bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin-Like Growth Factor-I Promotes Neurogenesis and Synaptogenesis in the Hippocampal Dentate Gyrus during Postnatal Development
Authors: O'Kusky John R. , Ye Ping , D'Ercole A. Joseph
Published: April 2018

Thein vivoactions of insulin-like growth factor-I (IGF-I) on the growth and development of the hippocampal dentate gyrus were investigated in transgenic mice that overexpress IGF-I postnatally in the brain and in normal nontransgenic littermate controls. Stereological analyses of the dentate gyrus were performed by light and electron microscopy on days 7, 14, 21, 28, 35, and 130 to determine postnatal changes in the numerical density and total number of neurons and synapses. The volumes of both the granule cell layer and the molecular layer of the dentate gyrus were significantly increased by 27–69% in transgenic mice after day 7, with the greatest relative increases occurring by day 35. Although the numerical density of neurons in the granule cell layer did not differ significantly between transgenic and control mice at any age studied, the total number of neurons was significantly greater in transgenic mice by 29–61% beginning on day 14. The total number of synapses in the molecular layer was significantly increased by 42–105% in transgenic mice from day 14 to day 130. A transient increase in the synapse-to-neuron ratio was found in transgenic mice at postnatal days 28 and 35 but not at day 130. This finding indicates a disproportionate increase in synaptogenesis, exceeding that expected for the observed increase in neuron number. Our results demonstrate that IGF-I overexpression produces persistent increases in the total number of neurons and synapses in the dentate gyrus, indicating that IGF-I promotes both neurogenesis and synaptogenesis in the developing hippocampusin vivo.
Three-Dimensional Topography of Corticopontine Projections from Rat Barrel Cortex: Correlations with Corticostriatal Organization
Authors: Leergaard Trygve B. , Alloway Kevin D. , Mutic Joshua J. , Bjaalie Jan G.
Published: April 2018

Subcortical re-entrant projection systems connecting cerebral cortical areas with the basal ganglia and cerebellum are topographically specific and therefore considered to be parallel circuits or “closed loops.” The precision of projections within these circuits, however, has not been characterized sufficiently to indicate whether cortical signals are integrated within or among presumed compartments. To address this issue, we studied the first link of the rat cortico-ponto-cerebellar pathway with anterograde axonal tracing from physiologically defined, individual whisker “barrels” of the primary somatosensory cortex (SI). The labeled axons in the pontine nuclei formed several, sharply delineated clusters. Dual tracer injections into different SI whisker barrels gave rise to partly overlapping, paired clusters, indicating somatotopic specificity. Three-dimensional reconstructions revealed that the clusters were components of concentrically organized lamellar subspaces. Whisker barrels in the same row projected to different pontine lamellae (side by side), the somatotopic representation of which followed an inside-out sequence. By contrast, whisker barrels from separate rows projected to clusters located within the same lamellar subspace (end to end). In the neostriatum, this lamellar topography was the opposite, with barrels in the same row contacting different parts of the same lamellar subspace (end to end). The degree of overlap among pontine clusters varied as a function of the proximity of the cortical injections. Furthermore, corticopontine overlap was higher among projections from barrels in the same row than among projections from different whisker barrel rows. This anisotropy was the same in the corticostriatal projection. These findings have important implications for understanding convergence and local integration in somatosensory-related subcortical circuits.
Protein Synthesis Inhibition Blocks the Induction of Mossy Fiber Long-Term PotentiationIn Vivo
Authors: Barea-Rodrı́guez Edwin J. , Rivera Domingo T. , Jaffe David B. , Martinez Joe L.
Published: April 2018

Protein synthesis inhibitors block the maintenance of NMDA receptor-dependent long-term potentiation (LTP) bothin vivoandin vitro. Protein synthesis inhibitors block mossy fiber(MF) LTP maintenancein vitro, but little is known about the effect of protein synthesis inhibitors on either induction or maintenance in MF-LTPin vivo. Here we study the role of protein synthesis in the induction of long-term potentiation at the mossy fiber–CA3 hippocampal synapsein vivoin anesthetized rats. The protein synthesis inhibitor anisomycin was administered at different doses (0.04, 10, or 40 nmol) into area CA3 15 min before delivering high-frequency stimulation (two times at 100 Hz, 1 sec). Anisomycin blocked MF-LTP induction in a dose-dependent manner; both 40 and 10 nmol blocked MF-LTP induction, but a lower dose of 0.04 nmol was without effect. The inhibitory effect of anisomycin on protein synthesis was determined by measuring the incorporation of [35S]methionine into the newly synthesized proteins. Percentages of protein synthesis inhibition were determined by comparing [35S] incorporation of anisomycin-treated samples with vehicle controls. Doses of 0.04, 10, or 40 nmol of anisomycin produced 21, 82, or 83% inhibition of [35S]methionine incorporation, respectively. The effect of anisomycin was verified using a single dose of the protein synthesis inhibitor cycloheximide (40 nmol). Cycloheximide also blocked MF-LTP induction. These results suggest that protein synthesis plays an important role in the induction of mossy fiber long-term potentiationin vivo.
Hypothalamic Melanin-Concentrating Hormone and Estrogen-Induced Weight Loss
Authors: Mystkowski Paul , Seeley Randy J. , Hahn Tina M. , Baskin Denis G. , Havel Peter J. , Matsumoto Alvin M. , Wilkinson Charles W. , Peacock-Kinzig Kimberly , Blake Kathleen A. , Schwartz Michael W.
Published: April 2018

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.
D2Dopamine Receptors in Striatal Medium Spiny Neurons Reduce L-Type Ca2+Currents and Excitability via a Novel PLCβ1–IP3–Calcineurin-Signaling Cascade
Authors: Hernández-López Salvador , Tkatch Tatiana , Perez-Garci Enrique , Galarraga Elvira , Bargas José , Hamm Heidi , Surmeier D. James
Published: April 2018

In spite of the recognition that striatal D2receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D2receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca2+currents through L-type Ca2+channels, resulting in diminished excitability. This modulation is mediated by Gβγactivation of phospholipase C, mobilization of intracellular Ca2+stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D2receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.
Ionic Currents and Spontaneous Firing in Neurons Isolated from the Cerebellar Nuclei
Authors: Raman Indira M. , Gustafson Amy E. , Padgett Daniel
Published: April 2018

Neurons of the cerebellar nuclei fire spontaneous action potentials bothin vitro, with synaptic transmission blocked, andin vivo, in resting animals, despite ongoing inhibition from spontaneously active Purkinje neurons. We have studied the intrinsic currents of cerebellar nuclear neurons isolated from the mouse, with an interest in understanding how these currents generate spontaneous activity in the absence of synaptic input as well as how they allow firing to continue during basal levels of inhibition. Current-clamped isolated neurons fired regularly (∼20 Hz), with shallow interspike hyperpolarizations (approximately −60 mV), much like neurons in more intact preparations. The spontaneous firing frequency lay in the middle of the dynamic range of the neurons and could be modulated up or down with small current injections.

During step or action potential waveform voltage-clamp commands, the primary current active at interspike potentials was a tetrodotoxin-insensitive (TTX), cesium-insensitive, voltage-independent, cationic flux carried mainly by sodium ions. Although small, this cation current could depolarize neurons above threshold voltages. Voltage- and current-clamp recordings suggested a high level of inactivation of the TTX-sensitive transient sodium currents that supported action potentials. Blocking calcium currents terminated firing by preventing repolarization to normal interspike potentials, suggesting a significant role for K(Ca) currents. Potassium currents that flowed during action potential waveform voltage commands had high activation thresholds and were sensitive to 1 mmTEA. We propose that, after the decay of high-threshold potassium currents, the tonic cation current contributes strongly to the depolarization of neurons above threshold, thus maintaining the cycle of firing.
Discharge Profiles of Juxtacellularly Labeled and Immunohistochemically Identified GABAergic Basal Forebrain Neurons Recorded in Association with the Electroencephalogram in Anesthetized Rats
Authors: Manns Ian D. , Alonso Angel , Jones Barbara E.
Published: April 2018

The basal forebrain ostensibly plays a dual role in the modulation of cortical activation and behavioral state. It is essential for stimulating cortical activation in association with waking (and paradoxical sleep), yet also important for attenuating cortical activation and promoting slow wave sleep. Using juxtacellular recording and labeling of neurons with Neurobiotin followed by immunohistochemical staining for glutamic acid decarboxylase (GAD), we studied the discharge properties of identified GABAergic basal forebrain neurons in relation to electroencephalographic (EEG) activity in urethane-anesthetized rats to determine the part or parts that they may play in this dual role.

The GABAergic neurons displayed distinct discharge profiles in relation to somatosensory stimulation-evoked cortical activation. Whereas a significant minority increased its average discharge rate, the majority decreased its average discharge rate in association with cortical activation. Moreover, subgroups displayed distinct discharge patterns related to different cortical activities, including very regular high-frequency tonic spiking within a gamma EEG frequency range and rhythmic cluster spiking within a theta-like frequency range during cortical activation. During irregular slow EEG activity in absence of stimulation, one subgroup displayed spike bursts correlated with cortical slow oscillations. As relatively large in size and also antidromically activated from the cortex, many GABAergic neurons recorded were considered to be cortically projecting and thus capable of directly modulating cortical activity. Subgroups of GABAergic basal forebrain neurons would thus have the capacity to promote cortical activation by modulating gamma or theta activity and others to attenuate cortical activation by modulating irregular slow oscillations that normally occur during slow wave sleep.
Role of Voltage-Dependent Calcium Channel Long-Term Potentiation (LTP) and NMDA LTP in Spatial Memory
Authors: Borroni Albert M. , Fichtenholtz Harlan , Woodside Brian L. , Teyler Timothy J.
Published: April 2018

This experiment explores the role of two forms of long-term potentiation (LTP) in behavioral memory. NMDA and/or voltage-dependent calcium channels (VDCCs) were antagonized pharmacologically at levels that block nmdaLTP and vdccLTP, respectively, in rats learning an eight-arm radial maze task. Animals were trained twice a day for 11 d under the systemic influence of MK-801, verapamil, both drugs, or saline. During acquisition, the mixed drug group displayed significantly more working memory errors and reference memory errors than all other groups. The mixed drug group was markedly impaired on the first daily trial but improved dramatically on their second daily trial. After a 7 d delay, saline and MK-801 animals maintained their predelay level of performance. The performance of the verapamil groups declined significantly over the delay. These results demonstrate that: (1) vdccLTP is necessary for the retention of information over a 7 d period, (2) the blockade of both forms of LTP prevents the retention of information over a 21 hr period, and (3) blockade of both forms of LTP does not prevent the storing of information over a short period of time (3 hr).
Neuroplastic Changes Related to Pain Occur at Multiple Levels of the Human Somatosensory System: A Somatosensory-Evoked Potentials Study in Patients with Cervical Radicular Pain
Authors: Tinazzi Michele , Fiaschi Antonio , Rosso Tiziana , Faccioli Franco , Grosslercher Johannes , Aglioti Salvatore M.
Published: April 2018

Studies suggest that pain may play a major role in determining cortical rearrangements in the adult human somatosensory system. Most studies, however, have been performed under conditions whereby pain coexists with massive deafferentation (e.g., amputations). Moreover, no information is available on whether spinal and brainstem changes contribute to pain-related reorganizational processes in humans. Here we assess the relationships between pain and plasticity by recording somatosensory-evoked potentials (SEPs) in patients who complained of pain to the right thumb after a right cervical monoradiculopathy caused by compression of the sixth cervical root, but did not present with clinical or neurophysiological signs of deafferentation. Subcortical and cortical potentials evoked by stimulation of digital nerves of the right thumb and middle finger were compared with those obtained after stimulation of the left thumb and middle finger and with those obtained in a control group tested in comparable conditions. Amplitudes of spinal N13, brainstem P14, parietal N20 and P27, and frontal N30 potentials after stimulation of the painful right thumb were greater than those of the nonpainful left thumb and showed a positive correlation with magnitude of pain. This right–left asymmetry was absent after stimulation of the patients' middle fingers and in control subjects. Results suggest that chronic cervical radicular pain is associated with changes in neural activity at multiple levels of the somatosensory system. The absence of correlation between the amplitude of spinal, brainstem, and cortical components of SEPs suggests that enhancement of cortical activity is not a simple amplification of subcortical enhancement.
Aggressive Behavior, Increased Accumbal Dopamine, and Decreased Cortical Serotonin in Rats
Authors: van Erp Annemoon M. M. , Miczek Klaus A.
Published: April 2018

Dopamine (DA) and serotonin have been implicated in the regulation of aggressive behavior, but it has remained challenging to assess the dynamic changes in these neurotransmitters while aggressive behavior is in progress. The objective of this study was to learn about ongoing monoamine activity in corticolimbic areas during aggressive confrontations in rats. Male Long–Evans rats were implanted with a microdialysis probe aimed at the nucleus accumbens (NAC) or medial prefrontal cortex (PFC); next, 10 min samples were collected before, during, and after a 10 min confrontation. Rats continued to display aggressive behavior while being sampled, and they performed two to six attack bites as well as 140 sec of aggressive acts and postures. Dopamine levels in NAC were significantly increased up to 60 min after the confrontation. Peak levels of 140% were achieved ∼20–30 min after the confrontation. No concurrent changes in accumbal serotonin levels were seen during or after the confrontation. Dopamine and serotonin levels in PFC changed in the opposite direction, with a sustained decrease in serotonin to 80% of baseline levels during and after the confrontation and an increase in dopamine to 120% after the confrontation. The temporal pattern of monoamine changes, which followed rather than preceded the confrontation, points to a significant role of accumbal and cortical DA and 5-hydroxytryptamine in the consequences as opposed to the triggering of aggressive acts. The increase in accumbal DA in aggressive animals supports the hypothesis that this neural system is linked to the execution of biologically salient and demanding behavior.
κ-Opioid Receptor Activation Modifies Dopamine Uptake in the Nucleus Accumbens and Opposes the Effects of Cocaine
Authors: Thompson Alexis C. , Zapata Agustin , Justice Joseph B. , Vaughan Roxanne A. , Sharpe Lawrence G. , Shippenberg Toni S.
Published: April 2018

Coadministration of κ-opioid receptor agonists (κ-agonists) with cocaine prevents alterations in dialysate dopamine (DA) concentration in the nucleus accumbens (Acb) that occur during abstinence from repeated cocaine treatment. Quantitative microdialysis was used to determine the mechanism producing these effects. Rats were injected with cocaine (20 mg/kg, i.p.), or saline, and the selective κ-agonist U-69593 (0.32 mg/kg, s.c.), or vehicle, once daily for 5 d. Extracellular DA concentration (DAext) and extraction fraction (Ed), an indirect measure of DA uptake, were determined 3 d later. Repeated cocaine treatment increasedEd, whereas repeated U-69593 treatment decreasedEd, relative to controls. Coadministration of both drugs yielded intermediateEdvalues not different from controls.In vitroDA uptake assays confirmed that repeated U-69593 treatment produces a dose-related, region-specific decrease in DA uptake and showed that acute U-69593 administration increases DA uptake in a nor-binaltorphimine reversible manner. Repeated U-69593 also led to a decrease in [125I]RTI-55 binding to the DA transporter (DAT), but did not decrease total DAT protein. These results demonstrate that κ-opioid receptor activation modulates DA uptake in the Acb in a manner opposite to that of cocaine: repeated U-69593 administration decreases the basal rate of DA uptake, and acute U-69593 administration transiently increases DA uptake. κ-agonist treatment also alters DAT function. The action of κ-agonists on DA uptake or DAT binding, or both, may be the mechanism(s) mediating the previously reported “cocaine-antagonist” effect of κ-opioid receptor agonists.
Physiological Patterns of Electrical Stimulation Can Induce Neuronal Gene Expression by Activating N-Type Calcium Channels
Authors: Brosenitsch Teresa A. , Katz David M.
Published: April 2018

Activity-dependent neuronal gene expression is thought to require activation of L-type calcium channels, a view based primarily on studies in which chronic potassium (K+) depolarization was used to mimic neuronal activity. However, N-type calcium channels are primarily inactivated during chronic depolarization, and their potential contribution to gene expression induced by physiological patterns of stimulation has not been defined. In the present study, electrical stimulation of dissociated primary sensory neurons at 5 Hz, or treatment with elevated K+, produced a large increase in the percentage of neurons that express tyrosine hydroxylase (TH) mRNA and protein. However, blockade of L-type channels, which completely inhibited K+-induced expression, had no effect on TH expression induced by patterned stimulation. Conversely, blockade of N-type channels completely inhibited TH induction by patterned stimulation, whereas K+-induced expression was unaffected. Similar results were obtained for depolarization-induced expression of the immediate early genesNurr1andNur77. In addition, TH induction by patterned stimulation was significantly reduced by inhibitors of PKA and PKC but was unaffected by inhibition of the mitogen-activated protein kinase (MAPK) pathway. On the other hand, K+-induced TH expression was significantly reduced by inhibition of the MAPK pathway but was unaffected by inhibitors of PKA or PKC. These results demonstrate that N-type calcium channels can directly link phasic membrane depolarization to gene expression, challenging the view that activation of L-type channels is required for nuclear responses to physiological patterns of activity. Moreover, our data show that phasic and chronic depolarizing stimuli act through distinct mechanisms to induce neuronal gene expression.
Differential Mechanisms of Neuroprotection by 17 β-Estradiol in Apoptotic versus Necrotic Neurodegeneration
Authors: Harms Christoph , Lautenschlager Marion , Bergk Alexandra , Katchanov Juri , Freyer Dorette , Kapinya Krisztian , Herwig Ulrike , Megow Dirk , Dirnagl Ulrich , Weber Joerg R. , Hörtnagl Heide
Published: April 2018

The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 β-estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in necrotic neuronal cell death in primary neuronal cultures derived from rat hippocampus, septum, or cortex. Neuronal apoptosis was induced either by staurosporine or ethylcholine aziridinium (AF64A), as models for necrotic cell death glutamate exposure or oxygen–glucose deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 μm17 β-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 μm) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI 182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. In glutamate and OGD-induced neuronal damage, long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 β-estradiol in the dose range of 0.5–1.0 μmsignificantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or short-term pretreatment. The strong expression of the estrogen receptor-α and the modulation of Bcl proteins by 17 β-estradiol in hippocampal and septal but not in cortical cultures indicates that the prevention of apoptotic, but not of necrotic, neuronal cell death by 17 β-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-α.
Distinct K Currents Result in Physiologically Distinct Cell Types in the Inferior Colliculus of the Rat
Authors: Sivaramakrishnan Shobhana , Oliver Douglas L.
Published: April 2018

The inferior colliculus (IC) processes auditory information ascending from the brainstem. The response of the IC to this information and its ability to transform it is partly determined by the types of ionic currents that generate the intrinsic discharge patterns of IC neurons and their susceptibility to changes in the external environment. We have used whole-cell patch-clamp techniques on IC neurons in rat brain slices to characterize the potassium currents present and to correlate them with the firing patterns observed. Neurons in the IC can be classified into six physiologically distinct cell types. Each of these cell types has a firing pattern that is generated by a unique potassium current and set of cellular parameters. Sustained-regular cells show mainly delayed rectifier K+channels. Onset cells have a unique high-threshold tetraethylammonium-sensitive K+current. Pause–build cells have an A-current. Rebound-regular cells have calcium-dependent rebound depolarizations. Rebound-adapting cells have both an apamin-sensitive calcium-dependent K+current and a calcium-dependent rebound depolarization. Transient-rebound cells have a charybdotoxin-sensitive calcium-dependent K+current and a calcium-dependent rebound.

Our data suggest that there would be similarities as well as differences among IC neurons in their responses to excitatory or inhibitory inputs. Furthermore, some cells are likely to show little or no plasticity and behave as simple relays of temporal and intensity information, whereas others are likely to transform their inputs.
Growth and Functional Efficacy of Intrastriatal Nigral Transplants Depend on the Extent of Nigrostriatal Degeneration
Authors: Kirik Deniz , Winkler Christian , Björklund Anders
Published: April 2018

Previous studies have shown that the functional efficacy of intrastriatal transplants of fetal dopamine (DA) neurons in the rat Parkinson model depends on their ability to establish a new functional innervation of the denervated striatum. Here we report that the survival, growth, and function of the grafted DA neurons greatly depend on the severity of the lesion of the host nigrostriatal system. Fiber outgrowth, and to a lesser extent also cell survival, were significantly reduced in animals in which part of the intrinsic DA system was left intact. Moreover, graft-induced functional recovery, as assessed in the stepping, paw-use, and apomorphine rotation tests, was obtained only in severely lesioned animals, i.e., in rats with >70% DA denervation of the host striatum. Functional recovery seen in these animals in which the 6-hydroxydopamine (6-OHDA) lesion was confined to the striatum was more pronounced than that previously obtained in rats with complete lesions of the mesencephalic DA system, indicating that spared portions of the host DA system, particularly those innervating nonstriatal forebrain areas, may be necessary for the grafts to exert their optimal functional effect. These data have implications for the optimal use of fetal nigral transplants in Parkinson patients in different stages of the disease.
Src, Fyn, and Yes Are Not Required for Neuromuscular Synapse Formation But Are Necessary for Stabilization of Agrin-Induced Clusters of Acetylcholine Receptors
Authors: Smith Cynthia L. , Mittaud Peggy , Prescott Elizabeth D. , Fuhrer Christian , Burden Steven J.
Published: April 2018

Mice deficient insrcandfynorsrcandyesmove and breathe poorly and die perinatally, consistent with defects in neuromuscular function. Src and Fyn are associated with acetylcholine receptors (AChRs) in muscle cells, and Src and Yes can act downstream of ErbB2, suggesting roles for Src family kinases in signaling pathways regulating neuromuscular synapse formation. We studied neuromuscular synapses insrc−/−; fyn−/−andsrc−/−; yes−/−mutant mice and found that muscle development, motor axon pathfinding, clustering of postsynaptic proteins, and synapse-specific transcription are normal in these double mutants, showing that these pairs of kinases are not required for early steps in synapse formation. We generated muscle cell lines lackingsrcandfynand found that neural agrin and laminin-1 induced normal clustering of AChRs and that agrin induced normal tyrosine phosphorylation of the AChR β subunit in the absence of Src and Fyn. Another Src family member, most likely Yes, was associated with AChRs and phosphorylated by agrin in myotubes lacking Src and Fyn, indicating that Yes may compensate for the loss of Src and Fyn. Nevertheless, PP1 and PP2, inhibitors of Src-class kinases, did not inhibit agrin signaling, suggesting that Src class kinase activity is dispensable for agrin-induced clustering and tyrosine phosphorylation of AChRs. AChR clusters, however, were less stable in myotubes lacking Src and Fyn but not in PP1- or PP2-treated wild-type cells. These data show that the stabilization of agrin-induced AChR clusters requires Src and Fyn and suggest that the adaptor activities, rather than the kinase activities, of these kinases are essential for this stabilization.
The Role of the Nucleus Accumbens in Instrumental Conditioning: Evidence of a Functional Dissociation between Accumbens Core and Shell
Authors: Corbit Laura H. , Muir Janice L. , Balleine Bernard W.
Published: April 2018

In three experiments we examined the effect of bilateral excitotoxic lesions of the nucleus accumbens core or shell subregions on instrumental performance, outcome devaluation, degradation of the instrumental contingency, Pavlovian conditioning, and Pavlovian-instrumental transfer. Rats were food deprived and trained to press two levers, one delivering food pellets and the other a sucrose solution. All animals acquired the lever-press response although the rate of acquisition and overall response rates in core-lesioned animals were depressed relative to that in the shell- or sham-lesioned animals. Furthermore, in shell- and sham-lesioned rats, post-training devaluation of one of the two outcomes using a specific satiety procedure produced a selective reduction in performance on the lever that, in training, delivered the prefed outcome. In contrast, the core-lesioned rats failed to show a selective devaluation effect and reduced responding on both levers. Subsequent tests revealed that these effects of core lesions were not caused by an impairment in their ability to recall the devalued outcome, to discriminate the two outcomes, or to encode the instrumental action–outcome contingencies to which they were exposed. Additionally, the core lesions did not have any marked effect on Pavlovian conditioning or on Pavlovian-instrumental transfer. Importantly, although shell-lesioned rats showed no deficit in any test of instrumental conditioning or in Pavlovian conditioning, they failed to show any positive transfer in the Pavlovian-instrumental transfer test. This double dissociation suggests that nucleus accumbens core and shell differentially mediate the impact of instrumental and Pavlovian incentive processes, respectively, on instrumental performance.
Dishevelled Regulates the Metabolism of Amyloid Precursor Protein via Protein Kinase C/Mitogen-Activated Protein Kinase and c-Jun Terminal Kinase
Authors: Mudher A. , Chapman S. , Richardson J. , Asuni A. , Gibb G. , Pollard C. , Killick R. , Iqbal T. , Raymond L. , Varndell I. , Sheppard P. , Makoff A. , Gower E. , Soden P. E. , Lewis P. , Murphy M. , Golde T. E. , Rupniak H. T. , Anderton B. H. , Lovestone S.
Published: April 2018

Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC) is known to increase non-amyloidogenic α-secretase cleavage of APP, producing secreted APP (sAPPα), and glycogen synthase kinase (GSK)-3β is known to increase tau phosphorylation. Both PKC and GSK-3β are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPPα production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitogen-activated protein (MAP) kinase but not via p38 MAP kinase. These data position dvl-1 upstream of both PKC and JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1 and wnt-1 also reduce the phosphorylation of tau by GSK-3β. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.
Mild Cerebral Ischemia Induces Loss of Cyclin-Dependent Kinase Inhibitors and Activation of Cell Cycle Machinery before Delayed Neuronal Cell Death
Authors: Katchanov Juri , Harms Christoph , Gertz Karen , Hauck Ludger , Waeber Christian , Hirt Lorenz , Priller Josef , von Harsdorf Rüdiger , Brück Wolfgang , Hörtnagl Heide , Dirnagl Ulrich , Bhide Pradeep G. , Endres Matthias
Published: April 2018

After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16INK4ais an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemiain vivo. Loss of p27Kip1, another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen–glucose deprivationin vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number (∼1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell deathin vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.
Experience-Dependent Gene Expression in the Rat Hippocampus after Spatial Learning: A Comparison of the Immediate-Early GenesArc, c-fos, andzif268
Authors: Guzowski John F. , Setlow Barry , Wagner Edward K. , McGaugh James L.
Published: April 2018

Neuronal immediate-early gene (IEG) expression is regulated by synaptic activity and plays an important role in the neuroplastic mechanisms critical to memory consolidation. IEGs can be divided into two functional classes: (1) regulatory transcription factors (RTFs), which can broadly influence cell function depending on the “downstream” genes they regulate, and (2) “effector” proteins, which may directly modulate specific cellular functions. The objective of the current study was to determine whether the expression of an effector IEG (Arc) was similar to, or different from, that of two well characterized RTF IEGs (c-fosandzif268) after learning. IEG RNA levels from rats trained in spatial and nonspatial water tasks were determined using RNase protection assays andin situhybridization. Overall, the regulation of the three IEGs was similar in the hippocampus and the entorhinal and primary visual cortices. Consequently, IEG RNA levels were positively correlated within a structure. By contrast,Arcandzif268RNA levels were not correlated or only weakly correlated across structures, although c-fosRNA levels were moderately correlated across structures.ArcRNA expression differed from that ofzif268and c-fosin two regards: (1) hippocampalArcRNA levels were correlated with learning of the hippocampal-dependent spatial, but not hippocampal-independent cued response, water task, and (2)ArcRNA levels in the hippocampus and entorhinal cortex increased after spatial reversal learning relative to an asymptotic performance group. Thus, although the expression ofArc,zif268, and c-fosexhibited many similarities,Arcwas most responsive to differences in behavioral task demands.
A Novel p75NTR Signaling Pathway Promotes Survival, Not Death, of Immunopurified Neocortical Subplate Neurons
Authors: DeFreitas Michael F. , McQuillen Patrick S. , Shatz Carla J.
Published: April 2018

Subplate neurons of mammalian neocortex undergo pronounced cell death postnatally, long after they have matured and become incorporated into functional cortical circuits. They express the p75 neurotrophin receptor (p75NTR), which is known to signal cell death in some types of neurons via the activation of sphingomyelinase and the concomitant increase in the sphingolipid ceramide. To evaluate the role of p75NTR in subplate neurons, they were immunopurified and culturedin vitro. Contrary to its known function as a death receptor, ligand binding to p75NTR promotes subplate neuron survival. Moreover, p75NTR-dependent survival is blocked by inhibition of ceramide synthesis and rescued by addition of its precursor sphingomyelin. Inhibition of Trk signaling does not block survival, nor is Trk signaling alone sufficient to promote survival. Thus, ligand-dependent p75NTR regulation of the ceramide pathway mediates survival in certain neurons and may represent an important target for neuroprotective drugs in degenerative diseases involving p75NTR-expressing neurons, such as Alzheimer's disease.
Abnormal Development of Dendritic Spines inFMR1Knock-Out Mice
Authors: Nimchinsky Esther A. , Oberlander Adam M. , Svoboda Karel
Published: April 2018

Fragile X syndrome is caused by a mutation in theFMR1gene leading to absence of the fragile X mental retardation protein (FMRP). Reports that patients and adultFMR1knock-out mice have abnormally long dendritic spines of increased density suggested that the disorder might involve abnormal spine development. Because spine length, density, and motility change dramatically in the first postnatal weeks, we analyzed these properties in mutant mice and littermate controls at 1, 2, and 4 weeks of age. To label neurons, a viral vector carrying the enhanced green fluorescent protein gene was injected into the barrel cortex. Layer V neurons were imaged on a two-photon laser scanning microscope in fixed tissue sections. Analysis of >16,000 spines showed clear developmental patterns. Between 1 and 4 weeks of age, spine density increased 2.5-fold, and mean spine length decreased by 17% in normal animals. Early during cortical synaptogenesis, pyramidal cells in mutant mice had longer spines than controls. At 1 week, spine length was 28% greater in mutants than in controls. At 2 weeks, this difference was 10%, and at 4 weeks only 3%. Similarly, spine density was 33% greater in mutants than in controls at 1 week of age. At 2 or 4 weeks of age, differences were not detectable. The spine abnormality was not detected in neocortical organotypic cultures. The transient nature of the spine abnormality in the intact animal suggests that FMRP might play a role in the normal process of dendritic spine growth in coordination with the experience-dependent development of cortical circuits.
Global Structure, Robustness, and Modulation of Neuronal Models
Authors: Goldman Mark S. , Golowasch Jorge , Marder Eve , Abbott L. F.
Published: April 2018

The electrical characteristics of many neurons are remarkably robust in the face of changing internal and external conditions. At the same time, neurons can be highly sensitive to neuromodulators. We find correlates of this dual robustness and sensitivity in a global analysis of the structure of a conductance-based model neuron. We vary the maximal conductance parameters of the model neuron and, for each set of parameters tested, characterize the activity pattern generated by the cell as silent, tonically firing, or bursting. Within the parameter space of the five maximal conductances of the model, we find directions, representing concerted changes in multiple conductances, along which the basic pattern of neural activity does not change. In other directions, relatively small concurrent changes in a few conductances can induce transitions between these activity patterns. The global structure of the conductance-space maps implies that neuromodulators that alter a sensitive set of conductances will have powerful, and possibly state-dependent, effects. Other modulators that may have no direct impact on the activity of the neuron may nevertheless change the effects of such direct modulators via this state dependence. Some of the results and predictions arising from the model studies are replicated and verified in recordings of stomatogastric ganglion neurons using the dynamic clamp.
Enriched Rehabilitative Training Promotes Improved Forelimb Motor Function and Enhanced Dendritic Growth after Focal Ischemic Injury
Authors: Biernaskie Jeff , Corbett Dale
Published: April 2018

Chronic impairment of forelimb and digit movement is a common problem after stroke that is resistant to therapy. Previous studies have demonstrated that enrichment improves behavioral outcome after focal ischemia; however, postischemic enrichment alone is not capable of enhancing fine digit and forelimb function. Therefore, we combined environmental enrichment with daily skilled-reach training to assess the effect of intensive task-specific rehabilitation on long-term functional outcome. Rats were subjected to either endothelin-1-induced focal ischemia or sham surgery and subsequently designated to enriched-rehabilitation or standard-housing treatment groups starting 15 d after ischemia. Functional assessment of the affected forelimb at 4 and 9 weeks after treatment revealed that ischemic plus enrichment (IE) animals had improved ∼30% on the staircase-reaching task and were indistinguishable from sham animals for both latency and foot faults in a beam-traversing task. In contrast, ischemic plus standard (IS) animals remained significantly impaired on both tasks. Interestingly, both ischemic groups (IE and IS) relied on the nonaffected forelimb during upright weight-bearing movements, a pattern that persisted for the duration of the experiment. Dendritic arborization of layer V pyramidal cells within the undamaged motor cortex was examined using a Golgi–Cox procedure. IE animals showed enhanced dendritic complexity and length compared with both IS and sham groups. These results suggest that enrichment combined with task-specific rehabilitative therapy is capable of augmenting intrinsic neuronal plasticity within noninjured, functionally connected brain regions, as well as promoting enhanced functional outcome.
Negative Interspike Interval Correlations Increase the Neuronal Capacity for Encoding Time-Dependent Stimuli
Authors: Chacron Maurice J. , Longtin André , Maler Leonard
Published: April 2018

Accurate detection of sensory input is essential for the survival of a species. Weakly electric fish use amplitude modulations of their self-generated electric field to probe their environment. P-type electroreceptors convert these modulations into trains of action potentials. Cumulative relative refractoriness in these afferents leads to negatively correlated successive interspike intervals (ISIs). We use simple and accurate models of P-unit firing to show that these refractory effects lead to a substantial increase in the animal's ability to detect sensory stimuli. This assessment is based on two approaches, signal detection theory and information theory. The former is appropriate for low-frequency stimuli, and the latter for high-frequency stimuli. For low frequencies, we find that signal detection is dependent on differences in mean firing rate and is optimal for a counting time at which spike train variability is minimal. Furthermore, we demonstrate that this minimum arises from the presence of negative ISI correlations at short lags and of positive ISI correlations that extend out to long lags. Although ISI correlations might be expected to reduce information transfer, in fact we find that they improve information transmission about time-varying stimuli. This is attributable to the differential effect that these correlations have on the noise and baseline entropies. Furthermore, the gain in information transmission rate attributable to correlations exhibits a resonance as a function of stimulus bandwidth; the maximum occurs when the inverse of the cutoff frequency of the stimulus is of the order of the decay time constant of refractory effects. Finally, we show that the loss of potential information caused by a decrease in spike-timing resolution is smaller for low stimulus cutoff frequencies than for high ones. This suggests that a rate code is used for the encoding of low-frequency stimuli, whereas spike timing is important for the encoding of high-frequency stimuli.
Local Injection of Endothelin-1 Produces Pain-Like Behavior and Excitation of Nociceptors in Rats
Authors: Gokin Alexander P. , Fareed Moin U. , Pan Hui-Lin , Hans Guy , Strichartz Gary R. , Davar Gudarz
Published: April 2018

Neurobehavioral and neurophysiological actions of the peptide endothelin-1 (ET-1) were investigated after subcutaneous plantar hindpaw injections in adult male Sprague Dawley rats. Hindpaw flinching developed within minutes after ET-1 (8–16 nmol) injection, peaked at 30 min, lasted for 60 min, and was strongly inhibited by the endothelin-A (ETA) receptor antagonist, BQ-123 (3.2m). In separate experiments, impulse activity of single, physiologically characterized sensory C-, Aδ-, and Aβ-fibers was recorded from the sciatic nerve in anesthetized rats after subcutaneous injections of endothelin-1 (1–20 nmol), alone or together with BQ-123 (3.2m), into the plantar hindpaw receptive fields of these units. All nociceptive C-fibers (31 of 33 C-fibers studied) were excited by ET-1 (1–20 nmol) in a dose-dependent manner. For doses of 16–20 nmol, the mean latency for afferent activation after injection of ET-1 was 3.16 ± 0.31 min, and the mean and maximum response frequency were 2.02 ± 0.48 impulses (imp)/sec and 14.0 ± 3.2 imp/sec, respectively. All 10 nociceptive Aδ-fibers (of 12 Aδ-fibers studied) also responded to 1–20 nmol of ET-1 in a dose-dependent manner with a mean latency of 3.5 ± 0.12 min and mean response frequency of 3.3 ± 2.3 imp/sec. In contrast, most Aβ-fibers (9 of 12) did not respond to ET-1. BQ-123, when coinjected with ET-1, blocked ET-1-induced activation in all C- and Aδ-fibers tested. These data demonstrate that subcutaneous administration of ET-1 to the rat plantar hindpaw produces pain-like behavior and selective excitation of nociceptive fibers through activation of ETAreceptors.
Roles for Mitochondrial and Reverse Mode Na+/Ca2+Exchange and the Plasmalemma Ca2+ATPase in Post-Tetanic Potentiation at Crayfish Neuromuscular Junctions
Authors: Zhong Ning , Beaumont Vahri , Zucker Robert S.
Published: April 2018

We have explored the processes regulating presynaptic calcium concentration ([Ca2+]i) in the generation of post-tetanic potentiation (PTP) at crayfish neuromuscular junctions, using spectrophotometric dyes to measure changes in [Ca2+]iand [Na+]iand effects of inhibitors of Ca2+-transport processes. The mitochondrial Na+/Ca2+exchange inhibitor CGP 37157 was without effect, whereas the reverse mode plasmalemmal Na+/Ca2+exchange inhibitor KB R7943 reduced PTP and Ca2+accumulation caused by increased [Na+]i. Exchange inhibitory peptide and C28R2 had opposite effects, consistent with their block of the plasma membrane Ca2+ATPase. All drugs except CGP 37157 reduced Ca2+accumulation caused by Na+accumulation, which occurred on block of the Na+/K+pump, acting in proportion to their effects on plasmalemmal Na+/Ca2+exchange. We find no role for mitochondrial Na+/Ca2+exchange in presynaptic Ca2+regulation. The plasma membrane Na+/Ca2+exchanger acts in reverse mode to admit Ca2+into nerve terminals during and for some minutes after tetanic stimulation, while at the same time the plasma membrane Ca2+ATPase operates as an important Ca2+removal process. The interplay of these two Ca2+transport processes with Na+-independent mitochondrial Ca2+fluxes and the plasmalemma Na+/K+pump determines the magnitude of tetanic [Ca2+]iaccumulation and potentiation of excitatory transmission, and the post-tetanic time courses of decay of elevated [Ca2+]iand PTP.