the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. To test this hypothesis, we assessed the integrity of the circadian system in dMHbCKO mice. Here we show that the developmental lesion of the dMHb reduces WRA under both a light-dark cycle and constant darkness, increases the circadian period of WRA, but has no effect on the circadian amplitude or period of home cage activity or the daily amplitude of sleep stages, suggesting that the lengthening of period is a result of the decreased WRA in the mutant mice. Polysomnographic sleep recordings show that dMHbCKO mice have an overall unaltered daily amplitude of sleep stages but have fragmented sleep and an overall increase in total rapid eye movement (REM) sleep. Photoresponsiveness is intact in dMHbCKO mice, but compared with control animals, they reentrain faster to a 6-h abrupt phase delay protocol. Circadian changes in WRA of dMHbCKO mice do not appear to emerge within the central pacemaker, as circadian expression of the clock genes Per1 and Per2 within the SCN is normal. We do find some evidence for fragmented sleep and an overall increase in total REM sleep, supporting a model in which the dMHb is part of the neural circuitry encoding motivation and involved in the manifestation of some of the symptoms of depression. [ABSTRACT FROM AUTHOR]

The habenulopeduncular pathway consists of the medial habenula (MHb), its output tract, the fasciculus retroflexus, and its principal target, the interpeduncular nucleus (IP). Several IP subnuclei have been described, but their specific projections and relationship to habenula inputs are not well understood. Here we have used viral, transgenic, and conventional anterograde and retrograde tract-tracing methods to better define the relationship between the dorsal and ventral MHb, the IP, and the secondary efferent targets of this system. Although prior studies have reported that the IP has ascending projections to ventral forebrain structures, we find that these projections originate almost entirely in the apical subnucleus, which may be more appropriately described as part of the median raphe system. The laterodorsal tegmental nucleus receives inhibitory inputs from the contralateral dorsolateral IP, and mainly excitatory inputs from the ipsilateral rostrolateral IP subnucleus. The midline central gray of the pons and nucleus incertus receive input from the rostral IP, which contains a mix of inhibitory and excitatory neurons, and the dorsomedial IP, which is exclusively inhibitory. The lateral central gray of the pons receives bilateral input from the lateral IP, which in turn receives bilateral input from the dorsal MHb. Taken together with prior studies of IP projections to the raphe, these results form an emerging map of the habenulopeduncular system that has significant implications for the proposed function of the IP in a variety of behaviors, including models of mood disorders and behavioral responses to nicotine. [ABSTRACT FROM AUTHOR]

Hmx1 encodes a homeodomain transcription factor expressed in the developing lateral craniofacial mesenchyme, retina and sensory ganglia. Mutation or mis-regulation of Hmx1 underlies malformations of the eye and external ear in multiple species. Deletion or insertional duplication of an evolutionarily conserved region (ECR) downstream of Hmx1 has recently been described in rat and cow, respectively. Here, we demonstrate that the impact of Hmx1 loss is greater than previously appreciated, with a variety of lateral cranioskeletal defects, auriculofacial nerve deficits, and duplication of the caudal region of the external ear. Using a transgenic approach, we demonstrate that a 594 bp sequence encompassing the ECR recapitulates specific aspects of the endogenous Hmx1 lateral facial expression pattern. Moreover, we show that Hoxa2, Meis and Pbx proteins act cooperatively on the ECR, via a core 32 bp sequence, to regulate Hmx1 expression. These studies highlight the conserved role for Hmx1 in BA2-derived tissues and provide an entry point for improved understanding of the causes of the frequent lateral facial birth defects in humans. [ABSTRACT FROM AUTHOR]

ABSTRACT The lateral habenula (LHb) is part of the habenula complex of the dorsal thalamus. Recent studies of the LHb have focused on its projections to the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg), which contain γ-aminobutyric acid (GABA)ergic neurons that mediate reward prediction error via inhibition of dopaminergic activity. However, older studies in the rat have also identified LHb outputs to the lateral and posterior hypothalamus, median raphe, dorsal raphe, and dorsal tegmentum. Although these studies have shown that the medial and lateral divisions of the LHb have somewhat distinct projections, the topographic specificity of LHb efferents is not completely understood, and the relative extent of these projections to brainstem targets is unknown. Here we have used anterograde tracing with adeno-associated virus-mediated expression of green fluorescent protein, combined with serial two-photon tomography, to map the efferents of the LHb on a standard coordinate system for the entire mouse brain, and reconstruct the efferent pathways of the LHb in three dimensions. Using automated quantitation of fiber density, we show that in addition to the RMTg, the median raphe, caudal dorsal raphe, and pontine central gray are major recipients of LHb efferents. By using retrograde tract tracing with cholera toxin subunit B, we show that LHb neurons projecting to the hypothalamus, VTA, median raphe, caudal dorsal raphe, and pontine central gray reside in characteristic, but sometimes overlapping regions of the LHb. Together these results provide the anatomical basis for systematic studies of LHb function in neural circuits and behavior in mice. J. Comp. Neurol. 523:32-60, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The habenular complex in the epithalamus consists of distinct regions with diverse neuronal populations. Past studies have suggested a role for the habenula in voluntary exercise motivation and reinforcement of intracranial self-stimulation but have not assigned these effects to specific habenula subnuclei. Here, we have developed a genetic model in which neurons of the dorsal medial habenula (dMHb) are developmental eliminated, via tissue-specific deletion of the transcription factor Pou4f1 (Brn3a). Mice with dMHb lesions perform poorly in motivation-based locomotor behaviors, such as voluntary wheel running and the accelerating rotarod, but show only minor abnormalities in gait and balance and exhibit normal levels of basal locomotion. These mice also show deficits in sucrose preference, but not in the forced swim test, two measures of depression-related phenotypes in rodents. We have also used Cre recombinase-mediated expression of channelrhodopsin-2 and halorhodopsin to activate dMHb neurons or silence their output in freely moving mice, respectively. Optical activation of the dMHb in vivo supports intracranial self-stimulation, showing that dMHb activity is intrinsically reinforcing, whereas optical silencing of dMHb outputs is aversive. Together, our findings demonstrate that the dMHb is involved in exercise motivation and the regulation of hedonic state, and is part of an intrinsic reinforcement circuit. [ABSTRACT FROM AUTHOR]

Microtia is a term used to describe a wide array of phenotypic presentations of the outer ear. Although the majority of the cases are isolated in nature, much of our understanding of the causes of microtia has been driven by the identification of genes underlying syndromic forms where the anomaly co-presents with various other craniofacial and extra-craniofacial structural defects. In this review we discuss recent findings in mice deficient in Hoxa2, a key regulator of branchial arch patterning, which has necessitated a revision to the canonical model of pinna morphogenesis. The revised model will likely impact current classification schemes for microtia and, as we argue in this review, the interpretation of the developmental basis for various auricular malformations. In addition, we highlight recent studies in other mammalian species that are providing the first clues as to possible causes of at least some isolated anomalies and thus should now accelerate the search for the more elusive genetic contributions to the many isolated and non-syndromic cases of microtia. These findings, together with the application of new genome-level sequencing technologies and more thorough quantitative assessment of available mutant mouse resources, promise an exciting future for genetic studies in microtia. [ABSTRACT FROM AUTHOR]

The Chrna5 gene encodes theα5 nicotinic acetylcholine receptor subunit, an "accessory" subunit of pentameric nicotinic receptors, that has been shown to play a role in nicotine-related behaviors in rodents and is genetically linked to smoking behavior in humans. Here we have used a BAC transgenic mouse line,α5GFP, to examine the cellular phenotype, connectivity, and function ofα5-expressing neurons. Although the medial habenula (MHb) has been proposed as a site of α5 function, α5GFP is not detectable in the MHb, and α5 mRNA is expressed there only at very low levels. However,α5GFP is strongly expressed in a subset of neurons in the interpeduncular nucleus (IP), median raphe/paramedian raphe (MnR/PMnR), and dorsal tegmental area (DTg). Double-label fluorescence in situ hybridization reveals that these neurons are exclusively GABAergic. Transgenic and conventional tract tracing show that α5GFP neurons in the IP project principally to theMnR/PMnRand DTg/interfascicular dorsal raphe, both areas rich in serotonergic neurons. Theα5GFP neurons in the IP are located in a region that receives cholinergic fiber inputs from the ventral MHb, and optogenetically assisted circuit mapping demonstrates a monosynaptic connection between these cholinergic neurons and α5GFP IP neurons. Selective inhibitors of both α4β2- and α3β4-containing nicotinic receptors were able to reduce nicotine-evoked inward currents inα5GFP neurons in the IP, suggesting a mixed nicotinic receptor profile in these cells. Together, these findings show that theα5-GABAergic interneurons form a link from the MHb to serotonergic brain centers, which is likely to mediate some of the behavioral effects of nicotine. [ABSTRACT FROM AUTHOR]

The formation of functional connectivity in the nervous system is governed by axon guidance that instructs nerve growth and branching during development, implying a similarity between neuronal subtypes in terms of nerve extension. We demonstrate the molecular mechanism of another layer of complexity in vertebrates by defining a transcriptional program underlying growth differences between positionally different neurons. The rate of axon extension of the early subset of embryonic dorsal root ganglion sensory neurons is encoded in neurons at different axial levels. This code is determined by a segmental pattern of axial levels of Runx family transcription factor Runx3. Runx3 in turn determines transcription levels of genes encoding cytoskeletal proteins involved in axon extension, including Rock1 and Rock2 which have ongoing activities determining axon growth in early sensory neurons and blocking Rock activity reverses axon extension deficits of Runx3?/? neurons. Thus, Runx3 acts to regulate positional differences in axon extension properties apparently without affecting nerve guidance and branching, a principle that could be relevant to other parts of the nervous system. [ABSTRACT FROM AUTHOR]

Abstract: Hmx1 is a variant homeodomain transcription factor expressed in the developing sensory nervous system, retina, and craniofacial mesenchyme. Recently, mutations at the Hmx1 locus have been linked to craniofacial defects in humans, rats, and mice, but its role in nervous system development is largely unknown. Here we show that Hmx1 is expressed in a subset of sensory neurons in the cranial and dorsal root ganglia which does not correspond to any specific sensory modality. Sensory neurons in the dorsal root and trigeminal ganglia of Hmx1dm/dm mouse embryos have no detectable Hmx1 protein, yet they undergo neurogenesis and express sensory subtype markers normally, demonstrating that Hmx1 is not globally required for the specification of sensory neurons from neural crest precursors. Loss of Hmx1 expression has no obvious effect on the early development of the trigeminal (V), superior (IX/X), or dorsal root ganglia neurons in which it is expressed, but results in marked defects in the geniculate (VII) ganglion. Hmx1dm/dm mouse embryos possess only a vestigial posterior auricular nerve, and general somatosensory neurons in the geniculate ganglion are greatly reduced by mid-gestation. Although Hmx1 is expressed in geniculate neurons prior to cell cycle exit, it does not appear to be required for neurogenesis, and the loss of geniculate neurons is likely to be the result of increased cell death. Fate mapping of neural crest-derived tissues indicates that Hmx1-expressing somatosensory neurons at different axial levels may be derived from either the neural crest or the neurogenic placodes. [Copyright &y& Elsevier]

The combinatorial expression of transcription factors frequently marks cellular identity in the nervous system, yet how these factors interact to determine specific neuronal phenotypes is not well understood. Sensory neurons of the trigeminal ganglion (TG) and dorsal root ganglia (DRG) coexpress the homeodomain transcription factors Brn3a and Islet1, and past work has revealed partially overlapping programs of gene expression downstream of these factors. Here we examine sensory development in Brn3a/Islet1 double knock-out (DKO) mice. Sensory neurogenesis and the formation of the TG and DRG occur in DKO embryos, but the DRG are dorsally displaced, and the peripheral projections of the ganglia are markedly disturbed. Sensory neurons in DKO embryos show a profound loss of all early markers of sensory subtypes, including the Ntrk neurotrophin receptors, and the runt-family transcription factors Runx1 and Runx3. Examination of global gene expression in the E12.5 DRG of single and double mutant embryos shows that Brn3a and Islet1 are together required for nearly all aspects of sensory-specific gene expression, including several newly identified sensory markers. On a majority of targets, Brn3a and Islet1 exhibit negative epistasis, in which the effects of the individual knock-out alleles are less than additive in the DKO. Smaller subsets of targets exhibit positive epistasis, or are regulated exclusively by one factor. Brn3a/Islet1 double mutants also fail to developmentally repress neurogenic bHLH genes, and in vivo chromatin immunoprecipitation shows that Islet1 binds to a known Brn3a-regulated enhancer in the neurod4 gene, suggesting a mechanism of interaction between these genes. [ABSTRACT FROM AUTHOR]

Abstract: G-protein coupled receptor kinase-3 (GRK3), translated from the gene, ADRBK2 has been implicated as a candidate molecule for bipolar disorder through multiple, converging lines of evidence. In some individuals, the ADRBK2 gene harbors the A-haplotype, a collection of single nucleotide polymorphisms (SNPs) previously associated with an increased risk for bipolar disorder. Because the A-haplotype encompasses the ADRBK2 promoter, we hypothesized that it may alter the regulation of gene expression. Using histone H3 acetylation to infer promoter activity in lymphoblastoid cells from patients with bipolar disorder, we examined the A-haplotype within its genomic context and determined that at least four of its SNPs are present in transcriptionally active portions of the promoter. However, using chromatin immunoprecipitation followed by allele-specific PCR in samples heterozygous for the A-haplotype, we found no evidence of altered levels of acetylated histone H3 at the affected allele compared to the common allele. Similarly, using a transcribed SNP to discriminate expressed ADRBK2 mRNA strands by allele of origin; we found that the A-haplotype did not confer an allelic-expression imbalance. Our data suggest that while the A-haplotype is situated in active regulatory sequence, the risk-associated SNPs do not appear to affect ADRBK2 gene regulation at the level of histone H3 acetylation nor do they confer measurable changes in transcription in lymphoblastoid cells. However, tissue-specific mechanisms by which the A-haplotype could affect ADRBK2 in the central nervous system cannot be excluded. [Copyright &y& Elsevier]

The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a- VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes. [ABSTRACT FROM AUTHOR]

The habenula is a dorsal diencephalic structure consisting of medial and lateral subnuclei and a principal output tract, the fasciculus retroflexus, which together form a link between the limbic forebrain and ventral midbrain. Here, we have used microarray and bioinformatic approaches in the mouse to show that the habenula is a distinctive molecular territory of the CNS, with a unique profile of neurotransmitter, ion channel, and regulatory factor expression. Neurons of the medial habenula and part of the lateral habenula express the transcription factor Brn3a/Pou4f1, and Brn3a-expressing habenular neurons project exclusively to the interpeduncular nucleus in the ventral midbrain. In Brn3a mutant embryos, the fasciculus retroflexus is directed appropriately, but habenular neurons fail to innervate their targets. Microarray analysis of Brn3a null embryos shows that this factor regulates an extensive program of habenula-enriched genes, but not generic neural properties. The orphan nuclear receptorNurr1/Nr4a2is coexpressed with Brn3ainthe developing habenula, is downstream of Brn3a, and mediates expression of a subset of Brn3a-regulated transcripts. Together, these findings begin to define a gene regulatory pathway for habenula development in mammals. [ABSTRACT FROM AUTHOR]

We used conditional knockout strategies in mice to determine the developmental events and gene expression program regulated by the LIM-homeodomain factor Islet1 in developing sensory neurons. Early development of the trigeminal and dorsal root ganglia was grossly normal in the absence of Islet1. From E12.5 onward, however, Isl1 mutant embryos showed a loss of the nociceptive markers TrkA and Runx1 and a near absence of cutaneous innervation. Proprioceptive neurons characterized by the expression of TrkC, Runx3 and Etv1 were relatively spared. Microarray analysis of Isl1 mutant ganglia revealed prolonged expression of developmental regulators that are normally restricted to early sensory neurogenesis and ectopic expression of transcription factors that are normally found in the CNS, but not in sensory ganglia. Later excision of Isl1 did not reactivate early genes, but resulted in decreased expression of transcripts related to specific sensory functions. Together these results establish a central role for Islet1 in the transition from sensory neurogenesis to subtype specification. [ABSTRACT FROM AUTHOR]

The dorsal spinal cord synthesizes a variety of neuropeptides that modulate the transmission of nociceptive sensory information. Here, we used genetic fate mapping to show that Tlx3+ spinal cord neurons and their derivatives represent a heterogeneous population of neurons, marked by partially overlapping expression of a set of neuropeptide genes, including those encoding the anti-opioid peptide cholecystokinin, pronociceptive Substance P (SP), Neurokinin B, and a late wave of somatostatin. Mutations of Tlx3 and Tlx1 result in a loss of expression of these peptide genes. Brn3a, a homeobox transcription factor, the expression of which is partly dependent on Tlx3, is required specifically for the early wave of SP expression. These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons. [ABSTRACT FROM AUTHOR]

Abstract: The rostral part of the dorsal midbrain, known as the superior colliculus in mammals or the optic tectum in birds, receives a substantial retinal input and plays a diverse and important role in sensorimotor integration. However, little is known about the development of specific subtypes of neurons in the tectum, particularly those which contribute tectofugal projections to the thalamus, isthmic region, and hindbrain. Here we show that two homeodomain transcription factors, Brn3a and Pax7, are expressed in mutually exclusive patterns in the developing and mature avian midbrain. Neurons expressing these factors are generated at characteristic developmental times, and have specific laminar fates within the tectum. In mice expressing βgalactosidase targeted to the Pou4f1 (Brn3a) locus, Brn3a-expressing neurons contribute to the ipsilateral but not the contralateral tectofugal projections to the hindbrain. Using misexpression of Brn3a and Pax7 by electroporation in the chick tectum, combined with GFP reporters, we show that Brn3a determines the laminar fate of subsets of tectal neurons. Furthermore, Brn3a regulates the development of neurons contributing to specific ascending and descending tectofugal pathways, while Pax7 globally represses the development of tectofugal projections to nearly all brain structures. [Copyright &y& Elsevier]

Abstract: Numerous transcription factors have been identified which have profound effects on developing neurons. A fundamental problem is to identify genes downstream of these factors and order them in developmental pathways. We have previously identified 85 genes with changed expression in the trigeminal ganglia of mice lacking Brn3a, a transcription factor encoded by the Pou4f1 gene. Here we use locus-wide chromatin immunoprecipitation in embryonic trigeminal neurons to show that Brn3a is a direct repressor of two of these downstream genes, NeuroD1 and NeuroD4, and also directly modulates its own expression. Comparison of Brn3a binding to the Pou4f1 locus in vitro and in vivo reveals that not all high affinity sites are occupied, and several Brn3a binding sites identified in the promoters of genes that are silent in sensory ganglia are also not occupied in vivo. Site occupancy by Brn3a can be correlated with evolutionary conservation of the genomic regions containing the recognition sites and also with histone modifications found in regions of chromatin active in transcription and gene regulation, suggesting that Brn3a binding is highly context dependent. [Copyright &y& Elsevier]

Background: General somatic sensation is conveyed to the central nervous system at cranial levels by the trigeminal ganglion (TG), and at spinal levels by the dorsal root ganglia (DRG). Although these ganglia have similar functions, they have distinct embryological origins, in that both contain neurons originating from the neural crest, while only the TG includes cells derived from the placodal ectoderm. Results: Here we use microarray analysis of E13.5 embryos to demonstrate that the developing DRG and TG have very similar overall patterns of gene expression. In mice lacking the POUdomain transcription factor Brn3a, the DRG and TG exhibit many common changes in gene expression, but a subset of Brn3a target genes show increased expression only in the TG. In the wild-type TG these Brn3a-repressed genes are silent, yet their promoter regions exhibit histone H3-acetylation levels similar to constitutively transcribed gene loci. This increased H3-acetylation is not observed in the DRG, suggesting that chromatin modifications play a role in cell-specific target gene regulation by Brn3a. Conclusion: These results demonstrate that one developmental role of Brn3a is to repress potential differences in gene expression between sensory neurons generated at different axial levels, and to regulate a convergent program of developmental gene expression, in which functionally similar populations of neurons are generated from different embryological substrates. [ABSTRACT FROM AUTHOR]

Retinal ganglion cells (RGCs) innervate several specific CNS targets serving cortical and subcortical visual pathways and the entrainment of circadian rhythms. Recent studies have shown that retinal ganglion cells express specific combinations of POU- and LIM-domain transcription factors, but how these factors relate to the subsequent development of the retinofugal pathways and the functional identity of RGCs is mostly unknown. Here, we use targeted expression of an genetic axonal tracer, tau/β-galactosidase, to examine target innervation by retinal ganglion cells expressing the POU-domain factor Brn3a. Brn3a is expressed in RGCs innervating the principal retinothalamic/ retinocollicular pathway mediating cortical vision but is not expressed in RGCs of the accessory optic, pretectal, and hypothalamic pathways serving subcortical visuomotor and circadian functions. In the thalamus, Brn3a ganglion cell fibers are primarily restricted to the outer shell of the dorsal lateral geniculate, providing new evidence for the regionalization of this nucleus in rodents. Brn3a RGC axons have a relative preference for the contralateral hemisphere, but known mediators of the laterality of RGC axons are not repatterned in the absence of Brn3a. Brn3a is coexpressed extensively with the closely related factor Brn3b in the embryonic retina, and the effects of the loss of Brn3a in retinal development are not severe, suggesting partial redundancy of function in this gene class. [ABSTRACT FROM AUTHOR]

Mice lacking the POU-domain transcription factor Brn3a exhibit marked defects in sensory axon growth and abnormal sensory apoptosis. We have determined the regulatory targets of Brn3a in the developing trigeminal ganglion using microarray analysis of Brn3a mutant mice. These results show that Brn3 mediates the coordinated expression of neurotransmitter systems, ion channels, structural components of axons and inter- and intracellular signaling systems. Loss of Brn3a also results in the ectopic expression of transcription factors normally detected in earlier developmental stages and in other areas of the nervous system. Target gene expression is normal in heterozygous mice, consistent with prior work showing that autoregulation by Brn3a results in gene dosage compensation. Detailed examination of the expression of several of these downstream genes reveals that the regulatory role of Brn3a in the trigeminal ganglion appears to be conserved in more posterior sensory ganglia but not in the CNS neurons that express this factor. [ABSTRACT FROM AUTHOR]

Deals with a study which examined whether transcription factor Brn3a is a direct or indirect regulator of TrkA transcription by using genetic, biochemical and transgenic approaches. Materials and methods; Specificity of the TrkA antibody; Summary of transgenic analysis of the wild-type TrkA minimal enhancer and TrkA minimal enhancers with one or both Brn3a-binding-site mutations.