bluuebunny/crossref_metadata_2025 huggingface dataset:
Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors
Authors: O'Connor JJ , Rowan MJ , Anwyl R
Published: April 2018

Whole-cell patch-clamp recordings of evoked excitatory postsynaptic currents (EPSCs) were made from granule cells of the rat dentate gyrus in vitro. Tetanic stimulation in control media evoked a statistically identical long-term potentiation (LTP) of both the AMPA and NMDA receptor-mediated components of the dual component EPSC (AM-PAR and NMDAR EPSCs), as shown by a similar percentage increase in both components when measured at a holding potential of -30 mV, and also by an identical time course of the pre- and post-LTP induced EPSC at -30 mV and -70 mV. Application of the selective metabotropic glutamate receptor (mGluR) agonist 1S,3R-ACPD induced a transient depression followed by a rapid onset LTP of both the AMPAR and the NMDAR components of the dual component EPSC. The ACPD- and tetanically induced LTP of the AMPAR EPSC was NMDAR dependent, being abolished by the NMDAR antagonist AP5. Tetanic stimulation, and application of ACPD, also induced a relatively rapid onset LTP of the pharmacologically isolated NMDAR EPSC. Such tetanically and ACPD-induced LTP of the isolated NMDAR EPSC was also dependent on NMDAR activation, being strongly inhibited by AP5. The tetanically and the ACPD-induced LTP of the NMDAR EPSC were dependent on protein kinase C (PKC) stimulation, being strongly inhibited by the PKC inhibitor PKCI (19–31). The studies suggest that coactivation of the mGluR and NMDAR are required for induction of LTP of both the AMPAR- and NMDAR-mediated synaptic transmission. Moreover, LTP of the NMDAR-mediated synaptic transmission appears to be dependent on coincident activation of the NMDAR and mGluR.
Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex
Authors: Perrett SP , Mauk MD
Published: April 2018

We test the hypothesis that the cerebellar cortex is required for the extinction of conditioned eyelid responses in rabbits trained using standard Pavlovian delay procedures. Following 10 daily training sessions during which rabbits achieved asymptotic performance, lesions of the ipsilateral hemisphere of the cerebellar cortex were made by aspiration. The target of these lesions was the anterior lobe, as suggested by previous observations that this region is necessary for the learning-dependent timing of conditioned eyelid responses (Perrett et al., 1993). We report that anterior lobe damage, as indicated by disrupted response timing and confirmed by tissue analysis, produces severe deficits in conditioned response extinction. Postlesion responses show no significant decline over ten training sessions, whereas response timing and extinction are unaffected by lesions that do not include the anterior lobe. These conditioned responses that do not extinguish display stimulus specificity, excluding the possibility that they are unlearned responses unmasked by cerebellar cortex lesions. These observations suggest that Pavlovian eyelid conditioning is mediated by synaptic plasticity in at least two sites and the anterior lobe of the cerebellar cortex influences one of these sites during extinction. Based on these and previous data, we propose the hypothesis that eyelid conditioning can involve plasticity in both the cerebellar cortex and interpositus nucleus and that plasticity in the nucleus is controlled by input from Purkinje cell activity in the cortex. This hypothesis is consistent with observations that the cerebellar cortex may not always be required for the expression of conditioned responses, but it is necessary for response timing and for extinction.
Responses to glossopharyngeal stimulus in the early embryonic chick brainstem: spatiotemporal patterns in three dimensions from repeated multiple-site optical recording of electrical activity
Authors: Sato K , Momose-Sato Y , Sakai T , Hirota A , Kamino K
Published: April 2018

In an effort to assess the spatial patterning of glossopharyngeal responses in the early embryonic chick brainstem, we used a multiple- site optical recording system with a 12 x 12 element photodiode array and a voltage-sensitive merocyanine-rhodanine dye (NK2761) to monitor neural transmembrane voltage activities. Seven and 8 d old embryonic chick brainstems were sliced into 1400–1600 microns thick sections with the glossopharyngeal and vagal nerves attached, and then stained with the dye. Neural voltage-related optical signals were evoked by a positive brief (depolarizing) square current pulse applied to the glossopharyngeal nerve with a microsuction electrode, and then recorded simultaneously from many loci in the objective two-dimensional image plane of a compound microscope. In addition to the multiple-site optical recording technique, we tried to introduce an optical sectioning method by changing the focal plane of the microscope to obtain three-dimensional information. Thus, we have been able to assess semiquantitatively the three-dimensional profiles of two glossopharyngeal response areas corresponding to the nucleus of the glossopharyngeal nerve (nucleus nervi glossopharyngei) and the nucleus of the tractus solitarius. Furthermore, glutaminergic excitatory postsynaptic potentials were determined within the response area corresponding to the nucleus of the tractus solitarius. In addition, we also compared the glossopharyngeal and vagal response areas and found that the cores of the related nuclei are separated in three dimensions.
Cloning of neurotrimin defines a new subfamily of differentially expressed neural cell adhesion molecules
Authors: Struyk AF , Canoll PD , Wolfgang MJ , Rosen CL , D'Eustachio P , Salzer JL
Published: April 2018

Previous studies in the laboratory indicated that glycosylphosphatidylinositol (GPI)-anchored proteins may generate diversity of the cell surface of different neuronal populations (Rosen et al., 1992). In this study, we have extended these findings and surveyed the expression of GPI-anchored proteins in the developing rat CNS. In addition to several well characterized GPI-anchored cell adhesion molecules (CAMs), we detected an unidentified broad band of 65 kDa that is the earliest and most abundantly expressed GPI-anchored species in the rat CNS. Purification of this protein band revealed that it is comprised of several related proteins that define a novel subfamily of immunoglobulin-like (Ig) CAMs. One of these proteins is the opiate binding-cell adhesion molecule (OBCAM). We have isolated a cDNA encoding a second member of this family, that we have termed neurotrimin, and present evidence for the existence of additional family members. Like OBCAM, with which it shares extensive sequence identity, neurotrimin contains three immunoglobulin-like domains. Both proteins are encoded by distinct genes that may be clustered on the proximal end of mouse chromosome 9. Characterization of the expression of neurotrimin and OBCAM in the developing CNS by in situ hybridization reveals that these proteins are differentially expressed during development. Neurotrimin is expressed at high levels in several developing projection systems: in neurons of the thalamus, subplate, and lower cortical laminae in the forebrain and in the pontine nucleus, cerebellar granule cells, and Purkinje cells in the hindbrain. Neurotrimin is also expressed at high levels in the olfactory bulb, neural retina, dorsal root ganglia, spinal cord, and in a graded distribution in the basal ganglia and hippocampus. OBCAM has a much more restricted distribution, being expressed at high levels principally in the cortical plate and hippocampus. These results suggest that these proteins, together with other members of this family, provide diversity to the surfaces of different neuronal populations that could be important in the specification of neuronal connectivity.
Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner
Authors: Qiu WQ , Ferreira A , Miller C , Koo EH , Selkoe DJ
Published: April 2018

beta-Amyloid precursor protein (beta APP) is an integral membrane polypeptide expressed in many neural and non-neural cells. beta APP occurs in part at the cell surface and undergoes proteolytic processing to release the large soluble ectodomain (APPs) and the amyloid beta- peptide (A beta), both of which have apparent trophic activity in vitro. Despite intense interest in beta APP expression and metabolism, there is limited knowledge about the function mediated by beta APP inserted at the cell-surface. We established a coculture system in which beta APP-transfected CHO cells serve as a substrate for the growth of primary rat hippocampal neurons. Compared to nontransfected CHO cells, the increased surface beta APP of the transfectants stimulated short-term neuronal adhesion and longer-term neurite outgrowth, whereas the increased amount of secreted APPs and A beta in conditioned medium produced no such effects when neurons were grown either on untransfected CHO cells or on a polylysine substrate. Moreover, a peptide which has been shown to block the trophic effects of secreted APPs (Ninomiya et al., 1993) failed to interrupt the neurite promoting activity mediated by the surface-expressed beta APP. Surface-expressed beta APP751 or beta APP770 isoforms mediated more neurite outgrowth than did the beta APP695 isoform. Antibody blocking and regional deletion experiments indicated that the mid-region of the beta APP ectodomain (residues 361–648) is involved in promoting neurite outgrowth. We conclude that surface-expressed cellular beta APP has a neurite-promoting function which is distinct from the trophic function of the secreted beta APP derivatives and may have special significance during brain development.
Dopaminergic regulation of transcription factor expression in organotypic cultures of developing striatum
Authors: Liu FC , Takahashi H , McKay RD , Graybiel AM
Published: April 2018

Dopamine is a major neurotransmitter in neural systems innervating the striatum, and dopamine receptors are expressed during early pattern formation in the developing striatum. To test for the functional responsiveness of developing striatal neurons to dopaminergic stimulation, we established an organotypic slice culture of newborn rat striatum. We analyzed the effects of dopamine receptor agonists and of adenylate cyclase and protein kinase activation on striatal neurons by measuring the induction of Fos-like and Fra-like proteins in the cultured striatum. Fos-like and Fra-like proteins were induced in striatal neurons by activation of D1-like dopamine receptors but not by activation of D2-like receptors. The induction of Fos-like protein was mainly in striosomes and a medial compartment next to the ventricular zone, whereas Fra-like protein was induced in the striatal matrix as well. cAMP analogs and forskolin induced widespread expression of both Fos-like and Fra-like proteins. Our findings thus suggest that neurons of developing striosome and matrix compartments not only have different functional coupling of D1-like receptors to adenylate cyclase, but also have distinct maturational programs for dopaminergic regulation of individual transcription factors. Finally, despite evidence that protein kinase was involved in the induction of Fos-like protein, experiments with kinase inhibitors suggested that the induction of Fos- like protein had unusual pharmacological characteristics and raised the possibility that a novel protein kinase A-like molecule may have been involved in the induction. The cultured striatal slice preparation should provide a valuable tool for analyzing the molecular determinants of striatal development and function.
Enhancement of GABA-activated membrane currents in aged Fischer 344 rat basal forebrain neurons [published erratum appears in J Neurosci 1995 Jul;15(7):following table of contents]
Authors: Griffith WH , Murchison DA
Published: April 2018

Changes in GABAergic systems have been widely documented during development. Similar changes might also occur during aging, but little information is currently available. Whole-cell and single-channel GABAA- activated currents were studied in acutely dissociated basal forebrain neurons. An age-related increase in whole-cell GABA currents was observed in cells from aged (19–25 month) Fischer 344 rats. The GABA current from aged animals displayed a greater maximum response, with no change in EC50 or slope of the GABA response curve. A reduction in use- dependent slow receptor desensitization was also observed in aged cells. Single-channel conductance and channel open time were unchanged with age, suggesting no alteration in the properties of single GABA channels. The benzodiazepine, midazolam, potentiated GABA currents to a greater degree in aged animals, consistent with previous reports of enhanced benzodiazepine activity with age. Ontogeny of the GABAA receptor/ion channel complex may continue through the stages of development, maturation, and aging.
Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat
Authors: Staubli U , Xu FB
Published: April 2018

Serotonergic brainstem projections to hippocampus are thought to preferentially target and increase, via 5-HT3 receptors, the excitability of a distinct subpopulation of interneurons that primarily regulate GABAB-mediated inhibition in the dendritic region of pyramidal cells. Hippocampal slice work suggests that the between-burst hyperpolarization caused by slow (GABAB) IPSPs plays a significant role in controlling the strength of LTP induced with theta burst stimulation. According to the above observations it was assumed that blockade of hippocampal 5-HT3 receptors should reduce the hyperpolarization and thereby enhance both the frequency of the naturally occurring theta rhythm and the induction of LTP; moreover, if LTP-like mechanisms provide the substrate for certain forms of memory, such treatment was expected to facilitate learning. Each of the above predictions was tested and confirmed in the present set of experiments. The effects of ondansetron, a potent and selective antagonist of the 5- HT3 receptor, were examined on (1) frequency of the hippocampal theta rhythm, (2) induction of LTP in field CA1 of freely moving rats, and (3) retention of olfactory and spatial memory in tasks known to depend on an intact hippocampus. When injected intraperitoneally into freely moving rats, the drug reliably and significantly increased the frequency of the hippocampal theta rhythm in a dose-dependent manner. Second, at concentrations that facilitate theta frequency (100 micrograms/kg and 500 micrograms/kg), an injection of the drug 30 min prior to delivering electrical stimulation bursts significantly increased the magnitude and duration of LTP compared to that obtained in the same animals after vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)
Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs
Authors: Fitzgerald LW , Deutch AY , Gasic G , Heinemann SF , Nestler EJ
Published: April 2018

Because glutamate is an important modulator of subcortical dopamine (DA) function, and abnormal glutamate/DA interactions may be involved in the pathophysiology of schizophrenia, we examined the effect of chronically administered antipsychotic drugs (APDs) on the levels of specific glutamate receptor subunits in the terminal fields of nigrostriatal and mesocorticolimbic DA systems. By immunoblotting procedures using antibodies specific for the NMDAR1, GluR1, and GluR2 subunits, we found that haloperidol (predominantly a D2-like antagonist) increased NMDAR1 subunit immunoreactivity (and mRNA levels) in the striatum, while the D1-like antagonist SCH 23390 had the opposite effect. No effect was seen on GluR1 or GluR2 levels. The result that D1-like and D2-like receptor antagonism can reciprocally regulate NMDAR1 expression is consistent with our observation that complete unilateral destruction of the nigrostriatal DA pathway with 6- hydroxy-dopamine had no effect on striatal NMDAR1 subunit levels. Further examination of these striatal effects revealed that chronic treatment with the D2-like receptor antagonist raclopride significantly increased NMDAR1 levels in the striatum, while the 5-HT2a/2c antagonist mianserin tended to produce an increase that did not achieve statistical significance. These findings indicate that the dopaminergic antagonist properties of haloperidol are likely most responsible for its regulation of this subunit. In contrast, the atypical APD clozapine had no effect on striatal NMDAR1 levels, consistent with the relatively weaker influence of this drug on nigrostriatal DA function. The second major finding of the present study was the ability of haloperidol and clozapine to increase GluR1 levels in the medial prefrontal cortex (PFC), whereas chronic SCH 23390 treatment decreased GluR1 levels.
PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine
Authors: Douglass J , McKinzie AA , Couceyro P
Published: April 2018

involves alterations in specific patterns of gene expression. In order to screen for brain region specific mRNAs which are transcriptionally regulated by acute cocaine and amphetamine, PCR differential display was employed. This approach identified a previously uncharacterized mRNA whose relative levels in the striatum are induced four- to fivefold by acute psychomotor stimulant administration. Isolation and characterization of corresponding cDNA clones resulted in complete nucleotide sequence analysis, including prediction of the encoded protein product. Alternate polyA site utilization in the predicted 3′ noncoding region results in the appearance of an RNA doublet, approximately 700 and 900 bases in length, following Northern analysis. A presumed alternate splicing event further generates diversity within the transcripts, and results in the presence or absence of an in-frame 39 base insert within the putative protein coding region. As a result, the predicted translation products are either 129 or 116 amino acids in length. A common hydrophobic leader sequence at the amino terminus is present within each predicted polypeptide, suggesting that the protein product is targeted for entry into the secretory pathway. Basal expression of the RNA doublet is limited to neuroendocrine tissues, further implying that the protein product plays a functional role in both neuronal and endocrine tissues.
Differences in the anatomic distribution of immediate-early gene expression in amygdala and angular bundle kindling development
Authors: Hosford DA , Simonato M , Cao Z , Garcia-Cairasco N , Silver JM , Butler L , Shin C , McNamara JO
Published: April 2018

Kindling is a model in which fleeting changes of neuronal activity produce a lifelong modification of neuronal structure and function in the mature nervous system. Immediate-early genes (IEGs) such as c-fos have been implicated as a causal link in the chain of molecular events coupling fleeting pathologic activity to lasting hyperexcitability. Identification of the brain structures exhibiting IEG expression during the evolution of kindling is necessary to guide investigations of the phenotypic consequences. We used in situ hybridization histochemistry to identify the structures exhibiting expression of multiple IEGs during the evolution of amygdala kindling and compared this to the pattern following angular bundle kindling. The principal findings included that: (1) generalized limbic and clonic motor (class 5) kindled seizures evoked by stimulation of one amygdala induced the expression of IEGs in a small subset of limbic structures with remarkable symmetry between the two hemispheres; (2) the anatomic extent of seizure-evoked expression of c-fos mRNA expanded progressively following focal limbic and motor (classes 0–3) seizures during the development of amygdala kindling; c-fos mRNA was detected first ipsilaterally in AM, ACO, and PC and with higher-class seizures in hippocampal formation and homologous structures contralaterally, and (3) class 5 seizures evoked by stimulation of two different sites in the limbic system (amygdala or angular bundle) induced IEG expression in distinct but partially overlapping anatomic structures. We propose that synaptic activation of glutamate receptors contributes to the expression of these diverse IEGs throughout the forebrain. The findings provide a constellation of anatomic structures in which to investigate the structural and functional consequences of IEG expression.
Cellular and Regional Distribution of the Glutamate Transporter GLAST in the CNS of Rats: NonradioactiveIn SituHybridization and Comparative Immunocytochemistry
Authors: Schmitt Angelika , Asan Esther , Püschel Bernd , Kugler Peter
Published: April 2018

Oligonucleotide and cRNA probes were used for nonradioactivein situhybridizations carried out to identify the neural cell types expressing the glutamate transporter GLAST mRNA in the rat CNS. Additionally, the regional distribution of GLAST mRNA-expressing cells was studied, and the results were complemented by immunocytochemical investigations using an antibody against a synthetic GLAST peptide. The findings documented that GLAST is expressed by Bergmann glia and by astrocytes throughout the CNS. The glial localization of GLAST mRNA was verified unequivocally by double-labeling with an astrocytic marker protein. Additionally, GLAST mRNA reactivity and GLAST immunoreactivity were found in ependymal cells. In other neural cell types of the CNS, GLAST expression was not detectable. A high level of astrocytic immunolabeling was observed in the entire gray matter of the brain, with variations in intensity in different regions. Those brain areas that are known to possess high glutamatergic activity and astrocytic glutamate metabolism stained intensely for both GLAST mRNA and GLAST protein. The latter observation suggests that the GLAST glutamate transporter participates in the regulation of extracellular glutamate concentrations, especially in brain areas receiving an intense glutamatergic innervation.
Reelin Is a Secreted Glycoprotein Recognized by the CR-50 Monoclonal Antibody
Authors: D’Arcangelo Gabriella , Nakajima Kazunori , Miyata Takaki , Ogawa Masaharu , Mikoshiba Katsuhiko , Curran Tom
Published: April 2018

The neurological mouse mutant strainreelerdisplays abnormal laminar organization of several brain structures as a consequence of a defect in cell migration during neurodevelopment. This phenotype is a result of the disruption ofreelin, a gene encoding a protein that has several structural characteristics of extracellular matrix proteins. To understand the molecular basis of the action of Reelin on neuronal migration, we constructed a full-lengthreelinclone and used it to direct Reelin expression. Here, we demonstrate that Reelin is a secreted glycoprotein and that a highly charged C-terminal region is essential for secretion. In addition, we demonstrate that an amino acid sequence present in the N-terminal region of Reelin contains an epitope that is recognized by the CR-50 monoclonal antibody. CR-50 was raised against an antigen expressed in normal mouse brain that is absent inreelermice. The interaction of CR-50 with its epitope leads to the disruption of neural cell aggregationin vitro. Here, we used CR-50 to precipitate Reelin from reticulocyte extracts programmed withreelinmRNA, from cells transfected withreelinclones, and from cerebellar explants. Thereelingene product seems to function as an instructive signal in the regulation of neuronal migration.
Functional Properties of AMPA and NMDA Receptors Expressed in Identified Types of Basal Ganglia Neurons
Authors: Götz Thomas , Kraushaar Udo , Geiger Jörg , Lübke Joachim , Berger Thomas , Jonas Peter
Published: April 2018

AMPA- and NMDA-type glutamate receptors (AMPARs and NMDARs) mediate excitatory synaptic transmission in the basal ganglia and may contribute to excitotoxic injury. We investigated the functional properties of AMPARs and NMDARs expressed by six main types of basal ganglia neurons in acute rat brain slices (principal neurons and cholinergic interneurons of striatum, GABAergic and dopaminergic neurons of substantia nigra, globus pallidus neurons, and subthalamic nucleus neurons) using fast application of glutamate to nucleated and outside-out membrane patches. AMPARs in different types of basal ganglia neurons were functionally distinct. Those expressed in striatal principal neurons exhibited the slowest gating (desensitization time constant τ = 11.5 msec, 1 mmglutamate, 22°C), whereas those in striatal cholinergic interneurons showed the fastest gating (desensitization time constant τ = 3.6 msec). The lowest Ca2+permeability of AMPARs was observed in nigral dopaminergic neurons (PCa/PNa= 0.10), whereas the highest Ca2+permeability was found in subthalamic nucleus neurons (PCa/PNa= 1.17). NMDARs of different types of basal ganglia neurons were less variable in their functional properties; those expressed in nigral dopaminergic neurons exhibited the slowest gating (deactivation time constant of predominant fast component τ1= 150 msec, 100 μmglutamate), and those of globus pallidus neurons showed the fastest gating (τ1= 67 msec). The Mg2+block of NMDARs was similar; the average chord conductance ratiog−60mV/g+40mVwas 0.18–0.22 in 100 μmexternal Mg2+. Hence, AMPARs expressed in different types of basal ganglia neurons are markedly diverse, whereas NMDARs are less variable in functional properties that are relevant for excitatory synaptic transmission and neuronal vulnerability.
Postnatal Development of Binocular Disparity Sensitivity in Neurons of the Primate Visual Cortex
Authors: Chino Yuzo M. , Smith III Earl L. , Hatta Shiro , Cheng Han
Published: April 2018

In macaque monkeys, the age at which neurons in the primary visual cortex (V1) become sensitive to interocular image disparities, a prerequisite for stereopsis, is a matter of conjecture. To resolve this fundamental issue in binocular vision development, we measured the responsiveness of individual V1 neurons in anesthetized and paralyzed infant monkeys as a function of the relative, interocular, spatial phase of dichoptic sine-wave gratings. We found that an adult-like proportion of units were sensitive to interocular image disparity as early as the sixth postnatal day, several weeks before the onset age for stereopsis in monkeys. The ocular dominance distributions of cells in infant monkeys were also indistinguishable from those of adults. Thus, at or only a few days after birth, V1 neurons are capable of combining neural signals from the two eyes as in adults and are sensitive to interocular image disparities. However, the monocular spatial-frequency response properties of these disparity-sensitive units were immature, and their overall responsiveness was far lower than that in adults. During the first 4 postnatal weeks, both the spatial frequency response properties and the peak response amplitude rapidly improved, which resulted in a corresponding increase in the absolute sensitivity of individual units to interocular disparity. The results demonstrate that early binocular vision development in monkeys is not constrained by a paucity of disparity-sensitive V1 neurons but, instead, by the relative immaturity of the spatial response properties and the overall unresponsiveness of existing disparity-sensitive neurons.
Synaptic Integration of Functionally Diverse Pallidal Information in the Entopeduncular Nucleus and Subthalamic Nucleus in the Rat
Authors: Bevan Mark D. , Clarke Nick P. , Bolam J. Paul
Published: April 2018

To determine the principles of synaptic innervation of neurons in the entopeduncular nucleus and subthalamic nucleus by neurons of functionally distinct regions of the pallidal complex, double anterograde labeling was carried out at both light and electron microscopic levels in the rat. Deposits of the anterograde tracersPhaseolus vulgaris-leucoagglutinin and biotinylated dextran amine were placed in different functional domains of the pallidal complex in the same animals. The tracer deposits in the ventral pallidum and the globus pallidus gave rise to GABA-immunopositive projections to the entopeduncular nucleus, the subthalamic nucleus, and the more medial lateral hypothalamus that were largely segregated but overlapped at the interface between the two fields of projection. In these regions the proximal parts of individual neurons in the entopeduncular nucleus, lateral hypothalamus, and subthalamic nucleus received synaptic input from terminals derived from both the ventral pallidum and the globus pallidus. Furthermore, the analysis of the afferent synaptic input to the dendrites of neurons in the subthalamic nucleus that cross functional boundaries of the nucleus defined by the pallidal inputs, revealed that terminals with the morphological and neurochemical characteristics of those derived from the pallidal complex make synaptic contact with all parts of the dendritic tree, including distal regions.

It is concluded that functionally diverse information carried by the descending projections of the pallidal complex is synaptically integrated by neurons of the entopeduncular nucleus, lateral hypothalamus, and subthalamic nucleus by two mechanisms. First, neurons located at the interface between functionally distinct, but topographically adjacent, projections could integrate diverse information by means of the synaptic convergence at the level of the cell body and proximal dendrites. Second, because the distal dendrites of neurons in the subthalamic nucleus receive input from the pallidum, those that extend across two distinct domains of pallidal input could also provide the morphological basis of integration.
Neurotrophin-3 Administration Attenuates Deficits of Pyridoxine-Induced Large-Fiber Sensory Neuropathy
Authors: Helgren Maureen E. , Cliffer Kenneth D. , Torrento Kim , Cavnor Chris , Curtis Rory , DiStefano Peter S. , Wiegand Stanley J. , Lindsay Ronald M.
Published: April 2018

Chronic treatment of adult rats for 2–3 weeks with high doses of pyridoxine (vitamin B6) produced a profound proprioceptive loss, similar to that found in humans overdosed with this vitamin or treated with the chemotherapeutic agent cisplatin. Pyridoxine toxicity was manifest as deficits in simple and precise locomotion and sensory nerve function and as degeneration of large-diameter/large-fiber spinal sensory neurons. As assessed quantitatively in a beam-walking task and by EMG recording of H waves evoked by peripheral nerve stimulation, coadministration of the neurotrophic factor neurotrophin-3 (NT-3; 5–20 mg · kg−1· d−1, s.c.) during chronic pyridoxine treatment largely attenuated the behavioral and electrophysiological sequelae associated with pyridoxine toxicity. Furthermore, NT-3 administration prevented degeneration of sensory fibers in the dorsal column of the spinal cord. These data are consistent with the evidence that NT-3 is a target-derived neurotrophic factor for muscle sensory afferents and suggest that pharmacological doses of NT-3 may be beneficial in the treatment of large-fiber sensory neuropathies.
Functional Stages in the Formation of Human Long-Term Motor Memory
Authors: Shadmehr Reza , Brashers-Krug Thomas
Published: April 2018

Previous research has demonstrated that the primate CNS has the ability to learn and store multiple and conflicting visuo-motor maps. Here we studied the ability of human subjects to learn to make reaching movements while interacting with one of two conflicting mechanical environments as produced by a robotic manipulandum. We demonstrate that two motor maps may be learned and retained, but only if the training sessions in the tasks are separated by an interval of ∼5 hr. If the interval is shorter, learning of the second map begins with an internal model appropriate for the first task and performance in the second task is significantly impaired. Analysis of the after-effects suggests that with a short temporal distance, learning of the second task leads to an unlearning of the internal model for the first. With the longer temporal distance, learning of the second task starts with an unbiased internal model, and performance approaches that of naives. Furthermore, the memory of the consolidated skill lasts for at least 5 months after training. These results argue for a distinct change in the state of resistance of motor memory (to disruption) within a few hours after acquisition. We suggest that motor practice results in memories that have at least two functional components: soon after completion of practice, one component fades while another is strengthened. A further experiment suggests that the hypothetical first stage is not merely a gateway to long-term memory, but also temporary storage for items of information, whether new or old, for use in the near-term. Our results raise the possibility that there are distinct neuronal mechanisms for representation of the two functional stages of motor memory.
Neuroprotection and Neuronal Differentiation Studies Using Substantia Nigra Dopaminergic Cells Derived from Transgenic Mouse Embryos
Authors: Son Jin H. , Chun Hong S. , Joh Tong H. , Cho Sunghee , Conti Bruno , Lee Jong W.
Published: April 2018

The major pathological lesion of Parkinson’s disease (PD) is the selective cell death of dopaminergic (DA) neurons in substantia nigra (SN). Although the initial cause and subsequent molecular signaling mechanisms leading to DA cell death underlying the PD process remain elusive, brain-derived neurotrophic factor (BDNF) is thought to exert neuroprotective as well as neurotrophic roles for the survival and differentiation of DA neurons in SN. Addressing molecular mechanisms of BDNF action in both primary embryonic mesencephalic cultures andin vivoanimal models has been technically difficult because DA neurons in SN are relatively rare and present with many heterogeneous cell populations in midbrain. We have developed and characterized a DA neuronal cell line of embryonic SN origin that is more accessible to molecular analysis and can be used as anin vitromodel system for studying SN DA neurons. A clonal SN DA neuronal progenitor cell line SN4741, arrested at an early DA developmental stage, was established from transgenic mouse embryos containing the targeted expression of the thermolabile SV40Tag in SN DA neurons. The phenotypic and morphological differentiation of the SN4741 cells could be manipulated by environmental cuesin vitro. Exogenous BDNF treatment produced significant neuroprotection against 1-methyl-4-phenylpyridinium, glutamate, and nitric oxide-induced neurotoxicity in the SN4741 cells. Simultaneous phosphorylation of receptor tyrosine kinase B accompanied the neuroprotection. This SN DA neuronal cell line provides a unique model system to circumvent the limitations associated with primary mesencephalic cultures for the elucidation of molecular mechanisms of BDNF action on DA neurons of the SN.
Synaptic Vesicle Populations in Saccular Hair Cells Reconstructed by Electron Tomography
Authors: Lenzi David , Runyeon Jonathan W. , Crum John , Ellisman Mark H. , Roberts William M.
Published: April 2018

We used electron tomography to map the three-dimensional architecture of the ribbon-class afferent synapses in frog saccular hair cells. The synaptic body (SB) at each synapse was nearly spherical (468 ± 65 nm diameter; mean ± SD) and was covered by a monolayer of synaptic vesicles (34.3 nm diameter; 8.8% coefficient of variation), many of them tethered to it by ∼20-nm-long filaments, at an average density of 55% of close-packed (376 ± 133 vesicles per SB). These vesicles could support ∼900 msec of exocytosis at the reported maximal rate, which the cells can sustain for at least 2 sec, suggesting that replenishment of vesicles on the SB is not rate limiting. Consistent with this interpretation, prolonged K+depolarization did not deplete vesicles on the SB. The monolayer of SB-associated vesicles remained after cell lysis in the presence of 4 mmCa2+, indicating that the association is tight and Ca2+-resistant. The space between the SB and the plasma membrane contained numerous vesicles, many of which (∼32 per synapse) were in contact with the plasma membrane. This number of docked vesicles could support maximal exocytosis for at most ∼70 msec. Additional docked vesicles were seen within a few hundred nanometers of the synapse and occasionally at greater distances. The presence of omega profiles on the plasma membrane around active zones, in the same locations as coated pits and coated vesicles labeled with an extracellular marker, suggests that local membrane recycling may contribute to the three- to 14-fold greater abundance of vesicles in the cytoplasm (not associated with the SB) near synapses than in nonsynaptic regions.
Nitric Oxide Acutely Inhibits Neuronal Energy Production
Authors: Brorson James R. , Schumacker Paul T. , Zhang He
Published: April 2018

Disruption of mitochondrial respiration has been proposed as an action of nitric oxide (NO) responsible for its toxicity, but the effects of NO on the energetics of intact central neurons have not been reported. We examined the effects of NO on mitochondrial function and energy metabolism in cultured hippocampal neurons. The application of NO from NO donors or from dissolved gas produced a rapid, reversible depolarization of mitochondrial membrane potential, as detected by rhodamine-123 fluorescence. NO also produced a progressive concentration-dependent depletion of cellular ATP over 20 min exposures. The energy depletion produced by higher levels of NO (2 μmor more) was profound and irreversible and proceeded to subsequent neuronal death.

In contrast to the effects of NO, mitochondrial protonophores produced complete depolarizations of mitochondrial membrane potential but depleted the neuronal ATP stores only partially. Inhibitors of mitochondrial oxidative phosphorylation (rotenone or 3-nitropropionic acid) or of glycolysis (iodoacetate plus pyruvate) also produced only partial ATP depletion, suggesting that either process alone could partially maintain ATP stores. Only by combining the inhibition of glycolytic energy production with the inhibition of mitochondria could the effects of NO in depleting energy and inducing delayed toxicity be duplicated.

These results show that NO has rapid inhibitory actions on mitochondrial metabolism in living neurons. However, the severe ATP-depleting effects of high concentrations of NO are not fully explained by the direct effects on mitochondrial activity alone but must involve the inhibition of glycolysis as well. These inhibitory effects on energy production may contribute to the delayed toxicity of NOin vitroand in ischemic stroke.
Regulation and Immunohistochemical Localization of βγ-Stimulated Adenylyl Cyclases in Mouse Hippocampus
Authors: Baker Lauren P. , Nielsen Mark D. , Impey Soren , Hacker Beth M. , Poser Steven W. , Chan Mandy Y. M. , Storm Daniel R.
Published: April 2018

Specific forms of synaptic plasticity such as long-term potentiation (LTP) are modulated by or require increases in cAMP. The various adenylyl cyclase isoforms possess unique regulatory properties, and thus cAMP increases in a given cell type or tissue in response to converging signals are subject to the properties of the adenylyl cyclase isoforms expressed. In most tissues, adenylyl cyclase activity is stimulated by neurotransmitters or hormones via stimulatory G-protein (Gs)-coupled receptors and is inhibited via inhibitory G-protein (Gi)-linked receptors. However, in the hippocampus, stimulation of Gi-coupled receptors potentiates Gs-stimulated cAMP levels. This effect may be associated with the regulatory properties of adenylyl cyclase types 2 and 4 (AC2 and AC4), isoforms that are potentiated by the βγ subunit of Giin vitro. Although AC2 has been shown to be stimulated by βγ in whole cells, reports describing the sensitivity of AC4 to βγin vivohave yet to emerge. Our results demonstrate that Gs-mediated stimulation of AC4 is potentiated by βγ released from activated Gi-coupled receptors in intact human embryonic kidney (HEK) 293 cells. Furthermore, we show that the AC2 and AC4 proteins are expressed in the mouse hippocampal formation and that they colocalize with MAP2, a dendritic and/or postsynaptic marker. The presence of AC2 and AC4 in the hippocampus and the ability of each of these enzymes to detect coincident activation of Gs- and Gi-coupled receptors suggest that they may play a crucial role in certain forms of synaptic plasticity by coordinating such overlapping synaptic inputs.
NMDA Receptor-Mediated Control of Presynaptic Calcium and Neurotransmitter Release
Authors: Cochilla Amanda J. , Alford Simon
Published: April 2018

Before action potential-evoked Ca2+transients, basal presynaptic Ca2+concentration may profoundly affect the amplitude of subsequent neurotransmitter release. Reticulospinal axons of the lamprey spinal cord receive glutamatergic synaptic input. We have investigated the effect of this input on presynaptic Ca2+concentrations and evoked release of neurotransmitter. Paired recordings were made between reticulospinal axons and the neurons that make axo-axonic synapses onto those axons. Both excitatory and inhibitory paired-cell responses were recorded in the axons. Excitatory synaptic inputs were blocked by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 μm) and by the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP-5; 50 μm). Application of NMDA evoked an increase in presynaptic Ca2+in reticulospinal axons. Extracellular stimulation evoked Ca2+transients in axons when applied either directly over the axon or lateral to the axons. Transients evoked by the two types of stimulation differed in magnitude and sensitivity to AP-5. Simultaneous microelectrode recordings from the axons during Ca2+imaging revealed that stimulation of synaptic inputs directed to the axons evoked Ca2+entry. By the use of paired-cell recordings between reticulospinal axons and their postsynaptic targets, NMDA receptor activation was shown to enhance evoked release of transmitter from the axons that received axoaxonic inputs. When the synaptic input to the axon was stimulated before eliciting an action potential in the axon, transmitter release from the axon was enhanced. We conclude that NMDA receptor-mediated input to reticulospinal axons increases basal Ca2+within the axons and that this Ca2+is sufficient to enhance release from the axons.
Stable Properties of Spontaneous EPSCs and Miniature Retinal EPSCs during the Development of ON/OFF Sublamination in the Ferret Lateral Geniculate Nucleus
Authors: Hohnke Carsten D. , Sur Mriganka
Published: April 2018

Retinal projections to the lateral geniculate nucleus (LGN) in ferrets progressively segregate into eye-specific laminae and subsequently into sublaminae that receive inputs from either ON-center or OFF-center afferents. To study the development of synaptic efficacy during a period of activity-dependent growth and reorganization in the CNS, we recorded spontaneous EPSCs (sEPSCs) from cells of the LGN during ON/OFF sublamination. We also examined retinal inputs specifically by stimulating the optic tract in the presence of strontium and recording evoked miniature EPSCs (emEPSCs). The rise times, areas, half-widths, and decay times of sEPSCs and emEPSCs and interevent intervals of sEPSCs recorded at the beginning of ON/OFF sublamination were not different from those recorded after its completion. Typically EPSC areas were small (10–20 fC) but varied greatly both within and between neurons. The frequency of sEPSCs was also quite variable, ranging from 0.2 to 5 Hz. sEPSCs were equivalent to miniature EPSCs recorded in the presence of tetrodotoxin, and both sEPSCs and emEPSCs were CNQX-sensitive. No difference was observed between sEPSCs recorded at room temperature and those recorded at 34°C, and strontium could be substituted for calcium with no effect on sEPSC shape. These data argue for a remarkable stability in the components of at least AMPA-mediated synaptic transmission during a period of major synaptic rearrangement in the LGN.
Homing in Pigeons: The Role of the Hippocampal Formation in the Representation of Landmarks Used for Navigation
Authors: Gagliardo Anna , Ioalé Paolo , Bingman Verner P.
Published: April 2018

When given repeated training from a location, homing pigeons acquire the ability to use familiar landmarks to navigate home. Both control and hippocampal-lesioned pigeons succeed in learning to use familiar landmarks for homing. However, the landmark representations that guide navigation are strikingly different. Control and hippocampal-lesioned pigeons were initially given repeated training flights from two locations. On subsequent test days from the two training locations, all pigeons were rendered anosmic to eliminate use of their navigational map and were phase- or clock-shifted to examine the extent to which their learned landmark representations were dependent on the use of the sun as a compass. We show that control pigeons acquire a landmark representation that allows them to directly use landmarks without reference to the sun to guide their flight home, called “pilotage”. Hippocampal-lesioned birds only learn to use familiar landmarks at the training location to recall the compass direction home, based on the sun, flown during training, called “site-specific compass orientation.” The results demonstrate that for navigation of 20 km or more in a natural field setting, the hippocampal formation is necessary if homing pigeons are to learn a spatial representation based on numerous independent landmark elements that can be used to directly guide their return home.
The Modulation of Presynaptic Inhibition in Single Muscle Primary Afferents during Fictive Locomotion in the Cat
Authors: Ménard Ariane , Leblond Hugues , Gossard Jean-Pierre
Published: April 2018

The aim of this study is to understand the functional organization of presynaptic inhibition in muscle primary afferents during locomotion. Primary afferent depolarization (PAD) associated with presynaptic inhibition was recorded intra-axonally in identified afferents from various hindlimb muscles in L6–L7 spinal segments during fictive locomotion in the decerebrate cat. PADs were evoked by the stimulation of peripheral muscle nerves and were averaged in the different epochs of the fictive step cycle. Fifty-three trials recorded from 39 muscle axons (37 from group I and two from group II) were retained for analysis. The results showed that there was a significant phase-dependent modulation of PAD amplitude (p< 0.05) in a majority of muscle afferents (30 of 39, 77%). However, not all stimulated nerves led to significantly modulated PADs in a given axon (36 of 53 trials, 68%). We also observed that the pattern of modulation (phase for maximum and minimum PAD amplitude and the depth of modulation) varied with each recorded afferent, as well as with each stimulated nerve. We further evaluated the effect of PAD modulation on the phasic transmission of the monosynaptic reflex (MSR) and found that PADs decreased the MSR amplitude in all phases of the fictive step cycle, independent of the PAD pattern in individual group I fibers. We conclude that (1) PAD modulation patterns of all group I fibers contacting motoneurons led to an overall reduction in monosynaptic transmission, and (2) individual PAD patterns could participate in the control of transmission in specific reflex pathways during locomotion.