bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical Role for Microglial NADPH Oxidase in Rotenone-Induced Degeneration of Dopaminergic Neurons
Authors: Gao Hui-Ming , Liu Bin , Hong Jau-Shyong
Published: April 2018

Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. Our previous studies with NADPH oxidase inhibitors, diphenylene iodonium and apocynin, suggested that NADPH oxidase-derived superoxide might be a major factor in mediating the microglia-enhanced rotenone neurotoxicity. However, because of the relatively low specificity of these inhibitors, the exact source of superoxide induced by rotenone remains to be further determined. In this study, using primary mesencephalic cultures from NADPH oxidase—null (gp91phox-/-) or wild-type (gp91phox+/+) mice, we demonstrated a critical role for microglial NADPH oxidase in mediating microglia-enhanced rotenone neurotoxicity. In neuron—glia cultures, dopaminergic neurons from gp91phox-/-mice were more resistant to rotenone neurotoxicity than those from gp91phox+/+mice. However, in neuron-enriched cultures, the neurotoxicity of rotenone was not different between the two types of mice. More importantly, the addition of microglia prepared from gp91phox+/+mice but not from gp91phox-/-mice to neuron-enriched cultures markedly increased rotenone-induced degeneration of dopaminergic neurons. Furthermore, apocynin attenuated rotenone neurotoxicity only in the presence of microglia from gp91phox+/+mice. These results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment.
Receptor Subtypes Involved in the Presynaptic and Postsynaptic Actions of Dopamine on Striatal Interneurons
Authors: Centonze Diego , Grande Cristina , Usiello Alessandro , Gubellini Paolo , Erbs Eric , Martín Ana B. , Pisani Antonio , Tognazzi Nadia , Bernardi Giorgio , Moratalla Rosario , Borrelli Emiliana , Calabresi Paolo
Published: April 2018

By stimulating distinct receptor subtypes, dopamine (DA) exerts presynaptic and postsynaptic actions on both large aspiny (LA) cholinergic and fast-spiking (FS) parvalbumin-positive interneurons of the striatum. Lack of receptor- and isoform-specific pharmacological agents, however, has hampered the progress toward a detailed identification of the specific DA receptors involved in these actions.

To overcome this issue, in the present study we used four different mutant mice in which the expression of specific DA receptors was ablated. In D1 receptor null mice, D1R-/-, DA dose-dependently depolarized both LA and FS interneurons. Interestingly, SCH 233390 (10 μm), a D1-like (D1 and D5) receptor antagonist, but notl-sulpiride (3–10 μm), a D2-like (D2, D3, D4) receptor blocker, prevented this effect, implying D5 receptors in this action. Accordingly, immunohistochemical analyses in both wild-type and D1R-/- mice confirmed the expression of D5 receptors in both cholinergic and parvalbumin-positive interneurons of the striatum.

In mice lacking D2 receptors, D2R-/-, the DA-dependent inhibition of GABA transmission was lost in both interneuron populations. Both isoforms of D2 receptor, D2L and D2S, were very likely involved in this inhibitory action, as revealed by the electrophysiological analysis of the effect of the DA D2-like receptor agonist quinpirole in two distinct mutants lacking D2L receptors and expressing variable contents of D2S receptors.

The identification of the receptor subtypes involved in the actions of DA on different populations of striatal cells is essential to understand the circuitry of the basal ganglia and to develop pharmacological strategies able to interfere selectively with specific neuronal functions.
Segregation and Coactivation of Developing Neocortical Layer 1 Neurons
Authors: Soda Takeshi , Nakashima Ryo , Watanabe Dai , Nakajima Kazunori , Pastan Ira , Nakanishi Shigetada
Published: April 2018

Layer 1 in the developing cerebral cortex is populated by two basic neuronal cell types, Cajal–Retzius (CR) cells and non-CR cells. We generated transgenic mice in which green fluorescent protein (GFP) was driven by the promoter of metabotropic glutamate receptor subtype 2 and expressed specifically in CR cells during cortical development. On the basis of the precise identification of CR cells with GFP fluorescence, we pursued developmental changes and synaptic mechanisms of both CR and non-CR cells during the postnatal period. Immunostaining in combination with GFP fluorescence imaging showed that GFP and reelin, a protein involved in corticogenesis, completely overlap in CR cells at postnatal day 0. At the subsequent postnatal stage, reelin-positive neurons are segregated and categorized into GFP-positive/GABA-negative CR cells and GFP-negative/GABA-positive non-CR cells. Individual and simultaneous whole-cell recordings of CR and non-CR cells in developing cerebral slices revealed that spontaneous and electrically evoked postsynaptic currents (sPSCs and ePSCs) measured in CR and non-CR cells are differentially mediated by GABAAreceptors versus GABAA, AMPA, and NMDA receptors, respectively. Furthermore, CR and non-CR cells show synchronized repetitive barrages of sPSCs that reflect a network-driven activity in the developing cerebral cortex. These findings imply that the layer 1 neurons dynamically change and play a distinct and integral role in the postnatal developing neocortex.
Electrical Synapses and Synchrony: The Role of Intrinsic Currents
Authors: Pfeuty Benjamin , Mato Germán , Golomb David , Hansel David
Published: April 2018

Electrical synapses are ubiquitous in the mammalian CNS. Particularly in the neocortex, electrical synapses have been shown to connect low-threshold spiking (LTS) as well as fast spiking (FS) interneurons. Experiments have highlighted the roles of electrical synapses in the dynamics of neuronal networks. Here we investigate theoretically how intrinsic cell properties affect the synchronization of neurons interacting by electrical synapses. Numerical simulations of a network of conductance-based neurons randomly connected with electrical synapses show that potassium currents promote synchrony, whereas the persistent sodium current impedes it. Furthermore, synchrony varies with the firing rate in qualitatively different ways depending on the intrinsic currents. We also study analytically a network of quadratic integrate-and-fire neurons. We relate the stability of the asynchronous state of this network to the phase-response function (PRF), which characterizes the effect of small perturbations on the firing timing of the neurons. In particular, we show that the greater the skew of the PRF toward the first half of the period, the more stable the asynchronous state. Combining our simulations with our analytical results, we establish general rules to predict the dynamic state of large networks of neurons coupled with electrical synapses. Our work provides a natural explanation for surprising experimental observations that blocking electrical synapses may increase the synchrony of neuronal activity. It also suggests different synchronization properties for LTS and FS cells. Finally, we propose to further test our predictions in experiments using dynamic clamp techniques.
Interaural Time Sensitivity Dominated by Cochlea-Induced Envelope Patterns
Authors: Joris Philip X.
Published: April 2018

To localize sounds in space, humans heavily depend on minute interaural time differences (ITDs) generated by path-length differences to the two ears. Physiological studies of ITD sensitivity have mostly used deterministic, periodic sounds, in which either the waveform fine structure or a sinusoidal envelope is delayed interaurally. For natural broadband stimuli, however, auditory frequency selectivity causes individual channels to have their own envelopes; the temporal code in these channels is thus a mixture of fine structure and envelope. This study introduces a method to disentangle the contributions of fine structure and envelope in both binaural and monaural responses to broadband noise. In the inferior colliculus (IC) of the cat, a population of neurons was found in which envelope fluctuations dominate ITD sensitivity. This population extends over a surprisingly wide range of frequencies, including low frequencies for which fine-structure information is also available. A comparison with the auditory nerve suggests that an elaboration of envelope coding occurs between the nerve and the IC. These results suggest that internally generated envelopes play a more important role in binaural hearing than is commonly thought.
Cognitive Impairments in Early Parkinson's Disease Are Accompanied by Reductions in Activity in Frontostriatal Neural Circuitry
Authors: Lewis Simon J. G. , Dove Anja , Robbins Trevor W. , Barker Roger A. , Owen Adrian M.
Published: April 2018

Studies in patients with Parkinson's disease (PD) suggest that the characteristic motor symptoms of the disorder are frequently accompanied by impairments in cognition that are most profound in tasks of executive function. Neuropsychological deficits are not an inevitable consequence of the disease, yet the reasons underlying cognitive heterogeneity in PD are not well understood. To determine the underlying neural correlate of these cognitive deficits, we used event-related functional magnetic resonance imaging (fMRI) to compare groups of cognitively impaired and unimpaired patients, matched on all other clinical measures. fMRI revealed significant signal intensity reductions during a working-memory paradigm in specific striatal and frontal lobe sites in patients with cognitive impairment compared with those patients who were not cognitively unimpaired. These results demonstrate that cognitive deficits in PD are accompanied by neural changes that are related to, but distinct from, those changes that underlie motoric deficits in these patients. Furthermore, they suggest that fMRI may provide a valuable tool for identifying patients who may benefit from targeted therapeutic strategies.
Experience-Dependent Regulation of the Immediate-Early Gene Arc Differs across Brain Regions
Authors: Kelly Michele P. , Deadwyler Sam A.
Published: April 2018

Previously, we demonstrated that initial acquisition of a lever-press task resulted in higher levels of activity-regulated cytoskeleton-associated protein (Arc) mRNA induction than did overtrained performance (Kelly and Deadwyler, 2002). The present study extends this finding by characterizing (1) the behavioral regulation of Arc protein expression, (2) the time course of decay of Arc mRNA signal in different brain regions immediately after the initial acquisition session, and (3) the persistence of Arc mRNA induction in those same brain regions across sessions. Rats killed after initial acquisition of a simple lever-press response demonstrated significantly elevated levels of Arc protein. Interestingly, of the brain regions that demonstrated Arc mRNA induction 30 min after the acquisition session, there was a differential rate in signal decay, with only half of the regions continuing to demonstrate elevated levels of Arc at 60 min. Similarly, the extent to which Arc mRNA induction persisted across days also varied across brain regions. An unexpected outcome was that areas such as CA1 and CA3 that showed the least persistence in Arc activation immediately after the initial acquisition session showed the greatest perseverance of induction across days of training. Finally, animals less proficient at the task expressed higher levels of Arc mRNA than animals that acquired the task more quickly. Taken together, the results show that Arc mRNA and protein were regulated in an experience-dependent manner; however, the fact that the time course of Arc mRNA expression differed across brain structures suggests a differential rate of consolidation of the newly acquired behavior across specific brain regions.
Critical Residues of theCaenorhabditis elegans unc-2Voltage-Gated Calcium Channel That Affect Behavioral and Physiological Properties
Authors: Mathews Eleanor A. , García Esperanza , Santi Celia M. , Mullen Gregory P. , Thacker Colin , Moerman Donald G. , Snutch Terrance P.
Published: April 2018

TheCaenorhabditis elegans unc-2gene encodes a voltage-gated calcium channel α1subunit structurally related to mammalian dihydropyridine-insensitive high-threshold channels. In the present paper we describe the characterization of seven alleles ofunc-2. Using anunc-2promoter-tagged green fluorescent protein construct, we show thatunc-2is primarily expressed in motor neurons, several subsets of sensory neurons, and the HSN and VC neurons that control egg laying. Examination of behavioral phenotypes, including defecation, thrashing, and sensitivities to aldicarb and nicotine suggests that UNC-2 acts presynaptically to mediate both cholinergic and GABAergic neurotransmission. Sequence analysis of theunc-2alleles shows thate55, ra605, ra606, ra609,andra610all are predicted to prematurely terminate and greatly reduce or eliminateunc-2function. In contrast, thera612andra614alleles are missense mutations resulting in the substitution of highly conserved residues in the C terminus and the domain IVS4-IVS5 linker, respectively. Heterologous expression of a rat brain P/Q-type channel containing thera612mutation shows that the glycine to arginine substitution affects a variety of channel characteristics, including the voltage dependence of activation, steady-state inactivation, as well as channel kinetics. Overall, our findings suggest that UNC-2 plays a pivotal role in mediating a number of physiological processes in the nematode and also defines a number of critical residues important for calcium channel functionin vivo.
Experience-Dependent Strengthening ofDrosophilaNeuromuscular Junctions
Authors: Sigrist Stephan J. , Reiff Dierk F. , Thiel Philippe R. , Steinert Joern R. , Schuster Christoph M.
Published: April 2018

The genetic analysis of larval neuromuscular junctions (NMJs) ofDrosophilahas provided detailed insights into molecular mechanisms that control the morphological and physiological development of these glutamatergic synapses. However, because of the chronic defects caused by mutations, a time-resolved analysis of these mechanisms and their functional relationships has been difficult so far. In this study we provide a first temporal map of some of the molecular and cellular key processes, which are triggered in wild-type animals by natural larval locomotor activity and then mediate experience-dependent strengthening of larval NMJs. Larval locomotor activity was increased either by chronically rearing a larval culture at 29°C instead of 18 or 25°C or by acutely transferring larvae from a culture vial onto agar plates. Within 2 hr of enhanced locomotor activity, NMJs showed a significant potentiation of signal transmission that was rapidly reversed by an induced paralysis of the temperature-sensitive mutantparats1. Enhanced locomotor activity was also associated with a significant increase in the number of large subsynaptic translation aggregates. After 4 hr, postsynaptic DGluR-IIA glutamate receptor subunits started to transiently accumulate in ring-shaped areas around synapses, and they condensed later on, after chronic locomotor stimulation at 29°C, into typical postsynaptic patches. These NMJs showed a reduced perisynaptic expression of the cell adhesion molecule Fasciclin II, an increased number of junctional boutons, and significantly more active zones. Such temporal mapping of experience-dependent adaptations at developing wild-type and mutant NMJs will provide detailed insights into the dynamic control of glutamatergic signal transmission.
Two Forms of Synaptic Plasticity with Distinct Dependence on Age, Experience, and NMDA Receptor Subtype in Rat Visual Cortex
Authors: Yoshimura Yumiko , Ohmura Tomohisa , Komatsu Yukio
Published: April 2018

In visual cortex, NMDA receptor (NMDAR) properties depend primarily on NR2A and NR2B subunits, and NR2 subunit composition changes with age and visual experience. We examined the roles of these NR2 subunits in activity-dependent long-term modification of synaptic responses, which were evoked in layer 2/3 cells by stimulation of layer 4 in rat visual cortical slices. We used theta-burst stimulation (TBS) of presynaptic fibers or low-frequency stimulation paired with postsynaptic depolarization, which has been commonly used to induce NMDAR-dependent long-term potentiation (LTP) in visual cortex. In pyramidal cells, however, TBS produced long-term depression (LTD) at inhibitory synapses rather than LTP at excitatory synapses. This was observed in association with LTP of extracellular field potentials that reflect postsynaptic potentials in a population of cells (field-LTP). This result is inconsistent with the previous view that field-LTP reflects LTP of excitatory connections. However, pairing stimulation produced LTP at excitatory synapses of pyramidal cells frequently during development but rarely in adulthood. In contrast, inhibitory LTD and field-LTP occurred similarly in both developing and mature cortex. Experiments using NR2B selective and NR2 subunit nonselective NMDAR antagonists demonstrated that NR2A- and NR2B-containing NMDARs contribute selectively to inhibitory LTD-field-LTP and excitatory LTP, respectively. In addition, we found that the developmental decline in the NR2B component was paralleled by a decline in the incidence of excitatory LTP, and these declines were both prevented by dark rearing. These results implicate NR2 subunit composition in the regulation of neocortical plasticity and demonstrate differential subunit regulation at inhibitory and excitatory connections.
Identification of Upregulated SCG10 mRNA Expression Associated with Late-Phase Long-Term Potentiation in the Rat Hippocampal Schaffer-CA1 PathwayIn Vivo
Authors: Peng Haixiang , Derrick Brian E. , Martinez Joe L.
Published: April 2018

The maintenance of long-term potentiation (LTP) depends on alteration of gene transcription. By screening a subtracted cDNA library that is enriched in upregulated transcripts in rat hippocampus 3 hr after Schaffer-CA1 LTP inductionin vivo, we identified a neural growth-associated protein SCG10 (superior cervical ganglia clone 10) gene. The semiquantitative reverse transcription-PCR and Northern blot experiments confirmed that SCG10 mRNA levels were elevated in tetanized rat hippocampi compared with those of sham controls that received only low-frequency stimulation. Both 1 and 2 kb forms of SCG10 mRNAs contributed to the increased expression. Using a riboprobe with a sequence specific to the 3′-untranslated region of rat SCG10 mRNA,in situhybridization further revealed a significant increase of the SCG10 mRNA 2 kb form in the ipsilateral CA3 and CA1 regions of LTP animals. In addition, we systemically injected the competitive NMDA receptor antagonistd,l-3[(±)-2-carboxypiperazine-4-yl]-propyl-1-phosphonic acid (CPP) to determine whether the alteration of SCG10 expression depends on NMDA receptor activation or tetanus alone. Administration of CPP 1 hr before tetanus completely blocked LTP induction and the increase of SCG10 mRNA levels. Thus, these results suggest that the transcription of SCG10in vivois regulated by long-lasting synaptic activity and may contribute to the maintenance of long-term synaptic plasticity via a presynaptic remodeling mechanism.
Coherent Oscillations in Neuronal Activity of the Supplementary Motor Area during a Visuomotor Task
Authors: Lee Daeyeol
Published: April 2018

Neural activity recorded in behaving animals is nonstationary, making it difficult to determine factors influencing its temporal patterns. In the present study, rhesus monkeys were trained to produce a series of visually guided hand movements according to the changes in target locations, and multichannel single-neuron activity was recorded from the caudal supplementary motor area. Coherent oscillations in neural activity were analyzed using the wavelet cross-spectrum, and its statistical significance was evaluated using various methods based on surrogate spike trains and trial shuffling. A population-averaged wavelet cross-spectrum displayed a strong tendency for oscillatory activity in the γ frequency range (30∼50 Hz) to synchronize immediately before and after the onset of movement target. The duration of synchronized oscillations in the γ frequency range increased when the onset of the next target was delayed. In addition, analysis of individual neuron pairs revealed that many neuron pairs also displayed coherent oscillations in the β frequency range (15-30 Hz). Coherent β frequency oscillations were less likely to be synchronized than γ frequency oscillations, consistent with the fact that coherent β frequency oscillations were not clearly seen in the population-averaged cross-spectrum. For a given neuron pair, the time course and phase of coherent oscillations were often similar across different movements. These results are consistent with the proposal that synchronized oscillations in the γ frequency range might be related to the anticipation of behaviorally relevant events and the contextual control of cortical information flow.
Evidence for Chelatable Zinc in the Extracellular Space of the Hippocampus, But Little Evidence for Synaptic Release of Zn
Authors: Kay Alan R.
Published: April 2018

Zinc colocalizes with glutamate in the synaptic vesicles of certain glutamatergic vesicles in the mammalian brain. Here, I introduce a method for detecting Zn in the extracellular space of brain slices and another method for detecting the passage of Zn out of the slice. In both cases, the fluorimetric Zn probe FluoZin-3 is used in conjunction with a slow Zn chelator, Ca-EDTA, to reduce background fluorescence. In addition, a new Zn chelator, ethylenediiminodi-2-pentanedioic acid, with little affinity for Ca or Mg is introduced. These tools are then used to show that little Zn (∼2 nm) is released during the course of synaptic transmission into the extracellular space. However, when hippocampal slices are subjected to a high potassium stimulus (50 mM) combined with an increase in osmolarity, Zn is externalized in the Timm's-stained areas (∼6 nm). This stimulus also leads to even greater Zn elevations in area CA1 that is only weakly stained by the Timm's method. Nevertheless, even under these conditions, little if any Zn makes its way out of the slices. I present evidence for a layer of Zn in the extracellular space that maps onto the Timm's stained region of the hippocampus. This Zn veneer appears to be loosely associated with molecules in the extracellular space and may be the raison d'être for vesicular Zn.
AII Amacrine Cells Express L-Type Calcium Channels at Their Output Synapses
Authors: Habermann Christopher J. , O'Brien Brendan J. , Wässle Heinz , Protti Dario A.
Published: April 2018

AII amacrine cells play a critical role in the high-fidelity signal transmission pathways involved with nighttime vision. The temporal properties of the light responses strongly depend on the transfer function at different synaptic stages and consequently on presynaptic calcium influx. AII light responses are complex waveforms generated by graded input, they comprise Na+-based spikes as well as a sustained component, and they are transferred to graded cone bipolar cells. It is, therefore, of interest to determine the properties of AII voltage-dependent calcium channels (VDCCs) to establish whether these cells express N-type and/or P/Q-type VDCCs, characteristic of spiking neurons, or whether they are more like graded neurons, which mostly use L-type VDCCs. We combined electrophysiological, molecular biological, and imaging techniques to characterize calcium currents and their sites of origin in mouse AII amacrine cells. Calcium currents activated at potentials more positive than -60 mV (maximally between -50 and -20 mV) and inactivated slowly. These currents were blocked by dihydropyridine (DHP) antagonists and were enhanced by the DHP agonist BayK 8644. Single-cell RT-PCR analysis of mRNA encoding for different calcium channel α subunits in AIIs revealed a consistent expression of the α1-D subunit. Calcium imaging of AII cells showed that the greatest change in intracellular calcium occurred in the lobular appendages, with minor changes being observed in the arboreal dendrites. Depolarization-induced calcium rises were also modulated by DHPs, suggesting that a particular kind of L-type VDCC, mainly localized to the lobular appendages, enables these spiking-capable neurons to release neurotransmitter in a sustained manner onto OFF-cone bipolar cells.
Presynaptic Mechanism for Anti-Analgesic and Anti-Hyperalgesic Actions of κ-Opioid Receptors
Authors: Bie Bihua , Pan Zhizhong Z.
Published: April 2018

Glutamate neurotransmission plays an important role in the processing of pain and in chronic opioid-induced neural and behavioral plasticity, such as opioid withdrawal and opioid dependence. κ-Opioid receptors also have been implicated in acute opioid modulation of pain and chronic opioid-induced plasticity, both of which are primarily mediated by μ-opioid receptors. Using whole-cell patch clamp recordings in brain slicesin vitroand system analysis of pain behaviors in ratsin vivo, this study investigated the functional role of glutamate synaptic transmission andκ-opioid receptors in two behavioral pain conditions:μ-opioid-induced analgesia (decreased pain) and μ-opioid withdrawal-induced hyperalgesia (increased pain). In the nucleus raphe magnus (NRM), a brainstem structure that controls spinal pain transmission, we found thatκ-receptor agonists presynaptically inhibited glutamate synaptic currents in both of the two cell types that are thought to respectively inhibit or facilitate spinal pain transmission. In rats, both glutamate receptor antagonists and the κ agonist microinjected into the NRM attenuated μ-opioid-induced analgesia, which is most likely mediated through activation of such pain-inhibiting neurons. However, during opioid abstinence-induced withdrawal, the same doses of glutamate receptor antagonists and the κ agonist administered in the NRM suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal. These results demonstrate that κ-opioid receptors antagonize μ-receptor-induced effects in both analgesic and hyperalgesic states, and suggest inhibition of glutamate synaptic transmission as a presynaptic mechanism for the κ antagonism of these two μ receptor-mediated actions.
Characterization of a Neurotrophin Signaling Mechanism that Mediates Neuron Survival in a Temporally Specific Pattern
Authors: Shalizi Aryaman , Lehtinen Maria , Gaudillière Brice , Donovan Nicole , Han Jiahuai , Konishi Yoshiyuki , Bonni Azad
Published: April 2018

The temporally specific nature of neurotrophic factor-induced responses is a general feature of mammalian nervous system development, the mechanisms of which remain to be elucidated. We characterized a mechanism underlying the temporal specificity by which BDNF selectively promotes the survival of newly generated, but not mature, granule neurons of the mammalian cerebellum. We found that BDNF specifically induces the extracellular signal-regulated kinase 5 (ERK5)-myocyte enhancer factor (MEF2) signaling pathway in newly generated granule neurons and thereby induces transcription of neurotrophin-3 (NT-3), a novel gene target of MEF2. Inhibition of endogenous ERK5, MEF2, or NT-3 in neurons by several approaches including disruption of the NT-3 gene in mice revealed a requirement for the ERK5-MEF2-NT-3 signaling pathway in BDNF-induced survival of newly generated granule neurons. These findings define a novel mechanism that underlies the antiapoptotic effect of neurotrophins in a temporally defined pattern in the developing mammalian brain.
Voltage- and Site-Dependent Control of the Somatic Impact of Dendritic IPSPs
Authors: Williams Stephen R. , Stuart Greg J.
Published: April 2018

Inhibitory interneurons target specific subcellular compartments of cortical pyramidal neurons, where location-specific interactions of IPSPs with voltage-activated ion channels are likely to influence the inhibitory control of neuronal output. To investigate this, we simulated IPSPs as a conductance source at sites across the somato-apical dendritic axis (up to 750 μm) of neocortical layer 5 pyramidal neurons. Analysis revealed that the electrotonic architecture of cortical pyramidal neurons is highly voltage dependent, resulting in a significant site-dependent disparity between the amplitude, kinetics, and dendro-somatic attenuation of IPSPs generated from depolarized (-50 mV) and hyperpolarized (-80 mV) membrane potentials. At the soma, the time course of IPSPs evoked from depolarized potentials was greatest when generated from proximal dendritic sites and decreased as events were generated more distally, whereas the somatic time course of IPSPs evoked from hyperpolarized potentials was independent of the dendritic site of generation. This behavior resulted from the concerted actions of axo-somatic sodium channels that increased the duration of proximal dendritic IPSPs generated at depolarized potentials and distal dendritic hyperpolarization-activated channels that mediated site independence of somatic IPSP time course at hyperpolarized potentials. Functionally, this voltage-dependent control of IPSPs shaped the spatial and temporal profile of inhibition of axonal action potential firing and dendritic spike generation. Together, these findings demonstrate that the somatic impact of dendritic IPSPs is highly voltage dependent and controlled by classes of ion channels differentially distributed across axodendritic domains, directly revealing site-dependent inhibitory synaptic processing in cortical pyramidal neurons.
Absence of Tissue Plasminogen Activator Gene or Activity Impairs Mouse Cerebellar Motor Learning
Authors: Seeds Nicholas W. , Basham Mark E. , Ferguson Jayne E.
Published: April 2018

Motor learning is thought to involve modulation of synaptic inputs in the cerebellar cortex, including granule neuron/Purkinje neuron contacts. During a complex motor task requiring mice to walk across irregularly spaced pegs, cerebellar granule neurons show a rapid and transient induction of mRNA for the extracellular protease tissue plasminogen activator (tPA). This induction of tPA mRNA is cerebellar specific, is not seen in the cerebella of exercised or stressed animals, and is distinct from simple performance phenomena. Knock-out mice lacking the tPA gene show a significant reduction in both rate and extent of learning. Furthermore, blocking tPA activity during training dramatically impaired motor learning. Thus, tPA plays an important role in motor learning, in which tPA may facilitate remodeling of the active synaptic zone.
Abnormal Neural Synchrony in Schizophrenia
Authors: Spencer Kevin M. , Nestor Paul G. , Niznikiewicz Margaret A. , Salisbury Dean F. , Shenton Martha E. , McCarley Robert W.
Published: April 2018

Schizophrenia has been conceptualized as a failure of cognitive integration, and abnormalities in neural circuitry (particularly inhibitory interneurons) have been proposed as a basis for this disorder. We used measures of phase locking and phase coherence in the scalp-recorded electroencephalogram to examine the synchronization of neural circuits in schizophrenia. Compared with matched control subjects, schizophrenia patients demonstrated: (1) absence of the posterior component of the early visual gamma band response to Gestalt stimuli; (2) abnormalities in the topography, latency, and frequency of the anterior component of this response; (3) delayed onset of phase coherence changes; and (4) the pattern of anterior-posterior coherence increases in response to Gestalt stimuli found in controls was replaced by a pattern of interhemispheric coherence decreases in patients. These findings support the hypothesis that schizophrenia is associated with impaired neural circuitry demonstrated as a failure of gamma band synchronization, especially in the 40 Hz range.
Topography of Interaural Temporal Disparity Coding in Projections of Medial Superior Olive to Inferior Colliculus
Authors: Oliver Douglas L. , Beckius Gretchen E. , Bishop Deborah C. , Loftus William C. , Batra Ranjan
Published: April 2018

Neurons in the medial superior olive encode interaural temporal disparity, and their receptive fields indicate the location of a sound source in the azimuthal plane. It is often assumed that the projections of these neurons transmit the receptive field information about azimuth from point to point, much like the projections of the retina to the brain transmit the position of a visual stimulus. Yet this assumption has never been verified. Here, we use physiological and anatomical methods to examine the projections of the medial superior olive to the inferior colliculus for evidence of a spatial topography that would support transmission of azimuthal receptive fields. The results show that this projection does not follow a simple point-to-point topographical map of receptive field location. Thus, the representation of sound location along the azimuth in the inferior colliculus most likely relies on a complex, nonlinear map.
Functional Mapping and Ca2+Regulation of Nicotinic Acetylcholine Receptor Channels in Rat Hippocampal CA1 Neurons
Authors: Khiroug Leonard , Giniatullin Rashid , Klein Rebecca C. , Fayuk Dmitriy , Yakel Jerrel L.
Published: April 2018

Diverse subtypes of nicotinic acetylcholine receptors (nAChRs), including fast-desensitizing α7-containing receptors thought to be Ca2+-permeable, are expressed in the CNS, where they appear to regulate cognitive processing and synaptic plasticity. To understand the physiological role of nAChRs in regulating neuronal excitability, it is important to know the distribution of functional receptors along the surface of neurons, whether they can increase [Ca2+]i, and/or are regulated by Ca2+. We mapped the distribution of receptors on the membrane of rat hippocampal CA1 stratum radiatum interneurons and pyramidal cells in acute slices by recording nAChR-mediated currents elicited by local UV laser-based photolysis of caged carbachol in patch-clamped neurons. The local application (∼7 μm patches) allowed mapping of functional nAChRs along the soma and dendritic tree, whereas the fast uncaging minimized the effects of desensitization of α7-containing nAChRs and allowed us to measure the kinetics of responses. The α7-containing nAChRs were the predominant subtype on interneurons, and were located primarily at perisomatic sites (<70 μm from the soma; in contrast to the more uniform distribution of glutamate receptors); no currents were detectable on pyramidal neurons. The activation of nAChRs increased [Ca2+]i, indicating that these native receptors in acute slices are significantly Ca2+-permeable, consistent with previous observations made with recombinant receptors. In addition, they exhibited strong desensitization, the rate of recovery from which was controlled by [Ca2+]i. Our results demonstrate the strategic location and Ca2+regulation of α7-containing nAChRs, which may contribute to understanding their involvement in hippocampal plasticity.
3,4-Methylenedioxymethamphetamine (Ecstasy) Inhibits Dyskinesia Expression and Normalizes Motor Activity in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Primates
Authors: Iravani Mahmoud M. , Jackson Michael J. , Kuoppamäki Mikko , Smith Lance A. , Jenner Peter
Published: April 2018

Ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] was shown to prolong the action ofl-3,4-dihydroxyphenylalanine (l-DOPA) while suppressing dyskinesia in a single patient with Parkinson's disease (PD). The clinical basis of this effect of MDMA is unknown but may relate to its actions on either dopaminergic or serotoninergic systems in brain.

In normal, drug-naive common marmosets, MDMA administration suppressed motor activity and exploratory behavior. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated,l-DOPA-primed common marmosets, MDMA transiently relieved motor disability but over a period of 60 min worsened motor symptoms. When given in conjunction withl-DOPA, however, MDMA markedly decreased dyskinesia by reducing chorea and to a lesser extent dystonia and decreased locomotor activity to the level observed in normal animals. MDMA similarly alleviated dyskinesia induced by the selective dopamine D2/3 agonist pramipexole. The actions of MDMA appeared to be mediated through 5-HT mechanisms because its effects were fully blocked by the selective serotonin reuptake inhibitor fluvoxamine. Furthermore, the effect of MDMA onl-DOPA-induced motor activity and dyskinesia was partially inhibited by 5-HT1a/b antagonists. The ability of MDMA to inhibit dyskinesia results from its broad spectrum of action on 5-HT systems. Serotoninergic receptors appear to play an important modulatory role inl-DOPA-induced dyskinesia, and this study may provide a framework for the use of serotoninergic agents in the treatment ofl-DOPA-induced dyskinesia.
Quantitative Estimate of Synaptic Inputs to Striatal Neurons during Up and Down StatesIn Vitro
Authors: Blackwell Kim T. , Czubayko Uwe , Plenz Dietmar
Published: April 2018

Up states are prolonged membrane potential depolarizations critical for synaptic integration and action potential generation in cortical and striatal neurons. They commonly result from numerous concurrent synaptic inputs, whereas neurons reside in a down state when synaptic inputs are few. By quantifying the composition, frequency, and amplitude of synaptic inputs for both states, we provide important constraints for state transitions in striatal network dynamics.

Up and down states occur naturally in cortex-striatum-substantia nigra cocultures, which were used as anin vitromodel in the present study. Spontaneous synaptic inputs during down states were extracted automatically in spiny projection neurons and fast spiking interneurons of the striatum using a newly developed computer algorithm. Consistent with a heterogeneous population of synaptic inputs, PSPs and PSCs showed no correlation in amplitude and rise time and occurred at relatively low frequencies of 10-40 Hz during the down state. The number of synaptic inputs during up states, estimated from the up-state charge and the unitary charge of down-state PSCs, was 217 ± 44. Given the average up-state duration of 284 ± 34 msec, synaptic input frequency was ∼800 Hz during up-states for both neuronal types. Many down-state events reversed at the chloride reversal potential and were blocked by GABAAantagonists. The high correlation between up- and down-state reversal potential suggests that despite these drastic changes in synaptic input frequency, the ratio of inhibitory to excitatory currents is similar during both states.
Cochlear Phase and Amplitude Retrieved from the Auditory Nerve at Arbitrary Frequencies
Authors: van der Heijden Marcel , Joris Philip X.
Published: April 2018

It is currently impossible to mechanically measure the overall vibration pattern of the intact mammalian cochlea because of its inaccessibility and vulnerability. At first sight, data from the auditory nerve are a poor substitute because of their limited temporal resolution. The nonlinear character of neural coding, however, causes low-frequency interactions among the components of multitone stimuli. We designed a novel stimulus for which these interactions take a particularly systematic form, and we recorded the response of the auditory nerve to this stimulus. A careful analysis of interactions in the data allowed us to reconstruct frequency transfer functions (both their amplitude and their phase) at multiple points spanning the entire length of the cochlea. The generic character of our stimuli and analysis suggests its wider use in nonlinear system analysis, particularly in those instances in which limitations in temporal resolution restrict the use of customary methods.
Brain Structures Differ between Musicians and Non-Musicians
Authors: Gaser Christian , Schlaug Gottfried
Published: April 2018

From an early age, musicians learn complex motor and auditory skills (e.g., the translation of visually perceived musical symbols into motor commands with simultaneous auditory monitoring of output), which they practice extensively from childhood throughout their entire careers. Using a voxel-by-voxel morphometric technique, we found gray matter volume differences in motor, auditory, and visual-spatial brain regions when comparing professional musicians (keyboard players) with a matched group of amateur musicians and non-musicians. Although some of these multiregional differences could be attributable to innate predisposition, we believe they may represent structural adaptations in response to long-term skill acquisition and the repetitive rehearsal of those skills. This hypothesis is supported by the strong association we found between structural differences, musician status, and practice intensity, as well as the wealth of supporting animal data showing structural changes in response to long-term motor training. However, only future experiments can determine the relative contribution of predisposition and practice.
Lack of Evidence for Sprouting of Aβ Afferents into the Superficial Laminas of the Spinal Cord Dorsal Horn after Nerve Section
Authors: Hughes David I. , Scott Dugald T. , Todd Andrew J. , Riddell John S.
Published: April 2018

The central arborizations of large myelinated cutaneous afferents normally extend as far dorsally as the ventral part of lamina II in rat spinal cord. Woolf et al. (1992) reported that after nerve injury some of these afferents sprouted into lamina I and the dorsal part of lamina II, and it has been suggested that this could contribute to allodynia associated with neuropathic pain. Part of the evidence for sprouting was on the basis of the use of cholera toxin B subunit as a selective tracer for A-fibers, and the validity of this approach has recently been questioned; however, sprouting was also reported in experiments involving intra-axonal labeling of chronically axotomized afferents.

We have used intra-axonal labeling in the rat to examine central terminals of 58 intact sciatic afferents of presumed cutaneous origin and 38 such afferents axotomized 7-10 weeks previously. Both normal and axotomized populations included axons with hair follicle afferent-like morphology and arbors that entered the ventral half of lamina II; however, none of these extended farther dorsally. We also performed bulk labeling of myelinated afferents by injecting biotinylated dextran into the lumbar dorsal columns bilaterally 8-11 weeks after unilateral sciatic nerve section. We observed that both ipsilateral and contralateral to the sectioned nerve, arbors of axons with hair follicle afferent-like morphology in the sciatic territory extended only as far as the ventral half of lamina II. Therefore these results do not support the hypothesis that Aβ afferents sprout into the superficial laminas after nerve section.
Cross-Repressive Interaction of the Olig2 and Nkx2.2 Transcription Factors in Developing Neural Tube Associated with Formation of a Specific Physical Complex
Authors: Sun Tao , Dong Hualing , Wu Lizi , Kane Michael , Rowitch David H. , Stiles Charles D.
Published: April 2018

In developing neural tube, the basic helix-loop-helix (bHLH) transcription factor Olig2 interacts with the homeodomain transcription factor Nkx2.2 at two distinct stages. During neuronogenesis, a cross-repressive interaction appears to establish the precise boundary between the p3 and pMN domains. At later times, a cooperative interaction is noted because Nkx2.2 promotes maturation of oligodendrocyte progenitor cells specified by expression of Olig2. We show here that the Olig2 protein can form a physical complex with Nkx2.2 protein in mammalian cells and yeast two-hybrid trap assay. This interaction is specific because Olig2 does not bind to a biologically irrelevant homeodomain transcription factor (Nkx6.1), and Nkx2.2 does not interact with a biologically irrelevant bHLH protein (NeuroD). Deletion mapping analysis suggests that formation of an Olig2-Nkx2.2 physical complex is insufficient for the induction of oligodendrocyte progenitors in developing spine; however, the protein-protein interaction observed might be important for the cross-repressive interaction between Olig2 and Nkx2.2 that helps to establish the pMN-p3 boundary in the developing spinal cord.
Multipolar Migration: The Third Mode of Radial Neuronal Migration in the Developing Cerebral Cortex
Authors: Tabata Hidenori , Nakajima Kazunori
Published: April 2018

Two distinct modes of radial neuronal migration, locomotion and somal translocation, have been reported in the developing cerebral cortex. Although these two modes of migration have been well documented, the cortical intermediate zone contains abundant multipolar cells, and they do not resemble the cells migrating by locomotion or somal translocation. Here, we report that these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers. Time-lapse analysis of living slices revealed that the multipolar cells do not have any fixed cell polarity, and that they very dynamically extend and retract multiple processes as their cell bodies slowly move. They do not usually move straight toward the pial surface during their radial migration, but instead frequently change migration direction and rate; sometimes they even remain in almost the same position, especially when they are in the subventricular zone. Occasionally, the multipolar cells jump tangentially during their radial migration. Because the migration modality of these cells clearly differs from locomotion or somal translocation, we refer to their novel type of migration as “multipolar migration.” In view of the high proportion of cells exhibiting multipolar migration, this third mode of radial migration must be an important type of migration in the developing cortex.
Are Changes in MAPK/ERK Necessary or Sufficient for Entrainment in Chick Pineal Cells?
Authors: Yadav Geetha , Straume Martin , Heath James , Zatz Martin
Published: April 2018

Chick pineal cells in culture display a circadian rhythm of melatonin release. Light pulses can entrain (phase shift) the rhythm. One candidate for the photoentrainment pathway uses a mitogen-activated protein kinase (MAPK), also known as extracellular signal-regulated kinase (ERK). We tested the hypothesis that activation of ERK (by phosphorylation to p-ERK) is necessary and/or sufficient for entrainment by measuring the ability of several drugs, light, and other perturbations to change levels of p-ERK and to induce phase shifts in the melatonin rhythm. If changes in the levels of p-ERK are sufficient for photoentrainment, then all perturbations that reduce its level must induce light-like phase shifts, and all those that increase its level must induce dark-like phase shifts. If such changes are necessary for photoentrainment, then light pulses must reduce p-ERK levels, and the duration of the light pulse, the magnitude and duration of the change in p-ERK, and the size of the phase shift must correlate. We found five perturbations that reduced p-ERK levels. Of these, two induced light-like phase shifts (PD 98059 and caffeine), one induced dark-like phase shifts (SB203580), and two did not induce phase shifts at all (U0126 and omitting a medium change). Serum increased p-ERK levels without inducing any phase shifts. Finally, light pulses did not elicit changes in p-ERK, nor was there a diurnal rhythm in p-ERK levels, nor could rapid changes in p-ERK levels have accounted for duration effects of light pulses on phase shifts. Taken together, these results argue strongly against the hypothesis that reduction (or increases) in MAPK/ERK activation is necessary or sufficient for entrainment in chick pineal cells.