bluuebunny/crossref_metadata_2025 huggingface dataset:
Dextroamphetamine Enhances “Neural Network-Specific” Physiological Signals: A Positron-Emission Tomography rCBF Study
Authors: Mattay Venkata S. , Berman Karen Faith , Ostrem Jill L. , Esposito Giuseppe , Van Horn John D. , Bigelow Llewellyn B. , Weinberger Daniel R.
Published: April 2018

Previous studies in animals and humans suggest that monoamines enhance behavior-evoked neural activity relative to nonspecific background activity (i.e., increase signal-to-noise ratio). We studied the effects of dextroamphetamine, an indirect monoaminergic agonist, on cognitively evoked neural activity in eight healthy subjects using positron-emission tomography and the O15water intravenous bolus method to measure regional cerebral blood flow (rCBF). Dextroamphetamine (0.25 mg/kg) or placebo was administered in a double-blind, counterbalanced design 2 hr before the rCBF study in sessions separated by 1–2 weeks. rCBF was measured while subjects performed four different tasks: two abstract reasoning tasks—the Wisconsin Card Sorting Task (WCST), a neuropsychological test linked to a cortical network involving dorsolateral prefrontal cortex and other association cortices, and Ravens Progressive Matrices (RPM), a nonverbal intelligence test linked to posterior cortical systems—and two corresponding sensorimotor control tasks. There were no significant drug or task effects on pCO2or on global blood flow. However, the effect of dextroamphetamine (i.e., dextroamphetamine vs placebo) on task-dependent rCBF activation (i.e., task − control task) showed double dissociations with respect to task and region in the very brain areas that most distinctly differentiate the tasks. In the superior portion of the left inferior frontal gyrus, dextroamphetamine increased rCBF during WCST but decreased it during RPM (ANOVAF(1,7) = 16.72, p < 0.0046). In right hippocampus, blood flow decreased during WCST but increased during RPM (ANOVAF(1,7) = 18.7, p < 0.0035). These findings illustrate that dextroamphetamine tends to “focus” neural activity, to highlight the neural network that is specific for a particular cognitive task. This capacity of dextroamphetamine to induce cognitively specific signal augmentation may provide a neurobiological explanation for improved cognitive efficiency with dextroamphetamine.
Impaired Cerebellar Synaptic Plasticity and Motor Performance in Mice Lacking the mGluR4 Subtype of Metabotropic Glutamate Receptor
Authors: Pekhletski Roman , Gerlai Robert , Overstreet Linda S. , Huang Xi-Ping , Agopyan Nadia , Slater N. Traverse , Abramow-Newerly Wanda , Roder John C. , Hampson David R.
Published: April 2018

The application of the glutamate analogl-2-amino-4-phosphonobutyric acid (l-AP4) to neurons produces a suppression of synaptic transmission. Althoughl-AP4 is a selective ligand at a subset of metabotropic glutamate receptors (mGluRs), the precise physiological role of thel-AP4-activated mGluRs remains primarily unknown. To provide a better understanding of the function ofl-AP4 receptors, we have generated and studied knockout (KO) mice lacking the mGluR4 subtype of mGluR that displays high affinity forl-AP4. The mGluR4 mutant mice displayed normal spontaneous motor activity and were unimpaired on the bar cross test, indicating that disruption of the mGluR4 gene did not cause gross motor abnormalities, impairments of novelty-induced exploratory behaviors, or alterations in fine motor coordination. However, the mutant mice were deficient on the rotating rod motor-learning test, suggesting that mGluR4 KO mice may have an impaired ability to learn complex motor tasks. Patch-clamp and extracellular field recordings from Purkinje cells in cerebellar slices demonstrated thatl-AP4 had no effect on synaptic responses in the mutant mice, whereas in the wild-type mice 100 μml-AP4 produced a 23% depression of synaptic responses with an EC50of 2.5 μm. An analysis of presynaptic short-term synaptic plasticity at the parallel fiber→Purkinje cell synapse demonstrated that paired-pulse facilitation and post-tetanic potentiation were impaired in the mutant mice. In contrast, long-term depression (LTD) was not impaired. These results indicate that an important function of mGluR4 is to provide a presynaptic mechanism for maintaining synaptic efficacy during repetitive activation. The data also suggest that the presence of mGluR4 at the parallel fiber→Purkinje cell synapse is required for maintaining normal motor function.
Gamma Oscillation by Synaptic Inhibition in a Hippocampal Interneuronal Network Model
Authors: Wang Xiao-Jing , Buzsáki György
Published: April 2018

Fast neuronal oscillations (gamma, 20–80 Hz) have been observed in the neocortex and hippocampus during behavioral arousal. Using computer simulations, we investigated the hypothesis that such rhythmic activity can emerge in a random network of interconnected GABAergic fast-spiking interneurons. Specific conditions for the population synchronization, on properties of single cells and the circuit, were identified. These include the following: (1) that the amplitude of spike afterhyperpolarization be above the GABAAsynaptic reversal potential; (2) that the ratio between the synaptic decay time constant and the oscillation period be sufficiently large; (3) that the effects of heterogeneities be modest because of a steep frequency–current relationship of fast-spiking neurons. Furthermore, using apopulation coherencemeasure, based on coincident firings of neural pairs, it is demonstrated that large-scale network synchronization requires a critical (minimal) average number of synaptic contacts per cell, which is not sensitive to the network size.

By changing the GABAAsynaptic maximal conductance, synaptic decay time constant, or the mean external excitatory drive to the network, the neuronal firing frequencies were gradually and monotonically varied. By contrast, the network synchronization was found to be high only within a frequency band coinciding with the gamma (20–80 Hz) range. We conclude that the GABAAsynaptic transmission provides a suitable mechanism for synchronized gamma oscillations in a sparsely connected network of fast-spiking interneurons. In turn, the interneuronal network can presumably maintain subthreshold oscillations in principal cell populations and serve to synchronize discharges of spatially distributed neurons.
Differential Expression of Bone Morphogenetic Proteins in the Developing Vestibular and Auditory Sensory Organs
Authors: Oh Seung-Ha , Johnson Randy , Wu Doris K.
Published: April 2018

The genes responsible for the formation of various sensory organs in the inner ear are not known. There are eight sensory organs in the chick inner ear, and our previous study showed that all presumptive sensory organs initially express bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor (TGF)-β gene family. To address the potential role of BMPs in the patterning of different sensory organ structures, we investigated the expression of BMP4, BMP5, and BMP7 during sensory organ differentiation in the chick inner ear. The gene expression pattern of BMP5, although similar to that of BMP4, was transient and disappeared by embryonic day 3.5 (E3.5). In contrast, BMP7 gene expression was quite extensive, starting in the otic placode. By E5, gene expression patterns of BMP4 and BMP7 differed among vestibular and auditory sensory organs. In the vestibular sensory organs, BMP7 gene expression segregated from the main sensory tissue areas at the onset of differentiation, whereas BMP4 expression concentrated in supporting cells. In the cochlea, however, BMP7 gene expression became restricted to sensory tissue over time and eventually concentrated in supporting cells, whereas BMP4 gene expression was localized to hair cells. The different BMP expression patterns in developing auditory and vestibular sensory organs may help to shape each respective sensory structure. Furthermore, the expression of BMP4 in the cochlea also revealed an interesting pattern of sensory cell differentiation: the distal portion of the cochlea differentiates first, and the tall hair cells develop before the short hair cells.
Effects of Early-Onset Artificial Strabismus on Pursuit Eye Movements and on Neuronal Responses in Area MT of Macaque Monkeys
Authors: Kiorpes Lynne , Walton Pamela J. , O’Keefe Lawrence P. , Movshon J. Anthony , Lisberger Stephen G.
Published: April 2018

In humans, esotropia of early onset is associated with a profound asymmetry in smooth pursuit eye movements. When viewing is monocular, targets are tracked well only when they are moving nasally with respect to the viewing eye. To determine whether this pursuit abnormality reflects an anomaly in cortical visual motion processing, we recorded eye movements and cortical neural responses in nonamblyopic monkeys made strabismic by surgery at the age of 10–60 d. Eye movement recordings revealed the same asymmetry in the monkeys’ pursuit eye movements as in humans with early-onset esotropia. With monocular viewing, pursuit was much stronger for nasalward motion than for temporalward motion, especially for targets presented in the nasal visual field. However, for targets presented during ongoing pursuit, temporalward and nasalward image motion was equally effective inmodulatingeye movement. Single-unit recordings made from the same monkeys, under anesthesia, revealed that MT neurons were rarely driven binocularly, but otherwise had normal response properties. Most were directionally selective, and their direction preferences were uniformly distributed. Our neurophysiological and oculomotor measurements both suggest that the pursuit defect in these monkeys is not due to altered cortical visual motion processing. Rather, the asymmetry in pursuit may be a consequence of imbalances in the two eyes’ inputs to the “downstream” areas responsible for the initiation of pursuit.
Coordinated Expression of Dopamine Receptors in Neostriatal Medium Spiny Neurons
Authors: Surmeier D. James , Song Wen-Jie , Yan Zhen
Published: April 2018

In recent years, the distribution of dopamine receptor subtypes among the principal neurons of the neostriatum has been the subject of debate. Conventional anatomical and physiological approaches have yielded starkly different estimates of the extent to which D1and D2class dopamine receptors are colocalized. One plausible explanation for the discrepancy is that some dopamine receptors are present in physiologically significant numbers, but the mRNA for these receptors is not detectable with conventional techniques. To test this hypothesis, we examined the expression of DA receptors in individual neostriatal neurons by patch-clamp and RT-PCR techniques. Because of the strong correlation between peptide expression and projection site, medium spiny neurons were divided into three groups on the basis of expression of mRNA for enkephalin (ENK) and substance P (SP). Neurons expressing detectable levels of SP but not ENK had abundant mRNA for the D1areceptor. A subset of these cells (∼50%) coexpressed D3or D4receptor mRNA. Neurons expressing detectable levels of ENK but not SP had abundant mRNA for D2receptor isoforms (short and long). A subset (10–25%) of these neurons coexpressed D1aor D1bmRNAs. Neurons coexpressing ENK and SP mRNAs consistently coexpressed D1aand D2mRNAs in relatively high abundance. Functional analysis of neurons expressing lower abundance mRNAs revealed clear physiological consequences that could be attributed to these receptors. These results suggest that, although colocalization of D1aand D2receptors is limited, functional D1and D2class receptors are colocalized in nearly one-half of all medium spiny projection neurons.
Suppression of Noxious Stimulus-Evoked Activity in the Ventral Posterolateral Nucleus of the Thalamus by a Cannabinoid Agonist: Correlation between Electrophysiological and Antinociceptive Effects
Authors: Martin William J. , Hohmann Andrea G. , Walker J. Michael
Published: April 2018

The CNS contains a putative cannabinergic neurotransmitter and an abundance of G-protein-coupled cannabinoid receptors. However, little is known about the function of this novel neurochemical system. Cannabinoid agonists produce antinociception in behavioral tests, suggesting the possibility that this system serves in part to modulate pain sensitivity. To explore this possibility, the effects of the cannabinoid agonist WIN 55,212-2 on nociceptive neurons in the ventroposterolateral (VPL) nucleus of the thalamus were examined in urethane-anesthetized rats. After identification of a nociresponsive neuron, a computer-controlled device delivered graded pressure stimuli to the contralateral hindpaw. WIN 55,212-2 (0.0625, 0.125, and 0.25 mg/kg, i.v.) suppressed noxious stimulus-evoked activity of VPL neurons in a dose-dependent and reversible manner. Noxious stimulus-evoked firing was affected more than spontaneous firing. These effects were apparently mediated by cannabinoid receptors, because the cannabinoid receptor-inactive enantiomer of the drug (WIN 55,212–3, 0.25 mg/kg) failed to alter the activity of this population of cells. Administration of morphine (0.5 mg/kg, i.v.) produced effects that were very similar to those produced by the cannabinoid. WIN 55,212-2 (0.25 mg/kg, i.v.) failed to alter the responses of non-nociceptive low-threshold mechanosensitive neurons in the VPL. WIN 55,212-2 produced antinociceptive effects with a potency and time course similar to that observed in the electrophysiological experiments, despite the differences in the anesthetic states of the animals used in these experiments. The antinociceptive and electrophysiological effects on VPL neurons outlasted the motor effects of the drug. Furthermore, the changes in nociceptive responding could not be attributed to changes in skin temperature. Taken together, these findings suggest that cannabinoids decrease nociceptive neurotransmission at the level of the thalamus and that one function of endogenous cannabinoids may be to modulate pain sensitivity.
STEP61: A Member of a Family of Brain-Enriched PTPs Is Localized to the Endoplasmic Reticulum
Authors: Bult Abel , Zhao Feisha , Dirkx Jr. Ronald , Sharma Ela , Lukacsi Erika , Solimena Michele , Naegele Janice R. , Lombroso Paul J.
Published: April 2018

The STEP family of protein tyrosine phosphatases is highly enriched within the CNS. Members of this family are alternatively spliced to produce both transmembrane and cytosolic variants. This manuscript describes the distinctive intracellular distribution and enzymatic activity of the membrane-associated isoform STEP61. Transfection experiments in fibroblasts, as well as subcellular fractionations, sucrose density gradients, immunocytochemical labeling, and electron microscopy in brain tissue, show that STEP61is an intrinsic membrane protein of striatal neurons and is associated with the endoplasmic reticulum. In addition, structural analysis of the novel N-terminal region of STEP61reveals several motifs not present in the cytosolic variant STEP46. These include two putative transmembrane domains, two sequences rich in Pro, Glu, Asp, Ser, and Thr (PEST sequences), and two polyproline-rich domains. Like STEP46, STEP61is enriched in the brain, but the recombinant protein has less enzymatic activity than STEP46. Because STEP46is contained in its entirety within STEP61and differs only in the extended N terminus of STEP61, this amino acid sequence is responsible for the association of STEP61with membrane compartments and may also regulate its enzymatic activity.
Thyroid Hormone-Responsive Genes in Developing Cerebellum Include a Novel Synaptotagmin and ahairlessHomolog
Authors: Thompson Catherine C.
Published: April 2018

Proper development of the mammalian CNS requires sufficient thyroid hormone; thyroid hormone deficiency during a brief perinatal period produces severe neurological defects in humans and experimental animals. Thyroid hormone exerts its effects through nuclear receptors, which modulate the transcription of downstream genes in response to hormone binding. Surprisingly, few genes that are regulated by thyroid hormone receptors in the CNS have been described. Here, I report the isolation and characterization of genes that are expressed in response to thyroid hormone in developing rat brain. One such gene (Srg1) encodes a novel protein related to synaptotagmin, a protein involved in regulating neurotransmitter release; another (hr) encodes a putative zinc finger protein related to the product of a recently identified mouse gene,hairless. BothSrg1andhrare induced rapidly (<4 hr), suggesting that they are regulated directly by thyroid hormone. The temporal and spatial expression of bothSrg1andhris characteristic of genes important to nervous system development.Srg1andhrare likely part of a cascade of gene activation induced by thyroid hormone that is critical for CNS organization and development.
Human α4β2 Neuronal Nicotinic Acetylcholine Receptor in HEK 293 Cells: A Patch-Clamp Study
Authors: Buisson Bruno , Gopalakrishnan Murali , Arneric Stephen P. , Sullivan James P. , Bertrand Daniel
Published: April 2018

The cloning and expression of genes encoding for the human neuronal nicotinic acetylcholine receptors (nAChRs) has opened new possibilities for investigating their physiological and pharmacological properties. Cells (HEK 293) stably transfected with two of the major brain subunits, α4 and β2, were characterized electrophysiologically using the patch-clamp technique. Fast application of the natural ligand ACh can evoke currents up to 3500 pA, with an apparent affinity (EC50) of 3 μmand a Hill coefficient of 1.2. The rank order of potency of four nAChR ligands to activate human α4β2 receptors is (−)-nicotine > ACh > (−)-cytisine > ABT-418. At saturating concentrations, the efficacy of these ligands is ABT-418 ≫ (−)-nicotine > ACh ≫ (−)-cytisine > GTS-21 (previously named DMXB). Coapplication of 1 μmACh with known nAChR inhibitors such as dihydro-β-erythroidine and methyllycaconitine reversibly reduces the current evoked by the agonist with respective IC50values of 80 nmand 1.5 μm. The current–voltage relationship of human α4β2 displays a strong rectification at positive potentials. Experiments of ionic substitutions suggest that human α4β2 nAChRs are permeable to sodium and potassium ions. In the “outside-out” configuration, ACh evokes unitary currents (main conductance 46 pS) characterized by a very fast rundown. Potentiation of the ACh-evoked currents is observed when the extracellular calcium concentration is increased from 0.2 to 2 mm. In contrast, however, a reduction of the evoked currents is observed when calcium concentration is elevated above 2 mm.
Enhanced Cleavage of an Atypical Intron of Dopamine D3-Receptor Pre-mRNA in Chronic Schizophrenia
Authors: Schmauss Claudia
Published: April 2018

The D2-class of dopamine receptors (D2, D3, and D4) is a target for typical and atypical neuroleptic drugs. They have been considered, therefore, as factors that may contribute to the pathophysiology of psychotic disorders. Interestingly, in cortical brain tissues obtained postmortem form patients with chronic schizophrenia D3mRNA was found to be significantly lower than in the corresponding anatomic regions of controls. Because the expression of a truncated D3-like mRNA (named D3nf) appeared to be unaffected in schizophrenic brains, these findings suggest the possibility that the loss of D3mRNA results from an abnormal splicing of D3pre-mRNA in schizophrenia that is accompanied by an increased accumulation of the truncated D3nfmRNA. To test this, three approaches were taken. (1) Substrate D3pre-mRNA was splicedin vitroin HeLa nuclear extracts. Results from these experiments show that D3nfmRNA results from the alternative removal of a short spliceosomal intron in D3pre-mRNA that has a noncanonical 3′ splice site. (2) Substrate D3pre-mRNA was splicedin vivoin stably transfected rat GH3 cells. Despite the atypical 3′ cleavage that is necessary to generate D3nfmRNA, D3and D3nfmRNA were found to be processed at similar amounts. (3) The relative D3/D3nfsplicing efficiencies were then determined in the anterior cingulate cortex of postmortem brains obtained from controls and from patients with chronic schizophrenia. Significant differences were found between the relative levels of D3and D3nfmRNA, suggesting that an enhanced D3nf-specific splicing of D3pre-mRNA in schizophrenia leads to a decreased expression of D3mRNA.
Monoclonal Antibody O10 Defines a Conformationally Sensitive Cell-Surface Epitope of Proteolipid Protein (PLP): Evidence that PLP Misfolding Underlies Dysmyelination in Mutant Mice
Authors: Jung Martin , Sommer Ilse , Schachner Melitta , Nave Klaus-Armin
Published: April 2018

Mutations in the gene for proteolipid protein (PLP) have been associated with CNS dysmyelination and abnormal oligodendrocyte death in spontaneous mouse mutants and in Pelizaeus-Merzbacher disease; however, the effect of mutations on PLP structure and function are little understood. We have identified a monoclonal antibody directed against a novel cell surface epitope of PLP, termed O10. By immunofluorescence analysis, COS-7 cells transiently transfected to express PLP (or its isoform DM20) can be stained with antibody O10 and another antibody (A431) directed against the C terminus of PLP/DM20. The subcellular distribution of immunofluorescence labels for the two antibodies is not identical, suggesting that the O10 epitope is acquired post-translationally. When PLP/DM20 fromjimpy, jimpymsd, andrumpshakermutant mice is expressed in COS-7 cells and compared with wild-type PLP/DM20, none of the mutant isoforms displays the O10 epitope, whereas the C-terminal epitope is detected. Because the O10 but not the A431 epitope is also sensitive to SDS and reducing agents, this strongly suggests abnormal protein folding in the PLP mutants. PLP fromjimpymsdmice is obviously misfolded, because the amino acid substitution (Ala242→ Val) is located within a transmembrane domain to which the O10 antibody does not bind. We propose that the O10 epitope emerges as the full length protein reaches a functional tertiary structure and that the absence of this epitope marks a structural defect of PLP that leads to dysmyelination.
Cell Type-Specific Sorting of Neuropeptides: A Mechanism to Modulate Peptide Composition of Large Dense-Core Vesicles
Authors: Klumperman Judith , Spijker Sabine , van Minnen Jan , Sharp-Baker Hilary , Smit August B. , Geraerts Wijnand P. M.
Published: April 2018

The CNS ofLymnaea stagnaliscontains two populations of egg-laying hormone (ELH)-producing neurons that differ in size and topology. In type I neurons, all peptides located C-terminally from the cleavage site Arg-Ser-Arg-Arg180–183are sorted into secretory large dense-core vesicles (LDCV), whereas N-terminal-located peptides accumulate in a distinct type of vesicle, the large electrondense granule (LEG). Via immunoelectron microscopy, we now show that the second population of ELH-producing neurons, type II neurons, lack LEG and incorporate all proELH-derived peptides into LDCV. This finding provides the first example of a cell type-specific sorting of neuropeptides into LDCV. Furthermore, we provide evidence that LEG are formed through a differential condensation process in thetrans-Golgi network and that these bodies are ultimately degraded. Analysis of the endoprotease composition of the two types of proELH-producing neurons suggests that the formation of LEG, and consequently the retention of N-terminal peptides from the secretory pathway, requires the action of a furin-like protein.
Origin of Oligodendrocytes within the Human Spinal Cord
Authors: Hajihosseini Mohammad , Tham To Nam , Dubois-Dalcq Monique
Published: April 2018

To determine the time and site of origin of the oligodendrocyte lineage in the developing human spinal cord, we have examined tissues from 45 to 83 d postconception (dpc) using sets of probes and antibodies recognizing oligodendrocyte-specific glycolipids, transcripts, and proteins. We found that two clusters of oligodendrocyte precursors appear on or before 45 dpc on each side of the cord ventral ependyma above the floor plate. These precursors express glycolipids recognized by the O4 and Rmab antibodies, platelet-derived growth factor α-receptor, myelin basic protein (MBP), and 2′, 3′-cyclic nucleotide 3′ phosphodiesterase as well as MBP and proteolipid transcripts. Expression of the morphogen sonic hedgehog was detected in the floor plate at 45 dpc and decreased at 58 dpc. During this period, oligodendrocyte precursors emerged in the ventral and lateral region of the forming white matter, a process occurring first in cervical and later in lumbar cord. The majority of O4+cells express the proliferating cell nuclear antigen (PCNA), and their pattern of dispersion suggests that these cells progressively populate the lateral and dorsal cord regions. Oligodendrocytes expressing galactocerebroside appeared at 53 dpc and did not express PCNA. Oligodendrocyte precursors were detected in dorsal cord regions at 74 dpc and at 83 dpc when myelination started in the ventral roots. Thus, oligodendrocyte precursors expressing myelin transcripts and proteins emerge in the ventral region of the embryonic cord several weeks before myelination.
Chondroitin Sulfate Proteoglycan and Tenascin in the Wounded Adult Mouse NeostriatumIn Vitro: Dopamine Neuron Attachment and Process Outgrowth
Authors: Gates Monte A. , Fillmore Helen , Steindler Dennis A.
Published: April 2018

Extracellular matrix (ECM) molecules, including chondroitin-4 or chondroitin-6 sulfate proteoglycans (CSPGs) and tenascin, are upregulated in and around wounds and transplants to the adult CNS. In the present study, striatal wounds from adult mice were used in a novelin vitroparadigm to assess the effects of these wound-associated molecules on embryonic dopamine cell attachment and neurite outgrowth. Light and electron microscopic immunocytochemistry studies have shown that astroglial scar constituents persist in cultured explants for at least 1 weekin vitro, and despite the loss of neurons from adult striatal explants, there is a retention of certain structural features suggesting that the wound explant–neuron coplant is a viable model for analysis of graft–scar interactions. Explants from the wounded striatum taken at different times after a penetrating injuryin vivowere used as substrates for embryonic ventral mesencephalon neurons that were plated on their surfaces. Dopamine cell attachment is increased significantly in relation to the expression of both CSPG and tenascin. The increase in neuronal attachment in this paradigm, however, is accompanied by a postlesion survival time-dependent significant decrease in neuritic growth from these cells.In vitroECM antibody treatment suggests that CSPG may be responsible for heightened dopamine cell attachment and that tenascin simultaneously may support cell attachment while inhibiting neurite growth. The present study offers a new approach for thein vitroanalysis of cell and molecular interactions after brain injury and brain grafting, in essence acting as a nigrostriatal transplant-in-a-dish.
Release of Peptide Cotransmitters inAplysia: Regulation and Functional Implications
Authors: Vilim F. S. , Cropper E. C. , Price D. A. , Kupfermann I. , Weiss K. R.
Published: April 2018

To gain insights into the physiological role of cotransmission, we measured peptide release from cell B15, a motorneuron that utilizes ACh as its primary transmitter but also contains putative peptide cotransmitters, the small cardioactive peptides (SCPs) and the buccalins (BUCs). All stimulation parameters used were in the range in which B15 fires in freely moving animals. We stimulated neuron B15 in bursts and systematically varied the interburst interval, the intraburst frequency, and burst duration. Both peptides were preferentially released when B15 was stimulated at higher intra- or interburst frequencies or with longer burst durations. Across stimulation patterns, the amount of peptide released depended on the mean frequency of stimulation and was independent of the specific pattern of stimulation. The parameters of stimulation that produce a larger release of peptides correspond to those that evoke larger contractions. Large and frequent contractions are likely to fuse or summate, thus disrupting the rhythmic behavior mediated by the muscle innervated by motorneuron B15. Because the combined effect of the SCPs and BUCs is to accelerate the relaxation and shorten the duration of muscle contractions, these peptides reduce the probability of the disruptive fusion or summation of muscle contractions. Because these cotransmitters regulate an aspect of muscle contractions that is not controlled by acetylcholine (ACh), the primary transmitter of B15, we suggest that peptides and ACh form parallel but functionally distinct lines of transmission at the neuromuscular junction. Both types of transmission may be necessary to ensure that behavior remains efficient over a wide range of conditions.
Central Administration of a Growth Hormone (GH) Receptor mRNA Antisense Increases GH Pulsatility and Decreases Hypothalamic Somatostatin Expression in Rats
Authors: Pellegrini Elisabeth , Bluet-Pajot Marie Thérèse , Mounier Françoise , Bennett Pamela , Kordon Claude , Epelbaum Jacques
Published: April 2018

To test the hypothesis of the involvement of centrally expressed rat growth hormone receptors (rGH-R) in the ultradian rhythmicity of pituitary GH secretion, adult male rats were submitted to a 60 hr intracerebroventricular infusion of an antisense (AS) oligodeoxynucleotide (ODN) complementary to the sequence of rGH-R mRNA. Eight hour (10 A.M.–6 P.M.) GH secretory profiles, obtained from freely moving male rats infused with 2.0 nmol/hr of rGH-R AS, revealed a marked increase in GH peak amplitude (150 ± 12 vs 101 ± 10 ng/ml), trough levels (16.2 ± 3.0 vs 5.4 ± 1.4 ng/ml), and number of peaks (2.9 ± 0.3 vs 1.8 ± 0.2). No change was observed in rats treated with an ODN complementary to the prolactin receptor mRNA sequence (2.0 nmol/hr). Infusion of increasing ODN concentrations resulted in a dose-dependent stimulation of GH release. In parallel, somatogenic binding sites in the choroid plexus were decreased by 40%, and levels of rGH-R mRNA were increased in the periventricular nucleus (PeV) but unchanged in the arcuate nucleus (ARC). Levels of somatostatin mRNA, in the PeV but not in the ARC, were lowered by the treatment. Levels of GH-releasing hormone mRNA in the ARC were not affected. These data suggest that GH negative feedback results from a direct effect on central GH receptors and a subsequent activation of hypophysiotropic somatostatin neurons located in the anterior periventricular hypothalamus.
Behavior-Relevant Changes in Nucleus Accumbens Dopamine Transmission Elicited by Food Reinforcement: An Electrochemical Study in Rat
Authors: Richardson Nicole R. , Gratton Alain
Published: April 2018

Voltammetry was used to monitor dopamine (DA) transmission in nucleus accumbens (NAcc) of rats lever-pressing for food. Under standard conditions, animals responded on a fixed ratio 1 (FR1) schedule for 0.2 ml of milk delivered over 30 sec; milk delivery was paired with a 30 sec cue light. Consumption of the initial few milk rewards of the session caused DA signal increases. These initial signal increases were typical of the first and, at times, the second test days. On subsequent days, the most pronounced initial signal increases coincided with presentation of conditioned stimuli that marked the start of the session. Biphasic changes in DA signal that were time-locked to each reinforced lever-press were also observed; responses were preceded by increases and were followed, during milk consumption, by decreases in DA signal. At the end of milk delivery, the signal increased again in apparent anticipation of the next lever-press. Delaying milk delivery caused a corresponding delay in DA signal decreases, and the amount of time signals remained depressed was bound by the duration of milk consumption. Greater decreases in DA signal were observed when the rate of milk delivery was doubled or tripled, and such increases in reward value were associated with more pronounced signal increases during the period that preceded each lever-press. In contrast, DA signal increases were seen when milk was delivered at half the usual rate or was withheld altogether or when animals were denied access to the lever. Under partial reinforcement conditions, reinforced lever-presses were preceded by more pronounced signal increases and decreases of comparable magnitude accompanied milk consumption. These results suggest that meso-NAcc DA neurons are activated primarily in response to the incentive rather than to the reinforcing properties of rewards.
Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele
Authors: Arendt Thomas , Schindler Cornelia , Brückner Martina K. , Eschrich Klaus , Bigl Volker , Zedlick Dyrk , Marcova Lena
Published: April 2018

A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer’s disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system.

In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer’s disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE ε4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE ε4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE ε4 allele was very weak in the presence of one ε4 allele and completely lost in patients homozygous for the ε4 allele.

The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer’s disease carrying the apoE ε4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.
An Extracellular Proteolytic Cascade Promotes Neuronal Degeneration in the Mouse Hippocampus
Authors: Tsirka Stella E. , Rogove Andrew D. , Bugge Thomas H. , Degen Jay L. , Strickland Sidney
Published: April 2018

Mice lacking the serine protease tissue plasminogen activator (tPA) are resistant to excitotoxin-mediated hippocampal neuronal degeneration. We have used genetic and cellular analyses to study the role of tPA in neuronal cell death. Mice deficient for the zymogen plasminogen, a known substrate for tPA, are also resistant to excitotoxins, implicating an extracellular proteolytic cascade in degeneration. The two known components of this cascade, tPA and plasminogen, are both synthesized in the mouse hippocampus. tPA mRNA and protein are present in neurons and microglia, whereas plasminogen mRNA and protein are found exclusively in neurons. tPA-deficient mice exhibit attenuated microglial activation as a reaction to neuronal injury. In contrast, the microglial response of plasminogen-deficient mice was comparable to that of wild-type mice, suggesting a tPA-mediated, plasminogen-independent pathway for activation of microglia. Infusion of inhibitors of the extracellular tPA/plasmin proteolytic cascade into the hippocampus protects neurons against excitotoxic injury, suggesting a novel strategy for intervening in neuronal degeneration.
Pathway-Specific Synaptic Plasticity: Activity-Dependent Enhancement and Suppression of Long-Term Heterosynaptic Facilitation at Converging Inputs on a Single Target
Authors: Schacher Samuel , Wu Fang , Sun Zhong-Yi
Published: April 2018

To explore mechanisms of long-term, pathway-specific synaptic plasticity, we examined consequences of differential stimulation ofAplysiasensorimotor connections in culture where two sensory neuron (SN) inputs converge on a single target motor cell L7. A single pairing of tetanus in one SN with bath application of 5-HT evoked long-term (24 hr) increase in efficacy of the SN connection given paired stimulation that was comparable in magnitude to the increase in synaptic efficacy evoked with repeated applications of 5-HT. Repeated pairing of tetanus in one SN with applications of 5-HT evoked a significant increase in efficacy of the SN connection given paired stimuli, and significant reduction in facilitation that is normally evoked by repeated applications of 5-HT in the unpaired SN connection. Hyperpolarization of L7 or incubation with APV interfered with both enhancement of facilitation with paired stimulation and suppression of facilitation with unpaired stimulation, but without interfering with long-term facilitation evoked either by repeated applications of 5-HT or by a single pairing. The results suggest that a single connection can undergo at least two forms of activity-dependent, pathway-specific facilitation lasting more than 24 hr. One form, evoked with a single pairing, is initiated and maintained primarily by activity in the presynaptic neuron. The other form, evoked with repeated paired stimuli, requires target-dependent activity that differentially modulates long-term heterosynaptic facilitation at the converging inputs.
Activation of Hippocampal Adenosine A3Receptors Produces a Desensitization of A1Receptor-Mediated Responses in Rat Hippocampus
Authors: Dunwiddie Thomas V. , Diao Lihong , Kim Hea O. , Jiang Ji-Long , Jacobson Kenneth A.
Published: April 2018

The adenosine A3receptor is expressed in brain, but the consequences of activation of this receptor on electrophysiological activity are unknown. We have characterized the actions of a selective adenosine A3receptor agonist, 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (Cl-IB-MECA), and a selective A3receptor antagonist, 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS 1191), in brain slices from rat hippocampus. In the CA1 region, activation of A3receptors had no direct effects on synaptically evoked excitatory responses, long-term potentiation, or synaptic facilitation. However, activation of A3receptors with Cl-IB-MECA antagonized the adenosine A1receptor-mediated inhibition of excitatory neurotransmission. The effects of Cl-IB-MECA were blocked by pretreatment with MRS 1191, which by itself had no effect on A1receptor-mediated responses. The presynaptic inhibitory effects of baclofen and carbachol, mediated via GABABand muscarinic receptors, respectively, were unaffected by Cl-IB-MECA. The maximal response to adenosine was unchanged, suggesting that the primary effect of Cl-IB-MECA was to reduce the affinity of adenosine for the receptor rather than to uncouple it. Similar effects could be demonstrated after brief superfusion with high concentrations of adenosine itself. Under normal conditions, endogenous adenosine in brain is unlikely to affect the sensitivity of A1receptors via this mechanism. However, when brain concentrations of adenosine are elevated (e.g., during hypoxia, ischemia, or seizures), activation of A3receptors and subsequent heterologous desensitization of A1receptors could occur, which might limit the cerebroprotective effects of adenosine under these conditions.
Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAAReceptor
Authors: Ueno Shinya , Bracamontes John , Zorumski Chuck , Weiss David S. , Steinbach Joe Henry
Published: April 2018

Anesthetic drugs are known to interact with GABAAreceptors, both to potentiate the effects of low concentrations of GABA and to directly gate open the ion channel in the absence of GABA; however, the site(s) involved in direct gating by these drugs is not known. We have studied the ability of alphaxalone (an anesthetic steroid) and pentobarbital (an anesthetic barbiturate) to directly activate recombinant GABAAreceptors containing the α1, β2, and γ2L subunits. Steroid gating was not affected when either of two mutated β2 subunits [β2(Y157S) and β2(Y205S)] are incorporated into the receptors, although these subunits greatly reduce the affinity of GABA binding. These observations indicate that steroid binding and subsequent channel gating do not require these particular residues, as already shown for barbiturates. Bicuculline or gabazine (two competitive antagonists of GABA binding) reduced the currents elicited by alphaxalone and pentobarbital from wild-type GABAAreceptors; however, gabazine produced only a partial block of responses to pentobarbital or alphaxalone, and bicuculline only partially blocked responses to pentobarbital. These observations indicate that the blockers do not compete with alphaxalone or pentobarbital for a single class of sites on the GABAAreceptor. Finally, at receptors containing α1β2(Y157S)γ2L subunits, both bicuculline and gabazine showed weak agonist activity and actually potentiated responses to alphaxalone. These observations indicate that the blocking drugs can produce allosteric changes in GABAAreceptors, at least those containing this mutated β2 subunit. We conclude that the sites for binding steroids and barbiturates do not overlap with the GABA-binding site. Furthermore, neither gabazine nor bicuculline competes for binding at the steroid or barbiturate sites. The data are consistent with a model in which both gabazine and bicuculline act as allosteric inhibitors of channel opening for the GABAAreceptor after binding to the GABA-binding site.
The Type 1 Inositol 1,4,5-Trisphosphate Receptor Gene Is Altered in theopisthotonosMouse
Authors: Street Valerie A. , Bosma Martha M. , Demas Vasiliki P. , Regan Melissa R. , Lin Doras D. , Robinson Linda C. , Agnew William S. , Tempel Bruce L
Published: April 2018

Theopisthotonos(opt) mutation arose spontaneously in a C57BL/Ks-db2Jcolony and is the only known, naturally occurring allele ofopt. This mutant mouse was first identified based on its ataxic and convulsive phenotype. Genetic and molecular data presented here demonstrate that the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) protein, which serves as an IP3-gated channel to release calcium from intracellular stores, is altered in theoptmutant. A genomic deletion in the IP3R1 gene removes two exons from the IP3R1 mRNA but does not interrupt the translational reading frame. The altered protein is predicted to have lost several modulatory sites and is present at markedly reduced levels inopthomozygotes. Nonetheless, a strong calcium release from intracellular stores can be elicited in cerebellar Purkinje neurons treated with the metabotropic glutamate receptor (mGluR) agonist quisqualate (QA). QA activates Group I mGluRs linked to GTP-binding proteins that stimulate phospholipase C and subsequent production of the intracellular messenger IP3, leading to calcium mobilization via the IP3R1 protein. The calcium response inopthomozygotes shows less attenuation to repeated QA application than in control littermates. These data suggest that the convulsions and ataxia observed inoptmice may be caused by the physiological dysregulation of a functional IP3R1 protein.
Coupling of Muscarinic Cholinergic Receptors and cGMP in Nocturnal Regulation of the Suprachiasmatic Circadian Clock
Authors: Liu Chen , Ding Jian M. , Faiman Lia E. , Gillette Martha U.
Published: April 2018

Acetylcholine has long been implicated in nocturnal phase adjustment of circadian rhythms, yet the subject remains controversial. Although the suprachiasmatic nucleus (SCN), site of the circadian clock, contains no intrinsic cholinergic somata, it receives choline acetyltransferase-immunopositive projections from basal forebrain and mesopontine tegmental nuclei that contribute to sleep and wakefulness. We have demonstrated that the SCN of inbred rats in a hypothalamic brain slice is sensitive to cholinergic phase adjustment via muscarinic receptors (mAChRs) only at night. We used this paradigm to probe the muscarinic signal transduction mechanism and the site(s) gating nocturnal responsiveness. The cholinergic agonist carbachol altered the circadian rhythm of SCN neuronal activity in a pattern closely resembling that for analogs of cGMP; nocturnal gating of clock sensitivity to each is preservedin vitro.Specific inhibitors of guanylyl cyclase (GC) and cGMP-dependent protein kinase (PKG), key elements in the cGMP signal transduction cascade, blocked phase shifts induced by carbachol. Further, carbachol administration to the SCN at night increased cGMP production and PKG activity. The carbachol-induced increase in cGMP was blocked both by atropine, an mAChR antagonist, and by LY83583, a GC inhibitor. We conclude that (1) mAChR regulation of the SCN is mediated via GC→cGMP→PKG, (2) nocturnal gating of this pathway is controlled by the circadian clock, and (3) a gating site is positioned downstream from cGMP. This study is among the first to identify a functional context for mAChR–cGMP coupling in the CNS.
Increased Probability of GABA Release during Withdrawal from Morphine
Authors: Bonci Antonello , Williams John T.
Published: April 2018

Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABAA-mediated synaptic transmission to dopamine projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse; however, little is known about how this GABAAsynapse is affected after chronic morphine treatment. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6–7 d with morphine. Slices containing the VTA were prepared and maintained in morphine-free solutions, and GABAAIPSCs were recorded from dopamine cells. The amplitude of evoked IPSCs and the frequency of spontaneous miniature IPSCs measured in slices from morphine-treated guinea pigs were greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, with Sp-cAMPS, caused a larger increase in IPSCs in slices from morphine-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug treatment. The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment.