bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Susceptibility to Induction of Long-Term Depression and Long-Term Potentiation Reversal during Aging
Authors: Norris Christopher M. , Korol Donna L. , Foster Thomas C. 
Published: April 2018

Homosynaptic long-term depression (LTD) and reversal of long-term potentiation (LTP) were examined extracellularly at CA3–CA1 synapses in stratum radiatum of slices from adult (6–9 months) and aged (20–24 months) Fischer 344 rats. Prolonged low-frequency stimulation (LFS) (900 pulses/1 Hz) of the Schaffer collaterals depressed the initial slope of the excitatory postsynaptic potential (EPSP) in aged but not adult rats. LTD at aged synapses was pathway-specific, persistent, and sensitive to the NMDA receptor antagonistdl-2-amino-5-phosphonopentanoic acid (AP5). Adult slices exhibited AP5-sensitive LTD in high [Ca2+] medium, whereas LTD in aged slices was blocked by high [Mg2+], suggesting that differences in Ca2+regulation may underlie susceptibility to LTD.Despite age-related differences in LTD induction, no age difference in LTP magnitude was revealed. Additionally, LFS delivered 60 min after LTP induction resulted in similar LTP reversal for both age groups. Susceptibility differences to LTP reversal were indicated after multiple short-duration LFS bursts (30 pulses/1 Hz), with each burst separated by 10 min. Aged synapses exhibited significant reversal after a single burst and complete reversal after three LFS episodes. In adult slices, LTP reversal appeared after the fourth burst, and at no time was LTP depressed to initial baseline levels. This study provides the first characterization of homosynaptic LTD/LTP reversal in the aged animal and demonstrates that one form of plasticity, depression attributable to LFS, is increased during aging.
Mechanisms of H+and Na+Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes
Authors: Rose Christine R. , Ransom Bruce R. 
Published: April 2018

The excitatory transmitter glutamate (Glu), and its analogs kainate (KA), andd-aspartate (d-Asp) produce significant pH changes in glial cells. Transmitter-induced pH changes in glial cells, generating changes in extracellular pH, may represent a special form of neuronal–glial interaction. We investigated the mechanisms underlying these changes in intracellular H+concentration ([H+]i) in cultured rat hippocampal astrocytes and studied their correlation with increases in intracellular Na+concentration ([Na+]i), using fluorescence ratio imaging with 2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) or sodium-binding benzofuran isophthalate (SBFI). Glu, KA, ord-Asp evoked increases in [Na+]i; Glu ord-Asp produced parallel acidifications. KA, in contrast, evoked biphasic changes in [H+]i, alkaline followed by acid shifts, which were unaltered after Ca2+removal and persisted in 0 Cl−-saline, but were greatly reduced in CO2/HCO−3-free or Na+-free saline, or during 4,4′-diisothiocyanato-stilbene-2,2′-disulphonic acid (DIDS) application. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked KA-evoked changes in [H+]iand [Na+]i, indicating that they were receptor–ionophore mediated. In contrast, CNQX increased the [H+]ichange and decreased the [Na+]ichange induced by Glu.d-Asp, which is transported but does not act at Glu receptors, induced [H+]iand [Na+]ichanges that were virtually unaltered by CNQX. Our study indicates that [Na+]iincreases are not primarily responsible for Glu- or KA-induced acidifications in astrocytes. Instead, intracellular acidifications evoked by Glu ord-Asp are mainly caused by transmembrane movement of acid equivalents associated with Glu/Asp-uptake into astrocytes. KA-evoked biphasic [H+]ichanges, in contrast, are probably attributable to transmembrane ion movements mediated by inward, followed by outward, electrogenic Na+/HCO−3cotransport, reflecting KA-induced biphasic membrane potential changes.
Anatomical Demonstration of Ocular Dominance Columns in Striate Cortex of the Squirrel Monkey
Authors: Horton Jonathan C. , Hocking Davina R. 
Published: April 2018

The squirrel monkey is the only primate reported to lack ocular dominance columns. Nothing anomalous about the visual capacity of squirrel monkeys has been found to explain their missing columns, leading to the suggestion that ocular dominance columns might be “an epiphenomenon, not serving any purpose” (Livingstone et al., 1995). Puzzled by the apparent lack of ocular dominance columns in squirrel monkeys, we made eye injections with transneuronal tracers in four normal squirrel monkeys. An irregular mosaic of columns, averaging 225 μm in width, was found throughout striate cortex. They were double-labeled by placing wheat germ agglutinin-horseradish peroxidase into the left eye and [3H]proline into the right eye. The tracers labeled opposite sets of interdigitating columns, proving they represent ocular dominance columns. The columns were much clearer in layer IVcα (magno-receiving) than IVcβ (parvo-receiving). In the lateral geniculate body, the parvo laminae showed extensive mixing of ocular inputs, suggesting that increased label spillover contributes to the blurred columns in layer IVcβ. The cytochrome oxidase (CO) patches were organized into distinct rows, but they bore no consistent relationship to the ocular dominance columns. These experiments indicate that ocular dominance columns are less well segregated in squirrel monkeys than macaques, but they are present. This fact is pertinent to a recent study reporting that ocular dominance columns are absent in normal squirrel monkeys, but induced to form by strabismus (Livingstone, 1996).
Expression of Normal and Mutant Huntingtin in the Developing Brain
Authors: Bhide Pradeep G. , Day Michelle , Sapp Ellen , Schwarz Cordula , Sheth Ami , Kim Johnny , Young Anne B. , Penney John , Golden Jeffrey , Aronin Neil , DiFiglia Marian 
Published: April 2018

Huntington’s disease (HD) is caused by a genetic mutation that results in a polyglutamine expansion in huntingtin. The time course of neuronal loss in the HD striatum and other affected brain regions before the onset of symptoms is unknown. To determine the potential influence of huntingtin on brain development, we examined its expression in the developing mouse and in human control and HD brain. By Western blot, huntingtin was detected throughout the adult mouse brain and at all stages of embryonic and postnatal brain development. The protein increased significantly between postnatal day 7 (P7) and P15, which marks a period of active neuronal differentiation and enhanced sensitivity to excitotoxic injury in the rodent striatum. Immunoreactivity was found in neurons throughout the brain and localized mostly to the somatodendritic cytoplasm and to axons in fiber bundles. Staining was variable in different groups of neurons and within the same cell population. In developing brain, huntingtin was limited primarily to neuronal perikarya. Increased immunoreactivity in large neurons followed the gradient of neurogenesis and appeared in the basal forebrain and brainstem by embryonic days 15–17, in regions of cortex by P0–P1, and in the striatum by P7. In human brain at midgestation (19–21 weeks), huntingtin was detected in all regions. The brain of a 10-week-old infant with the expanded HD allele expressed a higher molecular weight mutant form of huntingtin at levels comparable to those of the wild-type protein. Thus, mutant huntingtin is expressed before neuronal maturation is complete. Results suggest that huntingtin has an important constitutive role in neurons during brain development, that heterogeneity in neuronal expression of the protein is developmentally regulated, and that the intraneuronal distribution of huntingtin increases in parallel with neuronal maturation. The presence of mutant huntingtin in the immature HD brain raises the possibility that neurons may be affected during brain development and possibly in the postnatal period when vulnerability to excitotoxic injury is at its peak.
Tau Binds to the Distal Axon Early in Development of Polarity in a Microtubule- and Microfilament-Dependent Manner
Authors: Kempf Martina , Clement Albrecht , Faissner Andreas , Lee Gloria , Brandt Roland 
Published: April 2018

Microtubule-associated protein tau is localized to the axonin situand has been implicated in the development of neuronal polarity. Here we report that tau is extracted differentially in cultured hippocampal neurons yielding an axon-specific localization under conditions that keep the integrity of the plasma membrane. The amount of bound tau increases toward the distal axon and is highest at the transition from the axonal shaft to the growth cone. This distribution is significantly different from the distribution of axonal microtubules that are most concentrated at the proximal axon. Distal binding of tau to one process appears early in development of polarity in culture and correlates with the onset of axon formation (day 2 in culture). Binding to the distal axon requires intact microtubules and microfilaments. Distal tau binding does not stabilize microtubules selectively against drug-induced disassembly, because colchicine-induced microtubule depolymerization is highest distally. We conclude that binding of tau to the distal axon follows a complex mechanism, is an early event in the development of polarity, and reproduces the axon-specific localization of tauin situ.
Selective Vulnerability of Mouse CNS Neurons to Latent Infection with a Neuroattenuated Herpes Simplex Virus-1
Authors: Kesari Santosh , Lee Virginia M.-Y. , Brown S. Moira , Trojanowski John Q. , Fraser Nigel W. 
Published: April 2018

Herpes simplex viruses that lack ICP34.5 are neuroattenuated and are presently being considered for cancer and gene therapy in the nervous system. Previously, we documented the focal presence of the latency-associated transcripts (LATs) in the hippocampi of immunocompromised mice after intracranial (IC) inoculation of an ICP34.5-deficient virus called strain 1716. To characterize further the biological properties of strain 1716 in the CNS of immunocompetent mice, we determined the extent of viral gene expression in different cell types and regions of the CNS after stereotactic IC inoculation of this virus. At survival times of >30 d after inoculation, we found that (1) infectious virus was not detectable by titration and immunohistochemical studies; (2) neurons harbored virus as demonstrated by the detection of the LATs byin situhybridization (ISH); (3) transcripts expressed during the lytic cycle of infection were not detected by ISH; and (4) subsets of neurons were selectively vulnerable to latent infection, depending on the site of inoculation. These results suggest that the absence of ICP34.5 does not abrogate latent infection of the CNS by strain 1716. Additional studies of strain 1716 in the model system described here will facilitate the elucidation of the mechanisms that regulate the selective vulnerability of CNS cells to latent viral infection and lead to the development of ICP34.5 mutant viruses as therapeutic vectors for CNS diseases.
Are the Interlaminar Zones of the Ferret Dorsal Lateral Geniculate Nucleus Actually Part of the Perigeniculate Nucleus?
Authors: Sanchez-Vives Maria V. , Bal Thierry , Kim Uhnoh , von Krosigk Marcus , McCormick David A. 
Published: April 2018

The ferret dorsal lateral geniculate nucleus (LGNd) contains interneurons within the interlaminar zones situated between the laminae corresponding to the ipsi- and contralateral eyes. We found that a subset of these neurons exhibits electrophysiological properties similar to those previously reported for perigeniculate (PGN) neurons, including the generation of rhythmic sequences of rebound low-threshold Ca2+spikes at a frequency of 1–4 Hz after the intracellular injection of a hyperpolarizing current pulse. These “PGN-like” interlaminar interneurons innervated restricted regions of the A-laminae, inhibited thalamocortical cells through GABAA, and perhaps GABAB, receptors, and were excited by axon collaterals from thalamocortical cells. This reciprocal relationship is identical to that formed by PGN cells and allowed the PGN-like interlaminar neurons to participate in the generation of spindle waves and other network oscillations. Pharmacologically, PGN-like interlaminar interneurons were also similar to PGN neurons: both generated a prolonged depolarization in response to the local application of serotonin, 1S,3R-ACPD, and CCK8S, and a rapid depolarization followed by a more prolonged hyperpolarization in response to acetylcholine.Examination of parvalbumin and calbindin staining in the ferret LGNd revealed that both PGN and a subset of interlaminar neurons were parvalbumin-positive. In contrast, calbindin-positive cells were relatively absent in the PGN and sparsely present in the interlaminar zones, but were numerous in the A and C laminae. Our results indicate that the interlaminar zone in between laminae A and A1 and A1 and C in the ferret LGNd possesses a cell type that is electrophysiologically, pharmacologically, anatomically, immunocytochemically, and functionally similar to neurons in the PGN.
Metabotropic Glutamate Receptors Activate G-Protein-Coupled Inwardly Rectifying Potassium Channels inXenopusOocytes
Authors: Saugstad Julie A. , Segerson Thomas P. , Westbrook Gary L. 
Published: April 2018

Receptor-mediated activation of a G-protein-coupled inwardly rectifying potassium channel (GIRK) is a common mechanism for synaptic modulation in the CNS. However, evidence for metabotropic glutamate receptor (mGluR) activation of GIRK is virtually nonexistent, despite the widespread and overlapping distribution of these proteins. We examined this apparent paradox by coexpressing mGluRs 1a, 2, and 7 with the GIRK subunits Kir3.1 and Kir3.4 inXenopusoocytes. Functional expression of GIRK was confirmed by coexpression with the D2 dopamine receptor that is known to activate GIRK in neurons. Agonist activation of each of the three mGluRs evoked inward potassium currents in symmetrical KCl solutions. The current amplitudes evoked by mGluR1a, mGluR2, and D2 were comparable, whereas mGluR7 currents were somewhat smaller. mGluR1a-evoked GIRK currents were not blocked in BAPTA-treated oocytes, demonstrating that GIRK activation was distinct from phospholipase C-mediated activation of the endogenous calcium-dependent chloride current (ICaCl). Pertussis toxin (PTX) treatment significantly reduced both the mGluR and D2 receptor-evoked GIRK currents. In oocytes in which mGluR2 and D2 were coexpressed, activation of mGluR2 occluded additional D2 receptor current, indicating that mGluR2 and D2 receptor coupling to GIRK involves a common G-protein. The efficient coupling of mGluRs to GIRK in oocytes suggests either that mGluR activation of GIRK has been overlooked in neurons or possibly that mGluRs are excluded from GIRK-containing microdomains.
Neuron Death in the Substantia Nigra of Weaver Mouse Occurs Late in Development and Is Not Apoptotic
Authors: Oo Tinmarlar F. , Blazeski Richard , Harrison Susan M. W. , Henchcliffe Claire , Mason Carol A. , Roffler-Tarlov Suzanne K. , Burke Robert E. 
Published: April 2018

Weaveris a spontaneous mutation in mice characterized by the postnatal loss of external granule cells in the cerebellum and dopaminergic neurons of the midbrain, especially in the substantia nigra. We have shown previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal development. We therefore sought to determine whether the loss of dopaminergic neurons in homozygous weaver mice occurs during the period of natural cell death in the substantia nigra and whether it has the morphology of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozygous weaver substantia nigra, it also does so with equal magnitude in wild-type and heterozygous weaver littermates. Unique to homozygous weavers is the occurrence of degenerating neurons in the nigra that are not apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24–25. The nonapoptotic nature of this cell death is confirmed by negativein situend labeling of nuclear DNA fragmentation and by ultrastructural analysis. Ultrastructural studies reveal irregular chromatin aggregates in the nucleus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic reticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative process mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.
Hair Cell Differentiation in Chick Cochlear Epithelium after Aminoglycoside Toxicity:In VivoandIn VitroObservations
Authors: Stone Jennifer S. , Leaño Sharon G. , Baker Lauren P. , Rubel Edwin W 
Published: April 2018

Inner ear epithelia of mature birds regenerate hair cells after ototoxic or acoustic insult. The lack of markers that selectively label cells in regenerating epithelia and of culture systems composed primarily of progenitor cells has hampered the identification of cellular and molecular interactions that regulate hair cell regeneration. In control basilar papillae, we identified two markers that selectively label hair cells (calmodulin and TUJ1 β tubulin antibodies) and one marker unique for support cells (cytokeratin antibodies). Examination of regenerating epithelia demonstrated that calmodulin and β tubulin are also expressed in early differentiating hair cells, and cytokeratins are retained in proliferative support cells. Enzymatic and mechanical methods were used to isolate sensory epithelia from mature chick basilar papillae, and epithelia were cultured in different conditions. In control cultures, hair cells are morphologically stable for up to 6 d, because calmodulin immunoreactivity and phalloidin labeling of filamentous actin are retained. The addition of an ototoxic antibiotic to cultures, however, causes complete hair cell loss by 2 din vitroand generates cultures composed of calmodulin-negative, cytokeratin-positive support cells. These cells are highly proliferative for the first 2–7 d after plating, but stop dividing by 9 d. Calmodulin- or TUJ1-positive cells reemerge in cultures treated with antibiotic for 5 d and maintained for an additional 5 d without antibiotic. A subset of calmodulin-positive cells was also labeled with BrdU when it was continuously present in cultures, suggesting that some cells generated in culture begin to differentiate into hair cells.
The Leaving or Q Fraction of the Murine Cerebral Proliferative Epithelium: A General Model of Neocortical Neuronogenesis
Authors: Takahashi Takao , Nowakowski Richard S. , Caviness Verne S. 
Published: April 2018

Neurons of neocortical layers II–VI in the dorsomedial cortex of the mouse arise in the pseudostratified ventricular epithelium (PVE) through 11 cell cycles over the six embryonic days 11–17 (E11–E17). The present experiments measure the proportion of daughter cells that leave the cycle (quiescent or Q fraction or Q) during a single cell cycle and the complementary proportion that continues to proliferate (proliferative or P fraction or P; P = 1 − Q). Q and P for the PVE become 0.5 in the course of the eighth cycle, occurring on E14, and Q rises to ∼0.8 (and P falls to ∼0.2) in the course of the 10th cycle occurring on E16. This indicates that early in neuronogenesis, neurons are produced relatively slowly and the PVE expands rapidly but that the reverse happens in the final phase of neuronogenesis. The present analysis completes a cycle of analyses that have determined the four fundamental parameters of cell proliferation: growth fraction, lengths of cell cycle, and phases Q and P. These parameters are the basis of a coherent neuronogenetic model that characterizes patterns of growth of the PVE and mathematically relates the size of the initial proliferative population to the neuronal population of the adult neocortex.
Functional Anatomic Studies of Memory Retrieval for Auditory Words and Visual Pictures
Authors: Buckner Randy L. , Raichle Marcus E. , Miezin Francis M. , Petersen Steve E. 
Published: April 2018

Functional neuroimaging with positron emission tomography was used to study brain areas activated during memory retrieval. Subjects (n = 15) recalled items from a recent study episode (episodic memory) during two paired-associate recall tasks. The tasks differed in that PICTURE RECALL required pictorial retrieval, whereas AUDITORY WORD RECALL required word retrieval. Word REPETITION and REST served as two reference tasks.Comparing recall with repetition revealed the following observations. (1) Right anterior prefrontal activation (similar to that seen in several previous experiments), in addition to bilateral frontal-opercular and anterior cingulate activations. (2) An anterior subdivision of medial frontal cortex [pre-supplementary motor area (SMA)] was activated, which could be dissociated from a more posterior area (SMA proper). (3) Parietal areas were activated, including a posterior medial area near precuneus, that could be dissociated from an anterior parietal area that was deactivated. (4) Multiple medial and lateral cerebellar areas were activated. Comparing recall with rest revealed similar activations, except right prefrontal activation was minimal and activations related to motor and auditory demands became apparent (e.g., bilateral motor and temporal cortex). Directly comparing picture recall with auditory word recall revealed few notable activations.Taken together, these findings suggest a pathway that is commonly used during the episodic retrieval of picture and word stimuli under these conditions. Many areas in this pathway overlap with areas previously activated by a different set of retrieval tasks using stem-cued recall, demonstrating their generality. Examination of activations within individual subjects in relation to structural magnetic resonance images provided anatomic information about the location of these activations. Such data, when combined with the dissociations between functional areas, provide an increasingly detailed picture of the brain pathways involved in episodic retrieval tasks.