bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of the Critical Period for Plasticity of Ocular Dominance Columns in Macaque Striate Cortex
Authors: Horton Jonathan C. , Hocking Davina R.
Published: April 2018

Visual deprivation induced by monocular eyelid suture, a laboratory model for congenital cataract, results in shrinkage of ocular dominance columns serving the closed eye. We performed monocular suture in macaques at ages 1, 3, 5, 7, and 12 weeks to define the critical period for plasticity of ocular dominance columns. After a minimum survival of 8 months, complete montages of [3H]proline-labeled columns were reconstructed from flat-mounts of striate cortex in both hemispheres. In any given monkey, visual deprivation induced the columns throughout striate cortex (V1) to retract the same distance from their original borders in layer IVcβ. After deprivation, the widest columns remained in the foveal representation and along the V1/V2 border, where columns are widest in control animals. The narrowest deprived columns belonged to the ipsilateral eye, especially along the horizontal meridian and in the periphery, where columns are narrowest in control animals. At the earliest age that we tested (1 week), visual deprivation reduced the columns to fragments. These fragments always coincided with a cytochrome oxidase patch, or a short string of patches, in the upper layers. More severe column shrinkage occurred in layer IVcβ (parvo) than layer IVcα (magno). The geniculate input to the patches in layer III (konio) appeared normal after deprivation, despite loss of CO activity. Surprisingly, the blind spot representation of the open eye was shrunken by monocular deprivation, although binocular competition is absent in this region. Our principal finding was that eyelid suture at age 1 week caused the most severe column shrinkage. With suture at later ages, the degree of column shrinkage showed a progressive decline. Deprivation commencing at age 12 weeks caused no column shrinkage. These results imply that primate visual cortex is most vulnerable to deprivation during the first weeks of life. Our experiments should provide further impetus for the treatment of children with congenital cataract at the earliest possible age.
Learning Impairment and Cholinergic Deafferentation after Cortical Nerve Growth Factor Deprivation
Authors: Gutiérrez Humberto , Miranda Marı́a Isabel , Bermúdez-Rattoni Federico
Published: April 2018

Cholinergic basal forebrain (CBF ) neurons have been shown to respondin vivoto exogenous administration of NGF. Although neurotrophins and their receptors are widely expressed in the CNS, little data exist for the physiological significance of endogenous neurotrophin signaling in CNS neurons. To test directly whether cortically derived NGF is functionally required for the cholinergic functions mediated by the cerebral cortex, repeated injections of anti-NGF mAbs were locally applied into the insular cortex (IC) of rats. The biochemical results, using anin vivomicrodialysis technique, showed a dramatic lack of extracellular release of acetylcholine after high potassium stimulation compared with controls. Furthermore, by using small injections of the neurotracer fluorogold, we found a corresponding disruption in the connectivity between the IC and the CBF. Behavioral experiments showed that the NGF antibodies applied into the IC produced a significant disruption on the acquisition of conditioned taste aversion and inhibitory avoidance learning. However, the same animals were able to recall the taste aversion when the conditioning trial was established before injections of NGF antibodies. Given these results, it seems that cortical cholinergic functions are actively dependent on locally derived NGF in the adult normal brain, and that the cholinergic activity from the CBF is not necessary for recalling aversive stimuli, but is necessary for the acquisition of aversively motivated conditionings.
Encoding of Smooth Pursuit Direction and Eye Position by Neurons of Area MSTd of Macaque Monkey
Authors: Squatrito Salvatore , Maioli Maria Grazia
Published: April 2018

The spike activity of neurons was recorded from the dorsal bank of the superior temporal sulcus (area MSTd) of alert behaving macaque monkeys performing visual fixation or target tracking tasks, with the aim of studying the tuning features of these neurons with both the direction of slow eye movement and the position of gaze. One hundred thirty-two neurons were tested for several fixation points and tracking directions. Many of them (43%) tuned to the direction of pursuit, regardless of the angle of gaze. Some (18%) showed a tonic discharge modulated by the static position of the eyes without pursuit direction specificity. A substantial number of cells (22%) were characterized by a discharge rate tuned to pursuit direction but influenced also by angle of gaze. Tuning curves for eye movement direction presented an average bandwidth of 130° and turned out to be continuously overlapping, suggesting a sort of vector coding of smooth pursuit direction. Gaze fields of eye position (EP) neurons were mostly ramp-like, with center of ramps shifted away from the straight ahead, implying a form of scalar coding of gaze eccentricity. The different categories of cells were intermingled and close to each other, suggesting possible reciprocal interactions within the same cortical area. These results show that EP and pursuit direction are signaled mainly by separate neuronal elements in area MSTd. Moreover, some cells can integrate both signals. Taking into account the visual responses of MSTd neurons to large, textured, moving fields, it is suggested that this area could be the site of interaction between visuo-oculomotor signals related to visual motion detection, slow eye movement direction, and EP. This signal interaction may be important for integrative functions such as analysis of external or self-induced visual motion, cortical control of pursuit eye movements, and eye/head coordination.
Rapid Synaptic Transmission in the Avian Ciliary Ganglion Is Mediated by Two Distinct Classes of Nicotinic Receptors
Authors: Ullian Erik M. , McIntosh J. Michael , Sargent Peter B.
Published: April 2018

We analyzed the kinetics and pharmacology of EPSCs in two kinds of neurons in the embryonic avian ciliary ganglion. Whole-cell voltage-clamp recordings revealed that the singly innervated ciliary neurons had large-amplitude (1.5–8.0 nA) EPSCs that could be classified according to the kinetics of their falling phases. Most of the neurons responded with an EPSC the falling phase of which followed a double exponential time course with time constants of ∼1 and 10 msec. The EPSCs of the remaining ciliary neurons followed a single time constant (∼8 msec). Multiple innervated choroid neurons had smaller-amplitude responses (0.2–1.5 nA when all inputs were activated) that appeared to contain only a slowly decaying component (τ = 12 msec). The fast and slow components of EPSC decay seen in most ciliary neurons could be pharmacologically isolated with two toxins against nicotinic acetylcholine receptors (AChRs). The fast component was blocked by 50 nmα-bungarotoxin (α-BuTx), which binds α7-subunit-containing AChRs. The slow component was selectively blocked by 50 nmα-conotoxin MII (α-CTx-MII), which blocks mammalian AChRs containing an α3/β2 subunit interface. A combination of both α-BuTx and α-CTx-MII abolished nearly all evoked current. Similar pharmacological results were found for ciliary neurons with monoexponentially decaying EPSCs and for choroid neurons. These results suggest that nerve-evoked transmitter acts on at least two different populations of AChRs on autonomic motor neurons in the ciliary ganglion.
Properties of GABAAReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons
Authors: Galarreta Mario , Hestrin Shaul
Published: April 2018

Rapid applications of GABA (from 10 μmto 10 mm) to outside-out patches were used to study the role that the kinetic properties of GABAAreceptors play in determining the time course of IPSCs in neocortical pyramidal neurons. Currents induced by rapid applications of brief (1 msec) pulses of GABA (1 mm) showed a biexponential decay phase that seems to involve the entry of GABAAreceptors into desensitized states. This conclusion is based on the similar fast decay kinetics of the response to brief and prolonged pulses of GABA and on the correlation between the degree of paired-pulse depression and the decay rate of the currents induced by brief pulses.

Under nonequilibrium conditions we found that the concentration–response curve of pyramidal GABAAreceptors has an EC50of 185 μm(GABA pulse of 1 msec). The decay time course of the patch currents in response to brief applications of GABA was insensitive to agonist concentrations at the range from 50 μmto 10 mm. Faster decay rates were observed only in response to pulses of 10 μmGABA. These data are compatible with the suggestion that briefer openings derive from a monoliganded state and that these are negligible when receptor activation is >2%. Assuming that GABA transients at neocortical synapses are fast, a several millimolar GABA concentration would be needed to saturate the postsynaptic GABAAreceptors.
Intracellular Calcium Transients and Potassium Current Oscillations Evoked by Glutamate in Cultured Rat Astrocytes
Authors: Chen Jianguo , Backus Kurt H. , Deitmer Joachim W.
Published: April 2018

Glutamate responses in cultured rat astrocytes from cerebella of neonatal rats were investigated using the perforated-patch configuration to record membrane currents without rundown of intracellular messenger cascades, and microfluorometric measurements to measure the intracellular Ca2+concentration ([Ca2+]i) and intracellular pH (pHi) with fura-2 AM and 2′,7′-bis-(2-carboxyethyl)-5,6-carboxyfluorescein acetoxy methylester respectively. In the perforated-patch mode, glutamate evoked single or multiple outward current transients in 82% of the cells, which disappeared when the recording technique was converted into a conventional whole-cell mode. The outward current transients were accompanied by [Ca2+]itransients, whereas pHifell monophasically, without any sign of oscillation. Pharmacological analysis of the glutamate-induced responses indicated that ionotropic receptor activation evoked an inward current but no outward current transients, and metabotropic receptor activation (of the mGluR1/5 type) elicited outward current transients but no inward current. The outward current transients were reduced in frequency, or even abolished, after depletion of the intracellular Ca2+-stores by the Ca2+-ATPase inhibitor cyclopiaconic acid (10 μm). They reversed near −85 mV and were reduced by tetraethylammonium (10 mm), suggesting that they were caused by K+channel activation. It is concluded that glutamate evoked these K+outward current transients by oscillatory Ca2+release mediated by mGluR activation. The corresponding membrane potential waves across the astroglial syncytium could provide spatial and temporal dynamics to the glial K+uptake capacity and other voltage-dependent processes.
Disruption of a Single Allele of the Nerve Growth Factor Gene Results in Atrophy of Basal Forebrain Cholinergic Neurons and Memory Deficits
Authors: Chen Karen S. , Nishimura Merry C. , Armanini Mark P. , Crowley Craig , Spencer Susan D. , Phillips Heidi S.
Published: April 2018

Administration of nerve growth factor (NGF) to aged or lesioned animals has been shown to reverse the atrophy of basal forebrain cholinergic neurons and ameliorate behavioral deficits. To examine the importance of endogenous NGF in the survival of basal forebrain cholinergic cells and in spatial memory, mice bearing a disruption mutation in one allele of the NGF gene were studied. Heterozygous mutant mice (ngf+/−) have reduced levels of NGF mRNA and protein within the hippocampus and were found to display significant deficits in memory acquisition and retention in the Morris water maze. The behavioral deficits observed in NGF-deficient mice were accompanied by both shrinkage and loss of septal cells expressing cholinergic markers and by a decrease in cholinergic innervation of the hippocampus. Infusions of NGF into the lateral ventricle of adultngf+/− mice abolished the deficits on the water maze task. Prolonged exposure to NGF may be required to induce cognitive effects, because reversal of the acquisition deficit was seen after long (5 weeks) but not short (3 d) infusion. Although NGF administration did not result in any improvement in the number of septal cells labeled for choline acetyltransferase, this treatment did effectively correct the deficits in both size of cholinergic neurons and density of cholinergic innervation of the hippocampus. These findings demonstrate the importance of endogenous NGF for survival and function of basal forebrain cholinergic neurons and reveal that partial depletion of this trophic factor is associated with measurable deficits in learning and memory.
Dopaminergic Modulation of Sodium Current in Hippocampal Neurons via cAMP-Dependent Phosphorylation of Specific Sites in the Sodium Channel α Subunit
Authors: Cantrell Angela R. , Smith Raymond D. , Goldin Alan L. , Scheuer Todd , Catterall William A.
Published: April 2018

Phosphorylation of brain Na+channel α subunits by cAMP-dependent protein kinase (PKA) decreases peak Na+current in cultured brain neurons and in mammalian cells andXenopusoocytes expressing cloned brain Na+channels. We have studied PKA regulation of Na+channel function by activation of D1-like dopamine receptors in acutely isolated hippocampal neurons using whole-cell voltage-clamp recording techniques. The D1 agonist SKF 81297 reversibly reduced peak Na+current in a concentration-dependent manner. No changes in the voltage dependence or kinetics of activation or inactivation were observed. This effect was mediated by PKA, as it was mimicked by application of the PKA activator Sp-5,6-dichloro-1-β-d-ribofuranosylbenzimidazole-3′,5′-monophosphorothioate(cBIMPS) and was inhibited by the specific PKA inhibitor peptide PKAI5–24. cBIMPS had similar effects on type IIA brain Na+channel α subunits expressed in tsA-201 cells, but no effect was observed on a mutant Na+channel α subunit in which serine residues in five PKA phosphorylation sites in the intracellular loop connecting domains I and II (LI–II) had been replaced by alanine. A single mutation, S573A, similarly eliminated cBIMPS modulation. Thus, activation of D1-like dopamine receptors results in PKA-dependent phosphorylation of specific sites in LI–IIof the Na+channel α subunit, causing a reduction in Na+current. Such modulation is expected to exert a profound influence on overall neuronal excitability. Dopaminergic input to the hippocampus from the mesocorticolimbic system may exert this influencein vivo.
Androgen Mitigates Axotomy-Induced Decreases in Calbindin Expression in Motor Neurons
Authors: Pérez Julio , Kelley Darcy B.
Published: April 2018

Androgens can rescue axotomized motor neurons from cell death. Here we examine a possible mechanism for this trophic action in juvenileXenopus laevis: regulation of a calcium-binding protein, calbindin, after axotomy. Western analysis revealed that a monoclonal antibody to calbindin D specifically recognizes a single ∼28 kDa band inX. laevisCNS and rat cerebellum. Retrograde transport of peroxidase combined with immunohistochemistry demonstrated that somata, axons, and synaptic terminals of laryngeal motor neurons in nucleus (N.) IX–X ofX. laevisare calbindin-positive. The number of calbindin-positive cells was compared in the intact and axotomized sides of N.IX–X of gonadectomized males that were either hormonally untreated or DHT-treated for 1 month. Although axotomy decreased the number of calbindin-positive cells by 86% in hormonally untreated males, the decrease was only 56% in DHT-treated animals. Compared with hormonally untreated animals, the number of calbindin-labeled cells in N.IX–X of DHT-treated males was increased in both the intact (14%) and axotomized sides (75%). We conclude that axotomy decreases and that DHT enhances calbindin immunoreactivity in N.IX–X. Axotomy-induced decrease in calbindin immunoreactivity precedes cell loss in N.IX–X and may impair the capacity of motor neurons to regulate cytoplasmic calcium. Androgen-mediated maintenance of calbindin expression is thus a candidate cellular mechanism for trophic maintenance of hormone target neurons.
The Glutamate Receptor Subunit δ1 Is Highly Expressed in Hair Cells of the Auditory and Vestibular Systems
Authors: Safieddine Saaid , Wenthold Robert J.
Published: April 2018

In the inner ear, fast excitatory synaptic transmission is mediated by ionotropic glutamate receptors, including AMPA, kainate, and NMDA receptors. The recently identified δ1 and δ2 glutamate receptors share low homology with the other three types, and no clear response or ligand binding has been obtained from cells transfected with δ alone or in combination with other ionotropic receptors. Studies of mice lacking expression of δ2 show that this subunit plays a crucial role in plasticity of cerebellar glutamatergic synapses. In addition, these mice show a deficit in vestibular compensation. These findings and the nature of glutamatergic synapses between vestibulocochlear hair cells and primary afferent dendrites suggest that δ receptors may be functionally important in the inner ear and prompted us to investigate the expression of δ receptors in the cochlea and peripheral vestibular system. Reverse transcription and DNA amplification by PCR combined with immunocytochemistry andin situhybridization were used. Our results show that the expression of δ1 in the organ of Corti is intense and restricted to the inner hair cells, whereas δ1 is expressed in all spiral ganglion neurons as well as in their satellite glial cells. In the vestibular end organ, δ1 was highly expressed in both hair cell types and also was expressed in the vestibular ganglion neurons. The prominent expression of δ1 in inner hair cells and in type I and type II vestibular hair cells suggests a functional role in hair cell neurotransmission.
Bidirectional Regulation of DARPP-32 Phosphorylation by Dopamine
Authors: Nishi Akinori , Snyder Gretchen L. , Greengard Paul
Published: April 2018

Dopamine has been shown to stimulate phosphorylation of DARPP-32, a phosphoprotein highly enriched in medium-sized spiny neurons of the neostriatum. Here, we investigated the contribution of D1-like and D2-like dopamine receptors in the regulation of DARPP-32 phosphorylation in mouse striatal slices. D1-like and D2-like receptors had opposing effects on the state of DARPP-32 phosphorylation. The D1 receptor agonist SKF82526 increased DARPP-32 phosphorylation. In contrast, the D2 receptor agonist quinpirole decreased basal as well as D1 agonist-, forskolin-, and 8-bromo-cAMP-stimulated phosphorylation of DARPP-32. The ability of quinpirole to decrease D1-stimulated DARPP-32 phosphorylation was calcium-dependent and was blocked by the calcineurin inhibitor cyclosporin A, suggesting that the D2 effect involved an increase in intracellular calcium and activation of calcineurin. In support of this interpretation, Ca2+-free/EGTA medium induced a greater than 60-fold increase in DARPP-32 phosphorylation and abolished the ability of quinpirole to dephosphorylate DARPP-32. The antipsychotic drug raclopride, a selective D2 receptor antagonist, increased phosphorylation of DARPP-32 under basal conditions and in D2 agonist-treated slices. The results of this study demonstrate that dopamine exerts a bidirectional control on the state of phosphorylation of DARPP-32.
Characterization of Delayed Rectifier Kv Channels in Oligodendrocytes and Progenitor Cells
Authors: Attali Bernard , Wang Ning , Kolot Alexandra , Sobko Alexander , Cherepanov Vera , Soliven Betty
Published: April 2018

We examined the molecular identity of K+channel genes underlying the delayed rectifier (IK) in differentiated cultured oligodendrocytes (OLGs) and oligodendrocyte progenitor (OP) cells. Using reverse transcription-PCR cloning, we found that OP cells and OLGs expressed multiple Kv transcripts, namely Kv1.2, Kv1.4, Kv.1.5, and Kv1.6. Immunocytochemical and Western blot analyses revealed that Kv1.5 and Kv1.6 as well as Kv1.2 and Kv1.4 channel proteins could be detected in these cells, but definitive evidence for functional K+channel expression was obtained only for the Kv1.5 channel. In addition, mRNA and immunoreactive protein levels of both Kv1.5 and Kv1.6 channels were significantly lower in differentiated OLGs when compared with levels in OP cells. Proliferation of OP cells was inhibited by K+channel blockers, but not by incubation with either Kv1.5 or Kv1.6 antisense oligonucleotides. We conclude that (1)IKin OP cells and OLGs is encoded partly by Kv1.5 subunits, possibly forming heteromultimeric channels with Kv1.6 or other Kv subunits; and (2) inhibition of Kv1.5 or Kv1.6 channel expression alone does not prevent mitogenesis. Concomitant inhibition of other Kv channels underlyingIKmay be necessary for OP cells to exit from cell cycle.
OSM-9, A Novel Protein with Structural Similarity to Channels, Is Required for Olfaction, Mechanosensation, and Olfactory Adaptation inCaenorhabditis elegans
Authors: Colbert Heather A. , Smith Tracy L. , Bargmann Cornelia I.
Published: April 2018

Although cyclic nucleotide-gated channels mediate sensory transduction in olfaction and vision, other forms of sensory transduction are independent of these channels.Caenorhabditis eleganscyclic nucleotide-gated channel mutants respond normally to some olfactory stimuli and to osmotic stimuli, suggesting that these chemosensory responses use an alternative sensory transduction pathway. One gene that may act in this pathway isosm-9, which is required for each of these responses as well as a mechanosensory response to nose touch.osm-9encodes a protein with ankyrin repeats and multiple predicted transmembrane domains that has limited similarity to theDrosophilaphototransduction channels transient receptor potential (TRP) and TRP-like (TRPL). The sequence of OSM-9 and other TRP-like genes reveals a previously unsuspected diversity of mammalian and invertebrate genes in this family.osm-9is required for the activity of the predicted G-protein-coupled odorant receptor ODR-10, which acts in the AWA olfactory neurons; its similarity to other G-protein-regulated transduction channels suggests that OSM-9 is involved in AWA signaling.osm-9:: GFPfusion genes are expressed in a subset of chemosensory, mechanosensory, and osmosensory neurons.osm-9also affects olfactory adaptation within neurons that require the cyclic nucleotide-gated channel for olfaction; in these neurons, the gene has a regulatory function and not a primary role in sensory transduction.
Angiotensin II AT1AReceptor mRNA Expression Is Induced by Estrogen–Progesterone in Dopaminergic Neurons of the Female Rat Arcuate Nucleus
Authors: Jöhren Olaf , Sanvitto Gilberto L. , Egidy Giorgia , Saavedra Juan M.
Published: April 2018

Brain angiotensin II (Ang II) inhibits pituitary prolactin release by an indirect mechanism requiring stimulation of dopamine formation and release. We report that [125I]Sar1–Ang II binding to AT1receptors and AT1Areceptor mRNA expression increase selectively in the dorsomedial arcuate nucleus of 17β-estradiol-primed ovariectomized rats after treatment with progesterone. In hormone-treated rats, arcuate nucleus AT1Areceptor mRNA expression is associated with tyrosine hydroxylase-positive neurons. No AT1Areceptor mRNA was detected in tyrosine hydroxylase-positive cells of the arcuate nucleus of intact male rats. Conversely, in the anterior pituitary, where local or circulating Ang II stimulates prolactin release, [125I]Sar1–Ang II binding to AT1receptors and AT1Breceptor mRNA expression are decreased in 17β-estradiol/progesterone-treated ovariectomized rats.

Thus, AT1Areceptors in the dorsal arcuate nucleus and AT1Breceptors in the anterior pituitary are regulated inversely by estrogen/progesterone treatment, supporting the hypothesis of a dual role for brain and pituitary Ang II on prolactin release. The colocalization of AT1Areceptor mRNA and tyrosine hydroxylase in neurons of the arcuate nucleus furthermore indicates that within this area central Ang II acts directly on dopaminergic neurons. These results support the hypothesis that central Ang II inhibits pituitary prolactin release indirectly via modulation of dopaminergic activity in the arcuate nucleus.
Activation of ErbB2 during Wallerian Degeneration of Sciatic Nerve
Authors: Kwon Yunhee Kim , Bhattacharyya Anita , Alberta John A. , Giannobile William V. , Cheon Kangwoo , Stiles Charles D. , Pomeroy Scott L.
Published: April 2018

We used anti-phosphopeptide-immunodetecting antibodies as immunohistochemical reagents to define the location and activity state of p185erbB2during Wallerian degeneration. Nerve damage induces a phosphorylation event at Y1248, a site that couples p185erbB2to the Ras–Raf–MAP kinase signal transduction pathway. Phosphorylation of p185erbB2occurs within Schwann cells and coincides in time and space with Schwann cell mitotic activity, as measured by bromodeoxyuridine uptake. These visual images of receptor autophosphorylation link activation of p185erbB2to the Schwann cell proliferation that accompanies nerve regeneration.
Fast Synaptic Signaling by Nicotinic Acetylcholine and Serotonin 5-HT3Receptors in Developing Visual Cortex
Authors: Roerig Birgit , Nelson Darin A. , Katz Lawrence C.
Published: April 2018

Cholinergic and serotonergic fiber systems invade the developing visual cortex several weeks before eye opening; both transmitters have been implicated in plasticity of neocortical circuits. These transmitters have been presumed to act predominantly through second messenger-coupled receptors, because fast cholinergic or serotonergic neurotransmission has never been observed in neocortex. However, acetylcholine and serotonin also act on ligand-gated ion channels; the nicotinic acetylcholine receptor and the serotonin 5-HT3receptor, respectively. Here, using whole-cell patch-clamp techniques in developing ferret visual cortex, we pharmacologically isolated fast, spontaneous, and evoked cholinergic and serotonergic synaptic events in pyramidal cells and interneurons of all cortical layers. The number of cells receiving such inputs increased with the ingrowth of thalamic afferents, and the frequencies of the spontaneous events increased at eye opening. Thus, both acetylcholine and serotonin can mediate fast synaptic transmission in the visual cortex; the early onset of these mechanisms suggests a role during initial stages of circuit formation and during subsequent experience-dependent remodeling of cortical connections.
Activity-Dependent Regulation of NMDAR1 Immunoreactivity in the Developing Visual Cortex
Authors: Catalano Susan M. , Chang Catherine K. , Shatz Carla J.
Published: April 2018

NMDA receptors have been implicated in activity-dependent synaptic plasticity in the developing visual cortex. We examined the distribution of immunocytochemically detectable NMDAR1 in visual cortex of cats and ferrets from late embryonic ages to adulthood. Cortical neurons are initially highly immunostained. This level declines gradually over development, with the notable exception of cortical layers 2/3, where levels of NMDAR1 immunostaining remain high into adulthood. Within layer 4, the decline in NMDAR1 immunostaining to adult levels coincides with the completion of ocular dominance column formation and the end of the critical period for layer 4. To determine whether NMDAR1 immunoreactivity is regulated by retinal activity, animals were dark-reared or retinal activity was completely blocked in one eye with tetrodotoxin (TTX). Dark-rearing does not cause detectable changes in NMDAR1 immunoreactivity. However, 2 weeks of monocular TTX administration decreases NMDAR1 immunoreactivity in layer 4 of the columns of the blocked eye. Thus, high levels of NMDAR1 immunostaining within the visual cortex are temporally correlated with ocular dominance column formation and developmental plasticity; the persistence of staining in layers 2/3 also correlates with the physiological plasticity present in these layers in the adult. In addition, visual experience is not required for the developmental changes in the laminar pattern of NMDAR1 levels, but the presence of high levels of NMDAR1 in layer 4 during the critical period does require retinal activity. These observations are consistent with a central role for NMDA receptors in promoting and ultimately limiting synaptic rearrangements in the developing neocortex.
Developmental Synaptic Depression Underlying Reorganization of Visceral Reflex Pathways in the Spinal Cord
Authors: Araki Isao , de Groat William C.
Published: April 2018

During development, neuronal connectivity has a remarkable plasticity. Synaptic refinement in the spinal autonomic nucleus might be involved in the elimination of primitive segmental reflexes and the emergence of mature spinobulbospinal reflexes, which occurs a few weeks after birth. To address this possibility, we examined the postnatal changes of segmental excitatory synaptic transmission by applying the whole-cell recording technique to parasympathetic preganglionic neurons in slice preparations of the rat lumbosacral spinal cord. The mean magnitude of unitary excitatory synaptic currents evoked in preganglionic neurons by stimulation of single interneurons remained unchanged during the first two postnatal weeks but was reduced by 50% during the third postnatal week. This reduction in synaptic efficacy was associated with a decrease in the amount of transmitter release from interneurons. Moreover, this developmental depression of segmental synaptic transmission was prevented by spinal cord transection at the thoracic level on postnatal day 14. Thus, developmental modification of excitatory synapses on preganglionic neurons appears to be attributable to competition between segmental interneuronal and descending bulbospinal inputs, which results in the developmental reorganization of parasympathetic excretory reflex pathways.
Transition from Growth Cone to Functional Motor Nerve Terminal inDrosophilaEmbryos
Authors: Yoshihara Motojiro , Rheuben Mary B. , Kidokoro Yoshiaki
Published: April 2018

As a motor axon grows from the CNS to its target muscle, the terminal has the form of a flattened growth cone with a planar central region, lamellipodia, and filopodia. A mature terminal usually has a stereotyped shape that may be elongated with varicosities, as in several invertebrate species, or have short branches with boutons, as in mammals. We examined inDrosophilathe developmental changes between growth cone and mature terminal using ultrastructural and immunocytochemical methods.

The transition period, which occurs 2–3 hr after the first growth cone reaches its target muscle, is marked by the formation of “prevaricosities,” smoothly contoured enlargements of the axons at the point where the nerve trunk first contacts the muscle fiber (MF). There is a 15–30 min ventral-to-dorsal gradient in the formation of prevaricosities on the individual abdominal MFs. Multineuronal innervation of each MF has occurred by this time, and two or more different axons undergo prevaricosity formation while they are intimately intertwined at the nerve entry point (NEP). Presynaptic active zones, both nerve–nerve and nerve–muscle, occur within the prevaricosities along broad contact regions. Synaptotagmin immunoreactive clusters form concurrently.

The first varicosities then develop as a result of constrictions of the larger prevaricosities rather than as enlargement of discrete portions of the filopodia or neurites. The prevaricosity stage therefore may include the key steps that lead to the differentiation of functional differences in terminal subtypes as well as those leading to the formation of a stable neuromuscular junction.
Neurturin and Glial Cell Line-Derived Neurotrophic Factor Receptor-β (GDNFR-β), Novel Proteins Related to GDNF and GDNFR-α with Specific Cellular Patterns of Expression Suggesting Roles in the Developing and Adult Nervous System and in Peripheral Organs
Authors: Widenfalk Johan , Nosrat Christopher , Tomac Andreas , Westphal Heiner , Hoffer Barry , Olson Lars
Published: April 2018

Cloning strategies were used to identify a gene termed glial cell line-derived neurotrophic factor receptor-β (GDNFR-β) related to GDNFR-α.In situhybridization was then used to map cellular expression of the GDNF-related trophic factor neurturin (NTN) and GDNFR-β mRNA in developing and adult mice, and comparisons with GDNFR-α and RET were made. Neurturin is expressed in postnatal cerebral cortex, striatum, several brainstem areas, and the pineal gland. GDNFR-β mRNA was more widely expressed in the developing and adult CNS, including cerebral cortex, cerebellum, thalamus, zona incerta, hypothalamus, brainstem, and spinal cord, and in subpopulations of sensory neurons and developing peripheral nerves. NTN colocalized with RET and GDNFR-α in ureteric buds of the developing kidney. The circular muscle layer of the developing intestines, smooth muscle of the urether, and developing bronchiolae also expressed NTN. GDNFR-β was found in myenteric but not submucosal intestinal plexuses. In developing salivary glands NTN had an epithelial expression, whereas GDNFR-β was expressed in surrounding tissue. Neurturin and GDNFR-β were present in developing sensory organs. In the gonads, NTN appeared to be expressed in Sertoli cells and in the epithelium of the oviduct, whereas GDNFR-β was expressed by the germ cell line. Our findings suggest multiple roles for NTN and GDNFR-β in the developing and adult organism. Although NTN and GDNFR-β expression patterns are sometimes complementary, this is not always the case, suggesting multiple modi operandi of GDNF and NTN in relation to RET and the two binding proteins, GDNFR-α and GDNFR-β.
Role of Dopamine D1and D2Receptors in the Nucleus Accumbens in Mediating Reward
Authors: Ikemoto Satoshi , Glazier Bradley S. , Murphy James M. , McBride William J.
Published: April 2018

The objectives of this study were to examine the involvement of D1and D2receptors within the nucleus accumbens (ACB) in mediating reinforcement. The intracranial self-administration (ICSA) of D1and D2agonists was used to determine whether activating D1and/or D2receptors within the ACB of Wistar rats is reinforcing. At concentrations of 0.25, 0.50, and 1.0 mm(25, 50, and 100 pmol/100 nl of infusion), neither the D1agonistR(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393 (SKF)] hydrochloride nor the D2agonist (−)-quinpirole (Quin) hydrochloride was self-administered into the shell region of the ACB. On the other hand, equimolar mixtures of SKF and Quin (SKF+Quin), at concentrations of 0.25, 0.50, and 1.0 mmeach, were significantly self-infused into the ACB shell. The core region of the ACB did not support the ICSA of SKF+Quin at any of these concentrations. Rats increased lever pressing when the response requirement was increased from a fixed ratio 1 (FR1) to FR3, and they responded significantly more on the infusion lever than they did on the control lever. Coadministration of either 0.50 mmR(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride, a D1antagonist, or 0.50 mmS(−)-sulpiride, a D2antagonist, completely abolished the ICSA of the mixture of SKF+Quin (each at 0.50 mm) into the ACB shell. The present results suggest that concurrent activation of D1- and D2-type receptors in the shell of the ACB had a cooperative effect on DA-mediated reward processes.
Brain-Derived Neurotrophic Factor, Neurotrophin-3, and Neurotrophin-4 Complement and Cooperate with Each Other Sequentially during Visceral Neuron Development
Authors: ElShamy Wael M. , Ernfors Patrik
Published: April 2018

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) are crucial target-derived factors controlling the survival of peripheral sensory neurons during the embryonic period of programmed cell death. Recently, NT3 has also been found to act in a local manner on somatic sensory precursor cells during early developmentin vivo. Culture studies suggest that these cells switch dependency to NGF at later stages. The neurotrophins acting on the developing placode-derived visceral nodose/petrosal (N/P) ganglion neurons are BDNF, NT3, and NT4. To assess their roles in development, we analyzed embryonic development in mice carrying a deletion in each of these genes, or combinations of them, and found that they are essential in preventing the death of N/P ganglion neurons during different periods of embryogenesis. Both NT3 and NT4 are crucial during the period of ganglion formation, whereas BDNF acts later in development. Many, but not all, of the NT3- and NT4-dependent neurons switch to BDNF at later stages. We conclude that most of the N/P ganglion neurons depend on more than one neurotrophin and that they act in a complementary as well as a collaborative manner in a developmental sequence for the establishment of a full complement of visceral neurons.
Activity-Dependent Calcium Sequestration in Dendrites of Hippocampal Neurons in Brain Slices
Authors: Pozzo-Miller Lucas D. , Pivovarova Natalia B. , Leapman Richard D. , Buchanan Roger A. , Reese Thomas S. , Andrews S. Brian
Published: April 2018

Synaptic activity-dependent changes in the spatio-temporal distribution of calcium ions regulate important neuronal functions such as dendritic integration and synaptic plasticity, but the processes that terminate the free Ca2+transients associated with these changes remain unclear. We have characterized at the electron microscopic level the intracellular compartments involved in buffering free Ca2+transients in dendritic cytoplasm of CA3 neurons by measuring the larger changes in the concentrations of total Ca that persist for several minutes after neuronal activity. Quantitative energy-dispersive x-ray microanalysis of cryosections from hippocampal slice cultures rapidly frozen 3 min after afferent synaptic activity identified a subset of dendritic endoplasmic reticulum (ER) as a high-capacity Ca2+buffer. Calcium sequestration by cisterns of this subset of ER was graded, reversible, and dependent on a thapsigargin-sensitive Ca2+-ATPase. Sequestration was so robust that after repetitive high-frequency stimulation the Ca content of responsive ER cisterns increased as much as 20-fold. These results demonstrate that a subpopulation of ER is the major dendritic Ca sequestration compartment in the minutes after neuronal activity.
Mechanoelectrical Transduction and Adaptation in Hair Cells of the Mouse Utricle, a Low-Frequency Vestibular Organ
Authors: Holt Jeffrey R. , Corey David P. , Eatock Ruth Anne
Published: April 2018

Hair cells of inner ear organs sensitive to frequencies above 10 Hz adapt to maintained hair bundle deflections at rates that reduce their responses to lower frequencies. Mammalian vestibular organs detect head movements at frequencies well below 10 Hz. We asked whether hair cells of the mouse utricle adapt, and if so, whether the adaptation was similar to that in higher frequency organs such as the frog saccule.

Whole-cell transduction currents were recorded from hair cells in the epithelium of the mouse utricle. Hair bundles were deflected by a fluid jet or a stiff probe. The transduction currents evoked by step deflections adapted over 10–100 msec. The mean operating range was 1.5 μm (deflection of the tip of the bundle), approximately threefold larger than in frog saccule. Taller and more compact bundles of the mouse utricle account for this difference. As in frog saccular hair cells, adaptation shifted the current–deflection (I(X)) relation along the deflection axis. These adaptive shifts had time constants of 10–20 msec and reached 60–80% of stimulus amplitude. The adaptive shift and voltage-dependent bundle movement are consistent with the motor model of adaptation. When the fluid jet was used, adaptation also broadened theI(X) relation and reduced the maximum current.

Adaptation attenuated the transduction currents evoked by sinusoidal bundle deflections below 5 Hz, within the frequency range of the utricle, but because it was incomplete, substantial responses remained. Moreover, the adaptive shift mechanism preserves sensitivity even in the presence of large stimuli that would otherwise saturate transduction.
Photoperiodically Driven Changes in Fos Expression within the Basal Tuberal Hypothalamus and Median Eminence of Japanese Quail
Authors: Meddle Simone L. , Follett Brian K.
Published: April 2018

The rapid photoperiodic response in Japanese quail is so precise that it allows neural analyses of how photoperiodic information is transduced into an endocrine response. After transfer from short [SD; 6L:18D (6:18 hr light/dark cycle)] to long (LD; 20L:4D) days, luteinizing hormone (LH) first rises 20 hr after dawn. Using Fos immunocytochemistry, we examined the basal tuberal hypothalamus (BtH) to determine the relationship between brain cell activation and the first endocrine changes. Two separate cell populations within the BtH expressed Fos-like immunoreactivity (FLI) by hour 18 of the first LD. Importantly, this activation occurred before the LH rise. Median eminence activation appeared within glial cells, whereas activated infundibular nucleus cells were neuronal, providing support to the view that gonadotropin-releasing hormone (GnRH) release can be controlled at the terminals by glia. The FLI induction parallels LH changes, suggesting that gene expression may be involved in events preceding photostimulation and is the earliest photoperiodically stimulated physiological change yet reported.

Additional experiments provided further support for this hypothesis. First, photoperiodically induced activation is not a result peculiar to castrates because intact birds displayed similar results. Second, the critical length of 14 hr of light had to be exceeded to cause both BtH activation and a LH rise 30 hr from dawn. Finally, valuable evidence of the response specificity was provided by using a unique property of the quail photoperiodic clock in which exposure to 10L:26D, but not 10L:14D, causes photoinduction. The 36 hr paradigm increased both plasma LH and BtH activation.
Development of Intrinsic and Synaptic Properties in a Forebrain Nucleus Essential to Avian Song Learning
Authors: Livingston Frederick S. , Mooney Richard
Published: April 2018

In male zebra finches, the lateral magnocellular nucleus of the anterior neostriatum (LMAN) is necessary for the development of learned song but is not required for the production of acoustically stereotyped (crystallized) adult song. One hypothesis is that the physiological properties of LMAN neurons change over development and thus limit the ability of LMAN to affect song. To test this idea, we usedin vitrointracellular recordings to characterize the intrinsic and synaptic properties of LMAN neurons in fledgling [posthatch days (PHD) 22–32] and juvenile zebra finches (PHD 40–51) when LMAN lesions disrupt normal song development, and in adults (>PHD 90) when LMAN lesions are without effect. In fledglings, depolarizing currents caused LMAN projection neurons to fire bursts of action potentials because of a putative low-threshold calcium spike (LTS). In contrast, juvenile and adult LMAN projection neurons fired accommodating trains of action potentials when depolarized but did not exhibit the burst mode of firing. Electrical stimulation of thalamic afferents elicited both monosynaptic EPSPs mediated by AMPA and NMDA receptors and polysynaptic IPSPs mediated by GABAAreceptors from LMAN neurons at all ages studied here. In whole-cell voltage-clamp recordings, the EPSCs (NMDA-EPSCs) consisted of fast and slow components. Unlike juvenile and adult NMDA-EPSCs, those in fledglings were dominated by the slower component. Thus, both the intrinsic and synaptic properties of LMAN neurons change markedly during early song development (PHD 22–40) and achieve several adult-like properties during early sensorimotor learning and well before the time when LMAN lesions no longer disrupt song development.
Neuronal and Non-Neuronal Collapsin-1 Binding Sites in Developing Chick Are Distinct from Other Semaphorin Binding Sites
Authors: Takahashi Takuya , Nakamura Fumio , Strittmatter Stephen M.
Published: April 2018

The collapsin and semaphorin family of extracellular proteins contributes to axonal path finding by repulsing axons and collapsing growth cones. To explore the mechanism of collapsin-1 action, we expressed and purified a truncated collapsin-1–alkaline phosphatase fusion protein (CAP-4). This protein retains biological activity as a DRG growth cone collapsing agent and saturably binds to DRG neurons with low nanomolar affinity. Specific CAP-4 binding sites are present on DRG neurons, sympathetic neurons, and motoneurons, but not on retinal, cortical, or brainstem neurons. Outside the nervous system, high levels of CAP-4 binding sites are present in the mesenchyme surrounding major blood vessels and developing bone and in lung. These sites provide a substrate for the collapsin-1-dependent patterning of non-neuronal tissues perturbed insema III(−/−) mice. The staining patterns for mouse semaphorin D/III and chick collapsin-1 fusion proteins are indistinguishable from one another but quite separate from that for semaphorin B and M-semaphorin F fusion proteins. These data imply that a family of high-affinity semaphorin binding sites similar in complexity to the semaphorin ligand family exists.
A Short-Range Signal Restricts Cell Movement between Telencephalic Proliferative Zones
Authors: Neyt Christine , Welch Melissa , Langston Alex , Kohtz Jhumku , Fishell Gord
Published: April 2018

During telencephalic development, a boundary develops that restricts cell movement between the dorsal cortical and basal striatal proliferative zones. In this study, the appearance of this boundary and the mechanism by which cell movement is restricted were examined through a number of approaches. The general pattern of neuronal dispersion was examined both with an early neuronal marker and through the focal application of DiI to telencephalic explants. Both methods revealed that, although tangential neuronal dispersion is present throughout much of the telencephalon, it is restricted within the boundary region separating dorsal and ventral telencephalic proliferative zones. To examine the cellular mechanism underlying this boundary restriction, dissociated cells from the striatum were placed within both areas of the boundary, where dispersion is limited, and areas within the cortex, where significant cellular dispersion occurs. Cells placed within the boundary region remain round and extend only thin processes, whereas progenitors placed onto the cortical ventricular zone away from this boundary are able to migrate extensively. This suggests that the boundary inhibits directly the migration of cells. To examine whether the signal inhibiting dispersion within the boundary region acts as a long- or short-range cue, we apposed explants of boundary and nonboundary regionsin vitro. Within these explants we found that migration was neither inhibited in nonboundary regions nor induced in boundary regions. This suggests that the boundary between dorsal and ventral telencephalon isolates these respective environments through either a contact-dependent or a short-range diffusible mechanism.