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Cy™3 AffiniPure Donkey Anti-Goat IgG (H+L) antibody

RRID:AB_2307351

Generation of six multiple sclerosis patient-derived induced pluripotent stem cell lines.

  • Miquel-Serra L
  • Stem Cell Res
  • 2018 Jul 3

Literature context:


Abstract:

Multiple sclerosis (MS) is considered a chronic autoimmune disease of the central nervous system that leads to gliosis, demyelination, axonal damage and neuronal death. The MS disease aetiology is unknown, though a polymorphism of the TNFRSF1A gene, rs1800693, is known to confer an increased risk for MS. Using retroviral delivery of reprogramming transgenes, we generated six MS patient-specific iPSC lines with two distinct genotypes, CC or TT, of the polymorphism rs1800693. iPSC lines had normal karyotype, expressed pluripotency genes and differentiated into the three germ layers. These lines offer a good tool to study MS pathomechanisms and for drug testing.

Funding information:
  • NIDDK NIH HHS - DK075386(United States)

Neurotransmitter diversity in pre-synaptic terminals located in the parvicellular neuroendocrine paraventricular nucleus of the rat and mouse hypothalamus.

  • Johnson CS
  • J. Comp. Neurol.
  • 2018 Jun 1

Literature context:


Abstract:

Virtually all rodent neuroendocrine corticotropin-releasing-hormone (CRH) neurons are in the dorsal medial parvicellular (mpd) part of the paraventricular nucleus of the hypothalamus (PVH). They form the final common pathway for adrenocortical stress responses. Their activity is controlled by sets of GABA-, glutamate-, and catecholamine-containing inputs arranged in an interactive pre-motor network. Defining the nature and arrangement of these inputs can help clarify how stressor type and intensity information is conveyed to neuroendocrine neurons. Here we use immunohistochemistry with high-resolution 3-dimensional image analyses to examine the arrangement of single- and co-occurring GABA, glutamate, and catecholamine markers in synaptophysin-defined pre-synaptic terminals in the PVHmpd of unstressed rats and Crh-IRES-Cre;Ai14 transgenic mice: respectively, vesicular glutamate transporter 2 (VGluT2), vesicular GABA transporter (VGAT), dopamine β-hydroxylase (DBH), and phenylethanolamine n-methyltransferase (PNMT). Just over half of all PVHmpd pre-synaptic terminals contain VGAT, with slightly less containing VGluT2. The vast majority of terminal appositions with mouse CRH neurons occur non-somatically. However, there are significantly more somatic VGAT than VGluT2 appositions. In the rat PVHmpd, about five times as many pre-synaptic terminals contain PNMT than DBH only. However, because epinephrine release has never been detected in the PVH, PNMT terminals may functionally be noradrenergic not adrenergic. PNMT and VGluT2 co-occur in some pre-synaptic terminals indicating the potential for co-transmission of glutamate and norepinephrine. Collectively, these results provide a structural basis for how GABA/glutamate/catecholamine interactions enable adrenocortical responses to fast-onset interosensory stimuli, and more broadly, how combinations of PVH neurotransmitters and neuromodulators interact dynamically to control adrenocortical activity.

Funding information:
  • NINDS NIH HHS - R01 NS029728()
  • NINDS NIH HHS - U54 NS048843(United States)

Ablation of the presynaptic organizer Bassoon in excitatory neurons retards dentate gyrus maturation and enhances learning performance.

  • Annamneedi A
  • Brain Struct Funct
  • 2018 Jun 18

Literature context:


Abstract:

Bassoon is a large scaffolding protein of the presynaptic active zone involved in the development of presynaptic terminals and in the regulation of neurotransmitter release at both excitatory and inhibitory brain synapses. Mice with constitutive ablation of the Bassoon (Bsn) gene display impaired presynaptic function, show sensory deficits and develop severe seizures. To specifically study the role of Bassoon at excitatory forebrain synapses and its relevance for control of behavior, we generated conditional knockout (Bsn cKO) mice by gene ablation through an Emx1 promoter-driven Cre recombinase. In these animals, we confirm selective loss of Bassoon from glutamatergic neurons of the forebrain. Behavioral assessment revealed that, in comparison to wild-type littermates, Bsn cKO mice display selectively enhanced contextual fear memory and increased novelty preference in a spatial discrimination/pattern separation task. These changes are accompanied by an augmentation of baseline synaptic transmission at medial perforant path to dentate gyrus (DG) synapses, as indicated by increased ratios of field excitatory postsynaptic potential slope to fiber volley amplitude. At the structural level, an increased complexity of apical dendrites of DG granule cells can be detected in Bsn cKO mice. In addition, alterations in the expression of cellular maturation markers and a lack of age-dependent decrease in excitability between juvenile and adult Bsn cKO mice are observed. Our data suggest that expression of Bassoon in excitatory forebrain neurons is required for the normal maturation of the DG and important for spatial and contextual memory.

Funding information:
  • Deutsche Forschungsgemeinschaft - CRC 779-Neurobiology of Motivated Behavior project A06()
  • Deutsche Forschungsgemeinschaft - CRC 779-Neurobiology of Motivated Behavior project B05()
  • Deutsche Forschungsgemeinschaft - CRC 779-Neurobiology of Motivated Behavior project B09()
  • Leibniz-Gemeinschaft - LGS SynaptoGenetics()
  • NIGMS NIH HHS - S06 GM061223-05A1(United States)

Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions.

  • Klug JR
  • Elife
  • 2018 May 1

Literature context:


Abstract:

Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior.

Funding information:
  • National Institutes of Health - R01AG047669()
  • National Institutes of Health - R01NS083815()
  • NHLBI NIH HHS - R01 HL073085-08(United States)

Role for Wnt Signaling in Retinal Neuropil Development: Analysis via RNA-Seq and In Vivo Somatic CRISPR Mutagenesis.

  • Sarin S
  • Neuron
  • 2018 Apr 4

Literature context:


Abstract:

Screens for genes that orchestrate neural circuit formation in mammals have been hindered by practical constraints of germline mutagenesis. To overcome these limitations, we combined RNA-seq with somatic CRISPR mutagenesis to study synapse development in the mouse retina. Here synapses occur between cellular layers, forming two multilayered neuropils. The outer neuropil, the outer plexiform layer (OPL), contains synapses made by rod and cone photoreceptor axons on rod and cone bipolar dendrites, respectively. We used RNA-seq to identify selectively expressed genes encoding cell surface and secreted proteins and CRISPR-Cas9 electroporation with cell-specific promoters to assess their roles in OPL development. Among the genes identified in this way are Wnt5a and Wnt5b. They are produced by rod bipolars and activate a non-canonical signaling pathway in rods to regulate early OPL patterning. The approach we use here can be applied to other parts of the brain.

Funding information:
  • NHGRI NIH HHS - NIH T32 HG002536(United States)

A Sub-population of Group A Streptococcus Elicits a Population-wide Production of Bacteriocins to Establish Dominance in the Host.

  • Hertzog BB
  • Cell Host Microbe
  • 2018 Mar 14

Literature context:


Abstract:

Bacteria use quorum sensing (QS) to regulate gene expression. We identified a group A Streptococcus (GAS) strain possessing the QS system sil, which produces functional bacteriocins, through a sequential signaling pathway integrating host and bacterial signals. Host cells infected by GAS release asparagine (ASN), which is sensed by the bacteria to alter its gene expression and rate of proliferation. We show that upon ASN sensing, GAS upregulates expression of the QS autoinducer peptide SilCR. Initial SilCR expression activates the autoinduction cycle for further SilCR production. The autoinduction process propagates throughout the GAS population, resulting in bacteriocin production. Subcutaneous co-injection of mice with a bacteriocin-producing strain and the globally disseminated M1T1 GAS clone results in M1T1 killing within soft tissue. Thus, by sensing host signals, a fraction of a bacterial population can trigger an autoinduction mechanism mediated by QS, which acts on the entire bacterial community to outcompete other bacteria within the infection.

Funding information:
  • NIGMS NIH HHS - R01GM090077(United States)

Injury Induces Endogenous Reprogramming and Dedifferentiation of Neuronal Progenitors to Multipotency.

  • Lin B
  • Cell Stem Cell
  • 2017 Dec 7

Literature context:


Abstract:

Adult neurogenesis in the olfactory epithelium is often depicted as a unidirectional pathway during homeostasis and repair. We challenge the unidirectionality of this model by showing that epithelial injury unlocks the potential for Ascl1+ progenitors and Neurog1+ specified neuronal precursors to dedifferentiate into multipotent stem/progenitor cells that contribute significantly to tissue regeneration in the murine olfactory epithelium (OE). We characterize these dedifferentiating cells using several lineage-tracing strains and single-cell mRNA-seq, and we show that Sox2 is required for initiating dedifferentiation and that inhibition of Ezh2 promotes multipotent progenitor expansion. These results suggest that the apparent hierarchy of neuronal differentiation is not irreversible and that lineage commitment can be overridden following severe tissue injury. We elucidate a previously unappreciated pathway for endogenous tissue repair by a highly regenerative neuroepithelium and introduce a system to study the mechanisms underlying plasticity in the OE that can be adapted for other tissues.

Funding information:
  • NIDCD NIH HHS - F30 DC013962()
  • NIDCD NIH HHS - F31 DC014398()
  • NIDCD NIH HHS - F31 DC014637()
  • NIDCD NIH HHS - R01 DC002167()
  • NIDCD NIH HHS - R21 DC015889()
  • NIGMS NIH HHS - 8 P20 GM103414-10(United States)

Distribution and diversity of intrinsically photosensitive retinal ganglion cells in tree shrew.

  • Johnson EN
  • J. Comp. Neurol.
  • 2017 Dec 14

Literature context:


Abstract:

Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate the pupillary light reflex, circadian entrainment, and may contribute to luminance and color perception. The diversity of ipRGCs varies from rodents to primates, suggesting differences in their contributions to retinal output. To further understand the variability in their organization and diversity across species, we used immunohistochemical methods to examine ipRGCs in tree shrew (Tupaia belangeri). Tree shrews share membership in the same clade, or evolutionary branch, as rodents and primates. They are highly visual, diurnal animals with a cone-dominated retina and a geniculo-cortical organization resembling that of primates. We identified cells with morphological similarities to M1 and M2 cells described previously in rodents and primates. M1-like cells typically had somas in the ganglion cell layer, with 23% displaced to the inner nuclear layer (INL). However, unlike M1 cells, they had bistratified dendritic fields ramifying in S1 and S5 that collectively tiled space. M2-like cells had dendritic fields restricted to S5 that were smaller and more densely branching. A novel third type of melanopsin immunopositive cell was identified. These cells had somata exclusively in the INL and monostratified dendritic fields restricted to S1 that tiled space. Surprisingly, these cells immunolabeled for tyrosine hydroxylase, a key component in dopamine synthesis. These cells immunolabeled for an RGC marker, not amacrine cell markers, suggesting that they are dopaminergic ipRGCs. We found no evidence for M4 or M5 ipRGCs, described previously in rodents. These results identify some organizational features of the ipRGC system that are canonical versus species-specific.

Funding information:
  • NEI NIH HHS - R01 EY024567()
  • NEI NIH HHS - R01 EY027193()
  • NHGRI NIH HHS - R01 HG004401(United States)

Generation of two induced pluripotent stem cell (iPSC) lines from X-linked adrenoleukodystrophy (X-ALD) patients with adrenomyeloneuropathy (AMN).

  • Son D
  • Stem Cell Res
  • 2017 Oct 25

Literature context:


Abstract:

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by a mutation in the ATP-binding cassette transporter subfamily D member 1 (ABCD1) gene. We generated two induced pluripotent stem cell (iPSC) lines from X-ALD patients with adrenomyeloneuropathy (AMN) by Sendai virus containing OCT4, SOX2, KLF4 and c-MYC. Established iPSC lines expressed various pluripotency markers, had differentiation potential of three germ layers in vitro, had normal karyotype and retained ABCD1 mutation.

Selective synaptic connections in the retinal pathway for night vision.

  • Beaudoin DL
  • J. Comp. Neurol.
  • 2017 Aug 30

Literature context:


Abstract:

The mammalian retina encodes visual information in dim light using rod photoreceptors and a specialized circuit: rods→rod bipolar cells→AII amacrine cell. The AII amacrine cell uses sign-conserving electrical synapses to modulate ON cone bipolar cell terminals and sign-inverting chemical (glycinergic) synapses to modulate OFF cone cell bipolar terminals; these ON and OFF cone bipolar terminals then drive the output neurons, retinal ganglion cells (RGCs), following light increments and decrements, respectively. The AII amacrine cell also makes direct glycinergic synapses with certain RGCs, but it is not well established how many types receive this direct AII input. Here, we investigated functional AII amacrine→RGC synaptic connections in the retina of the guinea pig (Cavia porcellus) by recording inhibitory currents from RGCs in the presence of ionotropic glutamate receptor (iGluR) antagonists. This condition isolates a specific pathway through the AII amacrine cell that does not require iGluRs: cone→ON cone bipolar cell→AII amacrine cell→RGC. These recordings show that AII amacrine cells make direct synapses with OFF Alpha, OFF Delta and a smaller OFF transient RGC type that co-stratifies with OFF Alpha cells. However, AII amacrine cells avoid making synapses with numerous RGC types that co-stratify with the connected RGCs. Selective AII connections ensure that a privileged minority of RGC types receives direct input from the night-vision pathway, independent from OFF bipolar cell activity. Furthermore, these results illustrate the specificity of retinal connections, which cannot be predicted solely by co-stratification of dendrites and axons within the inner plexiform layer.

Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State.

  • Li X
  • Cell Stem Cell
  • 2017 Aug 3

Literature context:


Abstract:

Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.

The polysialic acid mimetics idarubicin and irinotecan stimulate neuronal survival and neurite outgrowth and signal via protein kinase C.

  • Loers G
  • J. Neurochem.
  • 2017 Aug 25

Literature context:


Abstract:

Polysialic acid (PSA) is a large, negatively charged, linear homopolymer of alpha2-8-linked sialic acid residues. It is generated by two polysialyltransferases and attached to N- and/or O-linked glycans, and its main carrier is the neural cell adhesion molecule (NCAM). PSA controls the development and regeneration of the nervous system by enhancing cell migration, axon pathfinding, synaptic targeting, synaptic plasticity, by regulating the differentiation of progenitor cells and by modulating cell-cell and cell-matrix adhesions. In the adult, PSA plays a role in the immune system, and PSA mimetics promote functional recovery after nervous system injury. In search for novel small molecule mimetics of PSA that are applicable for therapy, we identified idarubicin, an antineoplastic anthracycline, and irinotecan, an antineoplastic agent of the topoisomerase I inhibitor class, as PSA mimetics using a competition enzyme-linked immunosorbent assay. Idarubicin and irinotecan compete with the PSA-mimicking peptide and colominic acid, the bacterial analog of PSA, for binding to the PSA-specific monoclonal antibody 735. Idarubicin and irinotecan stimulate neurite outgrowth and survival of cultured cerebellar neurons after oxidative stress via protein kinase C and Erk1/2 in a similar manner as colominic acid, whereas Fyn, casein kinase II and the phosphatase and tensin homolog are only involved in idarubicin and irinotecan-stimulated neurite outgrowth. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds irinotecan and idarubicin which trigger the same signaling cascades as PSA, thus introducing the possibility of retargeting these drugs to treat nervous system injuries.

Funding information:
  • NINDS NIH HHS - R01 NS078385(United States)
  • PHS HHS - HHSN261200800001E(United States)

Peripheral and central anatomical organization of cutaneous afferent subtypes in a rat nociceptive intersegmental spinal reflex.

  • Lee HJ
  • J. Comp. Neurol.
  • 2017 Jun 15

Literature context:


Abstract:

Stimulation of rat segmental dorsal cutaneous nerves (DCNs) evokes the nociceptive intersegmental cutaneus trunci muscle (CTM) reflex. The reflex consists of early and late responses, mediated by Aδ and C fibers, respectively, based on required stimulation strengths, and shows segmental differences in terms of amplitude and duration. We have now investigated whether the peripheral or central anatomy of nociceptive afferent subtypes in different DCNs also vary in a segmental manner. The numbers of different axon subtypes, determined by axon diameter, were analyzed across peripheral DCNs from T6 to L1. The central projections of T7 and T13 DCN afferents were traced using DCN injections of cholera toxin subunit B (CTB) for myelinated A fibers and isolectin B4 (IB4) for unmyelinated C fibers and both labels were quantified in the dorsal horns. Peripheral axon subtype numbers did not differ significantly across DCNs. Centrally, IB4+ , but not CTB+ , projection areas were different between T7 and T13, consistent with different segmental CTM neurogram responses. At both levels, A fibers projected to deeper layers of the dorsal horn than did C fibers. These termination sites are consistent with both mono- and polysynaptic connections between these afferents and the ascending propriospinal interneurons of the reflex. Also analyzed were the spatial distribution, the synaptic termination, and the glutamatergic transporter profiles of DCN A and C fibers and their relationship to calcitonin gene-related peptide (CGRP) staining in the dorsal horn.

Mosaic Analysis with Double Markers Reveals Distinct Sequential Functions of Lgl1 in Neural Stem Cells.

  • Beattie R
  • Neuron
  • 2017 May 3

Literature context:


Abstract:

The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms.

Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency.

  • Yang Y
  • Cell
  • 2017 Apr 6

Literature context:


Abstract:

Of all known cultured stem cell types, pluripotent stem cells (PSCs) sit atop the landscape of developmental potency and are characterized by their ability to generate all cell types of an adult organism. However, PSCs show limited contribution to the extraembryonic placental tissues in vivo. Here, we show that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues. Notably, a single mouse EPS cell shows widespread chimeric contribution to both embryonic and extraembryonic lineages in vivo and permits generating single-EPS-cell-derived mice by tetraploid complementation. Furthermore, human EPS cells exhibit interspecies chimeric competency in mouse conceptuses. Our findings constitute a first step toward capturing pluripotent stem cells with extraembryonic developmental potentials in culture and open new avenues for basic and translational research. VIDEO ABSTRACT.

Tridimensional Visualization and Analysis of Early Human Development.

  • Belle M
  • Cell
  • 2017 Mar 23

Literature context:


Abstract:

Generating a precise cellular and molecular cartography of the human embryo is essential to our understanding of the mechanisms of organogenesis in normal and pathological conditions. Here, we have combined whole-mount immunostaining, 3DISCO clearing, and light-sheet imaging to start building a 3D cellular map of the human development during the first trimester of gestation. We provide high-resolution 3D images of the developing peripheral nervous, muscular, vascular, cardiopulmonary, and urogenital systems. We found that the adult-like pattern of skin innervation is established before the end of the first trimester, showing important intra- and inter-individual variations in nerve branches. We also present evidence for a differential vascularization of the male and female genital tracts concomitant with sex determination. This work paves the way for a cellular and molecular reference atlas of human cells, which will be of paramount importance to understanding human development in health and disease. PAPERCLIP.

FGF13 Selectively Regulates Heat Nociception by Interacting with Nav1.7.

  • Yang L
  • Neuron
  • 2017 Feb 22

Literature context:


Abstract:

The current knowledge about heat nociception is mainly confined to the thermosensors, including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion (DRG). However, the loss of thermosensors only partially impairs heat nociception, suggesting the existence of undiscovered mechanisms. We found that the loss of an intracellular fibroblast growth factor (FGF), FGF13, in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in FGF13-deficient DRG neurons. Furthermore, FGF13 interacted with the sodium channel Nav1.7 in a heat-facilitated manner. FGF13 increased Nav1.7 sodium currents and maintained the membrane localization of Nav1.7 during noxious heat stimulation, enabling the sustained firing of action potentials. Disrupting the FGF13/Nav1.7 interaction reduced the heat-evoked action potential firing and nociceptive behavior. Thus, beyond the thermosensors, the FGF13/Nav1.7 complex is essential for sustaining the transmission of noxious heat signals.

Topographic organization of the basal forebrain projections to the perirhinal, postrhinal, and entorhinal cortex in rats.

  • Kondo H
  • J. Comp. Neurol.
  • 2016 Aug 15

Literature context:


Abstract:

Previous studies have shown that the basal forebrain (BF) modulates cortical activation via its projections to the entire cortical mantle. However, the organization of these projections is only partially understood or, for certain areas, unknown. In this study, we examined the topographic organization of cholinergic and noncholinergic projections from the BF to the perirhinal, postrhinal, and entorhinal cortex by using retrograde tracing combined with choline acetyltransferase (ChAT) immunohistochemistry in rats. The perirhinal and postrhinal cortex receives major cholinergic and noncholinergic input from the caudal BF, including the caudal globus pallidus and substantia innominata and moderate input from the horizontal limb of the diagonal band, whereas the entorhinal cortex receives major input from the rostral BF, including the medial septum and the vertical and horizontal limbs of the diagonal band. In the perirhinal cases, cholinergic projection neurons are distributed more caudally in the caudal globus pallidus than noncholinergic projection neurons. Compared with the perirhinal cases, the distribution of cholinergic and noncholinergic neurons projecting to the postrhinal cortex shifts slightly caudally in the caudal globus pallidus. The distribution of cholinergic and noncholinergic neurons projecting to the lateral entorhinal cortex extends more caudally in the BF than to the medial entorhinal cortex. The ratio of ChAT-positive projection neurons to total projection neurons is higher in the perirhinal/postrhinal cases (26-48%) than in the entorhinal cases (13-30%). These results indicate that the organization of cholinergic and noncholinergic projections from the BF to the parahippocampal cortex is more complex than previously described. J. Comp. Neurol. 524:2503-2515, 2016. © 2016 Wiley Periodicals, Inc.

Somatostatin 2a receptors are not expressed on functionally identified respiratory neurons in the ventral respiratory column of the rat.

  • Le S
  • J. Comp. Neurol.
  • 2016 May 1

Literature context:


Abstract:

Microinjection of somatostatin (SST) causes site-specific effects on respiratory phase transition, frequency, and amplitude when microinjected into the ventrolateral medulla (VLM) of the anesthetized rat, suggesting selective expression of SST receptors on different functional classes of respiratory neurons. Of the six subtypes of SST receptor, somatostatin 2a (sst2a ) is the most prevalent in the VLM, and other investigators have suggested that glutamatergic neurons in the preBötzinger Complex (preBötC) that coexpress neurokinin-1 receptor (NK1R), SST, and sst2a are critical for the generation of respiratory rhythm. However, quantitative data describing the distribution of sst2a in respiratory compartments other than preBötC, or on functionally identified respiratory neurons, is absent. Here we examine the medullary expression of sst2a with particular reference to glycinergic/expiratory neurons in the Bötzinger Complex (BötC) and NK1R-immunoreactive/inspiratory neurons in the preBötC. We found robust sst2a expression at all rostrocaudal levels of the VLM, including a large proportion of catecholaminergic neurons, but no colocalization of sst2a and glycine transporter 2 mRNA in the BötC. In the preBötC 54% of sst2a -immunoreactive neurons were also positive for NK1R. sst2a was not observed in any of 52 dye-labeled respiratory interneurons, including seven BötC expiratory-decrementing and 11 preBötC preinspiratory neurons. We conclude that sst2a is not expressed on BötC respiratory neurons and that phasic respiratory activity is a poor predictor of sst2a expression in the preBötC. Therefore, sst2a is unlikely to underlie responses to BötC SST injection, and is sparse or absent on respiratory neurons identified by classical functional criteria. J. Comp. Neurol. 524:1384-1398, 2016. © 2015 Wiley Periodicals, Inc.

Funding information:
  • NINDS NIH HHS - F31NS077750(United States)

Somatostatin in the rat rostral ventrolateral medulla: Origins and mechanism of action.

  • Bou Farah L
  • J. Comp. Neurol.
  • 2016 Feb 1

Literature context:


Abstract:

Somatostatin (SST) or agonists of the SST-2 receptor (sst2 ) in the rostral ventrolateral medulla (RVLM) lower sympathetic nerve activity, arterial pressure, and heart rate, or when administered within the Bötzinger region, evoke apneusis. Our aims were to describe the mechanisms responsible for the sympathoinhibitory effects of SST on bulbospinal neurons and to identify likely sources of RVLM SST release. Patch clamp recordings were made from bulbospinal RVLM neurons (n = 31) in brainstem slices prepared from juvenile rat pups. Overall, 58% of neurons responded to SST, displaying an increase in conductance that reversed at -93 mV, indicative of an inwardly rectifying potassium channel (GIRK) mechanism. Blockade of sst2 abolished this effect, but application of tetrodotoxin did not, indicating that the SST effect is independent of presynaptic activity. Fourteen bulbospinal RVLM neurons were recovered for immunohistochemistry; nine were SST-insensitive and did not express sst2a . Three out of five responsive neurons were sst2a -immunoreactive. Neurons that contained preprosomatostatin mRNA and cholera-toxin-B retrogradely transported from the RVLM were detected in: paratrigeminal nucleus, lateral parabrachial nucleus, Kölliker-Fuse nucleus, ventrolateral periaqueductal gray area, central nucleus of the amygdala, sublenticular extended amygdala, interstitial nucleus of the posterior limb of the anterior commissure nucleus, and bed nucleus of the stria terminalis. Thus, those brain regions are putative sources of endogenous SST release that, when activated, may evoke sympathoinhibitory effects via interactions with subsets of sympathetic premotor neurons that express sst2 .

Circuit formation and function in the olfactory bulb of mice with reduced spontaneous afferent activity.

  • Lorenzon P
  • J. Neurosci.
  • 2015 Jan 7

Literature context:


Abstract:

The type of neuronal activity required for circuit development is a matter of significant debate. We addressed this issue by analyzing the topographic organization of the olfactory bulb in transgenic mice engineered to have very little afferent spontaneous activity due to the overexpression of the inwardly rectifying potassium channel Kir2.1 in the olfactory sensory neurons (Kir2.1 mice). In these conditions, the topography of the olfactory bulb was unrefined. Odor-evoked responses were readily recorded in glomeruli with reduced spontaneous afferent activity, although the functional maps were coarser than in controls and contributed to altered olfactory discrimination behavior. In addition, overexpression of Kir2.1 in adults induced a regression of the already refined connectivity to an immature (i.e., coarser) status. Our data suggest that spontaneous activity plays a critical role not only in the development but also in the maintenance of the topography of the olfactory bulb and in sensory information processing.

Funding information:
  • NCI NIH HHS - R01 CA140550(United States)

Characterization of axons expressing the artemin receptor in the female rat urinary bladder: a comparison with other major neuronal populations.

  • Forrest SL
  • J. Comp. Neurol.
  • 2014 Dec 1

Literature context:


Abstract:

Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family that has been strongly implicated in development and regeneration of autonomic nerves and modulation of nociception. Whereas other members of this family (GDNF and neurturin) primarily target parasympathetic and nonpeptidergic sensory neurons, the artemin receptor (GFRα3) is expressed by sympathetic and peptidergic sensory neurons that are also the primary sites of action of nerve growth factor, a powerful modulator of bladder nerves. Many bladder sensory neurons express GFRα3 but it is not known if they represent a specific functional subclass. Therefore, our initial aim was to map the distribution of GFRα3-immunoreactive (-IR) axons in the female rat bladder, using cryostat sections and whole wall thickness preparations. We found that GFRα3-IR axons innervated the detrusor, vasculature, and urothelium, but only part of this innervation was sensory. Many noradrenergic sympathetic axons innervating the vasculature were GFRα3-IR, but the noradrenergic innervation of the detrusor was GFRα3-negative. We also identified a prominent source of nonneuronal GFRα3-IR that is likely to be glial. Further characterization of bladder nerves revealed specific structural features of chemically distinct classes of axon terminals, and a major autonomic source of axons labeled with neurofilament-200, which is commonly used to identify myelinated sensory axons within organs. Intramural neurons were also characterized and quantified. Together, these studies reveal a diverse range of potential targets by which artemin could influence bladder function, nerve regeneration, and pain, and provide a strong microanatomical framework for understanding bladder physiology and pathophysiology.

HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia.

  • Jacob C
  • J. Neurosci.
  • 2014 Apr 23

Literature context:


Abstract:

Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.