bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal Migration from the Forebrain to the Olfactory Bulb Requires a New Attractant Persistent in the Olfactory Bulb
Authors: Liu Guofa , Rao Yi
Published: April 2018

Interneurons in the olfactory bulb (OB) are generated not only in the developing embryo but also throughout the postnatal life of mammals from neuronal precursor cells migrating from the anterior subventricular zone (SVZa) of the mammalian forebrain. We discovered that the OB secretes a diffusible activity that attracts these neuronal precursor cells. The attractive activity is present in specific layers in the OB, including the glomerular layer but not the granule cell layer. The attractive activity and the neuronal responsiveness persist from embryonic through neonatal to adult stages. Removal of the rostral OB significantly reduces SVZa migration toward the OB, an effect that can be rescued by a transplant of the OB but not by that of the neocortex. The activity in the OB is not mimicked by the known attractants. These results provide an explanation for the continuous migration of SVZa neurons toward the OB, demonstrate an important role of the OB in neuronal migration, and reveal the existence of a new chemoattractant.
Temporal Resolution of Ensemble Visual Motion Signals in Primate Retina
Authors: Chichilnisky E. J. , Kalmar R. S.
Published: April 2018

Recent studies have examined the temporal precision of spiking in visual system neurons, but less is known about the time scale that is relevant for behaviorally important visual computations. We examined how spatiotemporal patterns of spikes in ensembles of primate retinal ganglion cells convey information about visual motion to the brain. The direction of motion of a bar was estimated by comparing the timing of responses in ensembles of parasol (magnocellular-projecting) retinal ganglion cells recorded simultaneously, using a cross-correlation approach similar to standard models of motion sensing. To identify the temporal resolution of motion signals, spike trains were low-pass filtered before estimating the direction of motion. The filter time constant that resulted in most accurate motion sensing was in the range of 10-50 msec for a range of stimulus speeds and contrasts and approached a lower limit of ∼10 msec at high speeds and contrasts. This time constant was, on average, comparable to the length of interspike intervals. These findings suggest that cortical neurons could filter their inputs on a time scale of tens of milliseconds, rather than relying on the precise times of individual input spikes, to sense motion most reliably.
Making Memories without Trying: Medial Temporal Lobe Activity Associated with Incidental Memory Formation during Recognition
Authors: Stark Craig E. L. , Okado Yoko
Published: April 2018

Structures in the medial portions of the human temporal lobes (MTL) play a vital role in the ability to learn new facts and events, whether such learning is intentional or incidental. We examined neural activity in the MTL both while participants studied pictures of novel scenes and while they attempted to recognize which scenes had been previously presented. In a second surprise test we assessed participants' memory for items that were presented only during the previous recognition memory test. We present a novel approach to cross-participant alignment of neuroimaging data that provides more precise localization and enhanced statistical power within regions such as the MTL. Using this technique, we observed that the amount of MTL activity predicted participants' ability to subsequently remember scenes not only during the intentional study task, but also during the first memory retrieval test when only incidental encoding occurred. This encoding-related activity during memory retrieval was in the same subregions of the MTL as encoding-related activity during intentional study and is hypothesized to be one of the primary reasons why retrieval-related activity is often difficult to observe with neuroimaging techniques.
N-Type Calcium Channel α1BSubunit (CaV2.2) Knock-Out Mice Display Hyperactivity and Vigilance State Differences
Authors: Beuckmann Carsten T. , Sinton Christopher M. , Miyamoto Norimasa , Ino Mitsuhiro , Yanagisawa Masashi
Published: April 2018

Differential properties of voltage-dependent Ca2+channels have been primarily ascribed to the α1subunit, of which 10 different subtypes are currently known. For example, channels that conduct the N-type Ca2+current possess the α1Bsubunit (Cav2.2), which has been localized,inter alia, to the piriform cortex, hippocampus, hypothalamus, locus coeruleus, dorsal raphe, thalamic nuclei, and granular layer of the cortex. Some of these regions have been previously implicated in metabolic and vigilance state control, and selective block of the N-type Ca2+channel causes circadian rhythm disruption. In this study of Cav2.2-/-knock-out mice, we examined potential differences in feeding behavior, spontaneous locomotion, and the sleep-wake cycle. Cav2.2-/-mice did not display an overt metabolic phenotype but were hyperactive, demonstrating a 20% increase in activity under novel conditions and a 95% increase in activity under habituated conditions during the dark phase, compared with wild-type littermates. Cav2.2-/-mice also displayed vigilance state differences during the light phase, including increased consolidation of rapid-eye movement (REM) sleep and increased intervals between non-REM (NREM) and wakefulness episodes. EEG spectral power was increased during wakefulness and REM sleep and was decreased during NREM sleep in Cav2.2-/-mice. These results indicate a role of the N-type Ca2+channel in activity and vigilance state control, which we interpret in terms of effects on neurotransmitter release.
Neurokinin-1 Projection Cells in the Rat Dorsal Horn Receive Synaptic Contacts from Axons That Possess α2C-Adrenergic Receptors
Authors: Olave M. Josune , Maxwell David J.
Published: April 2018

Theα2Csubclass of adrenergic receptor (α2C-AR) mediates some of the antinociceptive actions of norepinephrine in the spinal cord. Axon terminals, which possess this receptor, are concentrated in the superficial dorsal horn and originate from spinal interneurons. We performed a series of combined tract-tracing and immunocytochemical studies to determine whether α2C-AR-immunoreactive axons target projection neurons that possess the neurokinin-1 (NK-1) receptor because such cells are likely to transmit nociceptive information to the brain. Spinomedullary neurons were labeled by stereotaxic injection of the B-subunit of cholera toxin (CTb) into the caudal ventrolateral medulla of three anesthetized adult rats. After 3 d, the animals were anesthetized again and fixed by perfusion. Sections were cut from midlumbar segments and reacted with antibodies to reveal α2C-ARs, CTb, and NK-1 receptors. Retrogradely labeled neurons possessing the NK-1 receptor (n= 45) were examined with confocal microscopy to investigate their relationship with α2C-AR-immunoreactive axons. Numerous α2C-AR axons were apposed to cell bodies and proximal dendrites of cells in lamina I and also to distal dendrites that originate from labeled cell bodies in lamina III/IV. A combined confocal and electron microscopic method confirmed that these appositions were synaptic. Additional experiments showed that virtually all α2C-AR terminals in contact with labeled cells are also immunoreactive for the vesicular glutamate transporter 2 and therefore are glutamatergic.

These data suggest that norepinephrine can modulate excitatory synaptic transmission from spinal interneurons to projection cells by acting at α2C-ARs. This could be one of the mechanisms that underlie the antinociceptive actions of norepinephrine.
Axonal Dopamine Receptors Activate Peripheral Spike Initiation in a Stomatogastric Motor Neuron
Authors: Bucher Dirk , Thirumalai Vatsala , Marder Eve
Published: April 2018

We studied the effects of dopamine on the stomatogastric ganglion (STG) of the lobster,Homarus americanus.The two pyloric dilator (PD) neurons are active in the pyloric rhythm, have somata in the STG, and send axons many centimeters to innervate muscles of the stomach. Dopamine application to the stomatogastric nervous system when the PD neurons were rhythmically active evoked additional action potentials during the PD neuron interburst intervals. These action potentials were peripherally generated at a region between the STG and the first bilateral branch, ∼1 cm away from the STG, and traveled antidromically to the neuropil and orthodromically to the pyloric dilator muscles. Focal applications of dopamine to the nerves showed that spikes could be initiated in almost the entire peripheral axon of the PD neurons. Dopamine also evoked spikes in isolated peripheral axons. The concentration threshold for peripheral spike initiation was at or below 10-9mdopamine. Thus, the peripheral axon can play an important role in shaping the output signaling to the muscles by the motor neuron.
Hypertrophic Neuropathies and Malignant Peripheral Nerve Sheath Tumors in Transgenic Mice Overexpressing Glial Growth Factor β3 in Myelinating Schwann Cells
Authors: Huijbregts Richard P. H. , Roth Kevin A. , Schmidt Robert E. , Carroll Steven L.
Published: April 2018

The neuregulin-1 (NRG-1) family of growth and differentiation factors exerts a variety of effects on Schwann cells and their precursors during nervous system development; however, NRG-1 effects on adult Schwann cells are poorly defined. Several lines of evidence suggest that NRG-1 actions on adult Schwann cells are distinct from those observed during development. To test this hypothesis, we generated transgenic mice overexpressing the NRG-1 isoform glial growth factor β3 (GGFβ3) in myelinating Schwann cells [protein zero (P0)GGFβ3 mice]. P0-GGFβ3 mice develop resting tremors, gait abnormalities, decreased hindlimb strength, and paralysis by ∼7 months of age. Sciatic nerves from these animals show a hypertrophic neuropathy characterized by demyelination, remyelination, and “onion bulb” formation. Development of this hypertrophic neuropathy is preceded by Schwann cell hyperplasia that is prominent in 1-month-old mice and present but decreased in 2- and 4-month-old animals. P0-GGFβ3 mice also develop peripheral ganglion-associated malignant peripheral nerve sheath tumors. Motor, sensory, and sympathetic ganglia from 1-, 2-, and 4-month-old P0-GGFβ3 mice uniformly contain intraganglionic, likely preneoplastic, Schwann cell proliferations. Examination of bromodeoxyuridine incorporation and caspase-3 activation in sciatic nerves and trigeminal ganglia indicates that Schwann cell hyperplasia in P0-GGFβ3 mice reflects increased proliferation rather than decreased apoptosis. These observations are consistent with the hypothesis that GGFβ3 induces proliferation of adult Schwann cells and demyelination of peripheral nerve axons. Furthermore, overexpression of this NRG-1 isoform frequently induces neoplastic Schwann cell proliferation within PNS ganglia, suggesting that NRG-1 may contribute to human Schwann cell neoplasia.
The Retinotopic Organization of Primate Dorsal V4 and Surrounding Areas: A Functional Magnetic Resonance Imaging Study in Awake Monkeys
Authors: Fize Denis , Vanduffel Wim , Nelissen Koen , Denys Katrien , d'Hotel Christophe Chef , Faugeras Olivier , Orban Guy A.
Published: April 2018

Using functional magnetic resonance imaging (fMRI), we mapped the retinotopic organization throughout the visual cortex of fixating monkeys. The retinotopy observed in areas V1, V2, and V3 was completely consistent with the classical view. V1 and V3 were bordered rostrally by a vertical meridian representation, and V2 was bordered by a horizontal meridian. More anterior in occipital cortex, both areas V3A and MT-V5 had lower and upper visual field representations split by a horizontal meridian. The rostral border of dorsal V4 was characterized by the gradual transition of a representation of the vertical meridian (dorsally) to a representation of the horizontal meridian (more ventrally). Central and ventral V4, on the other hand, were rostrally bordered by a representation of the horizontal meridian. The eccentricity lines ran perpendicular to the ventral V3-V4 border but were parallel to the dorsal V3-V4 border. These results indicate different retinotopic organizations within dorsal and ventral V4, suggesting that the latter regions may not be merely the lower and upper visual field representations of a single area. Moreover, because the present fMRI data are in agreement with previously published electrophysiological results, reported distinctions in the retinotopic organization of human and monkey dorsal V4 reflect genuine species differences that cannot be attributed to technical confounds. Finally, aside from dorsal V4, the retinotopic organization of macaque early visual cortex (V1, V2, V3, V3A, and ventral V4) is remarkably similar to that observed in human fMRI studies. This finding indicates that early visual cortex is mostly conserved throughout hominid evolution.
Overexpression of a Hyperpolarization-Activated Cation Current (Ih) Channel Gene Modifies the Firing Activity of Identified Motor Neurons in a Small Neural Network
Authors: Zhang Ying , Oliva Ricardo , Gisselmann Günter , Hatt Hanns , Guckenheimer John , Harris-Warrick Ronald M.
Published: April 2018

The hyperpolarization-activated cation current (Ih) is widely distributed in excitable cells.Ihplays important roles in regulation of cellular excitability, rhythmic activity, and synaptic function. We previously showed that, in pyloric dilator (PD) neurons of the stomatogastric ganglion (STG) of spiny lobsters,Ihcan be endogenously upregulated to compensate for artificial overexpression of the Shal transient potassium channel; this maintains normal firing properties of the neuron despite large increases in potassium current. To further explore the function ofIhin the pyloric network, we injected cRNA ofPAIH, a lobster gene that encodesIh, into rhythmically active PD neurons. Overexpression of PAIH produced a fourfold increase inIh, although with somewhat different biophysical properties than the endogenous current. Compared with the endogenousIh, the voltage for half-maximal activation of the PAIH-evoked current was depolarized by 10 mV, and its activation kinetics were significantly faster. This increase inIhdid not affect the expression ofIAor other outward currents. Instead, it significantly altered the firing properties of the PD neurons. IncreasedIhdepolarized the minimum membrane potential of the cell, reduced the oscillation amplitude, decreased the time to the first spike, and increased the duty cycle and number of action potentials per burst. We used both dynamic-clamp experiments, injecting the modeled PAIH currents into PD cells in a functioning STG, and a theoretical model of a two-cell network to demonstrate that the increasedIhwas sufficient to cause the observed changes in the PD activity.
Firing Properties of Spinal Interneurons during Voluntary Movement. II. Interactions between Spinal Neurons
Authors: Prut Yifat , Perlmutter Steve I.
Published: April 2018

The relationship between the activity of pairs of simultaneously recorded spinal interneurons (INs) in the cervical enlargement was studied in five monkeys performing voluntary wrist movements. The tendency for INs to exhibit similar response properties and synchronized firing was tested as a function of physical distance between the cells and their correlational linkages with forearm muscles. Nearby INs tended to have more similar torque and direction turning (signal correlation) and more similar response profiles (e.g., tonic vs phasic firing) than INs that were far apart. This suggests that nearby cells receive common synaptic input. In contrast, the trial-to-trial covariation of rate around the mean rate for all trials (noise correlation) was independent of the distance between the neurons. Furthermore, signal and noise correlation were independent, suggesting different underlying mechanisms. Surprisingly, spike-to-spike correlation between INs was relatively infrequent and weak, as measured by cross-correlation histograms. In contrast, single motor units (SMUs) in forearm muscles fired more synchronously, particularly for SMUs in single extensor muscles. Either common drive to INs is too weak to induce synchronized firing, or there is an active decorrelation mechanism within IN networks.
Sleep Deprivation Causes Behavioral, Synaptic, and Membrane Excitability Alterations in Hippocampal Neurons
Authors: McDermott Carmel M. , LaHoste Gerald J. , Chen Chu , Musto Alberto , Bazan Nicolas G. , Magee Jeffrey C.
Published: April 2018

Although the function of sleep remains elusive, several lines of evidence suggest that sleep has an important role in learning and memory. In light of the available data and with the prevalence of sleep deprivation (SD), we sought to determine the effect of SD on neuronal functioning. We found that the exposure of rats to 72 hr of primarily rapid eye movement SD impaired their subsequent performance on a hippocampus-dependent spatial learning task but had no effect on an amygdala-dependent learning task. To determine the underlying cellular level mechanisms of this hippocampal deficit, we examined the impact of SD on several fundamental aspects of membrane excitability and synaptic physiology in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. We found that neuronal excitability was severely reduced in CA1 neurons but not in granule cells and that the production of long-term potentiation of synaptic strength was inhibited in both areas. Using multiple SD methods we further attempted to differentiate the effects of sleep deprivation from those associated with the nonspecific stress induced by the sleep deprivation methods. Together these data suggest that failure to acquire adequate sleep produces several molecular and cellular level alterations that profoundly inhibit hippocampal functioning.
Neonatal Alcohol Exposure Induces Long-Lasting Impairment of Visual Cortical Plasticity in Ferrets
Authors: Medina Alexandre E. , Krahe Thomas E. , Coppola David M. , Ramoa Ary S.
Published: April 2018

Fetal alcohol syndrome is a major cause of learning and sensory deficits. These disabilities may result from disruption of neocortex development and plasticity. Alcohol exposure during the third trimester equivalent of human gestation may have especially severe and long-lasting consequences on learning and sensory processing, because this is when the functional properties and connectivity of neocortical neurons start to develop. To address this issue, we used the monocular deprivation model of neural plasticity, which shares many common mechanisms with learning. Ferrets were exposed to ethanol (3.5 mg/kg, i.p.) on alternate days for 3 weeks starting on postnatal day (P) 10. Animals were then monocularly deprived at the peak of ocular dominance plasticity after a prolonged alcohol-free period (15-20 d). Quantitative single-unit electrophysiology revealed that alcohol exposure disrupted ocular dominance plasticity while preserving robust visual responses. Moreover, optical imaging of intrinsic signals revealed that the reduction in visual cortex area driven by the deprived eye was much less pronounced in ethanol-treated than in control animals. Alcohol exposure starting at a later age (P20) did not disrupt ocular dominance plasticity, indicating that timing of exposure is crucial for the effects on visual plasticity. In conclusion, alcohol exposure during a brief period of development impairs ocular dominance plasticity at a later age. This model provides a novel approach to investigate the consequences of fetal alcohol exposure and should contribute to elucidate how alcohol disrupts neural plasticity.
Interplay of Electroencephalogram Phase and Auditory-Evoked Neural Activity
Authors: Kruglikov Stepan Y. , Schiff Steven J.
Published: April 2018

Auditory-evoked potentials (AEPs) were triggered in real time as a function of ongoing electroencephalogram (EEG) phase. Phase triggering on-line or retrospective phase-selective averaging introduces phase artifacts such as spurious troughs or peaks, which mask mid-latency and affect the amplitude of late AEPs. We developed a method to control for phase artifacts by phase-selective averaging of trials, recorded without stimulation, and used this to uncover a previously unknown phase dependency of AEPs. Not only are such findings inconsistent with the standard additive evoked potential model, but we identified clear neural correlates at fixed latencies, which are inconsistent with the recently proposed phase-resetting model. Our findings suggest that a new conceptualization is required to account for the interplay between the correlates of neural-evoked activity and modulation of ongoing EEG that together constitute evoked potentials.
Phosphoinositide 3-Kinase Cascade Facilitates μ-Opioid Desensitization in Sensory Neurons by Altering G-Protein-Effector Interactions
Authors: Tan Miao , Groszer Matthias , Tan Aiko M. , Pandya Amy , Liu Xin , Xie Cui-Wei
Published: April 2018

Signaling via G-protein-coupled receptors undergoes desensitization after prolonged agonist exposure. Here we investigated the role of phosphoinositide 3-kinase (PI3K) and its downstream pathways in desensitization of μ-opioid inhibition of neuronal Ca2+channels. In cultured mouse dorsal root ganglion neurons, two mechanistically different forms of desensitization were observed after acute or chronic treatment with the μ agonist [d-Ala2,N-MePhe4, Gly-ol5]-enkephalin (DAMGO). Chronic DAMGO desensitization was heterologous in nature and significantly attenuated by blocking the activity of PI3K or mitogen-activated protein kinase (MAPK). A combined application of PI3K and MAPK inhibitors showed no additive effect, suggesting that these two kinases act in a common pathway to facilitate chronic desensitization. Acute DAMGO desensitization, however, was not affected by the inhibitors. Furthermore, upregulation of the PI3K-Akt pathway in mutant mice lacking phosphatase and tensin homolog, a lipid phosphatase counteracting PI3K, selectively enhanced chronic desensitization in a PI3K- and MAPK-dependent manner. Using the prepulse facilitation (PPF) test, we further examined changes in the voltage-dependent component of DAMGO action that requires direct interactions between βγ subunits of G-proteins and Ca2+channels. DAMGO-induced PPF was diminished after chronic treatment, suggesting disruption of G-protein-channel interactions. Such disruption could occur at the postreceptor level, because chronic DAMGO also reduced GTPγS-induced PPF that was independent of receptor activation. Again, inhibition of PI3K or MAPK reduced desensitization of PPF. Our data suggest that the PI3Kcascade involving MAPK and Akt enhances μ-opioid desensitization via postreceptor modifications that interfere with G-protein-effector interactions.
Optical Measurements of Presynaptic Release in Mutant Zebrafish Lacking Postsynaptic Receptors
Authors: Li Weiyan , Ono Fumihito , Brehm Paul
Published: April 2018

Differentiation of presynaptic nerve terminals is mediated, in part, through contact with the appropriate postsynaptic target cell. In particular, studies using dissociated nerve and muscle derived fromXenopusembryos have indicated that the properties of transmitter release from motor neurons are altered after contact with skeletal muscle. This maturation of presynaptic function has further been linked to retrograde signaling from muscle that involves activation of postsynaptic ACh receptors. Using FM1-43 optical determinants of exocytosis, we now compare calcium-mediated exocytosis at neuromuscular junctions of wild-type zebrafish to mutant fish lacking postsynaptic ACh receptors. In response to either high-potassium depolarization or direct electrical stimulation, we observed no differences in the rate or extent of FM1-43 destaining. These data indicate that the acquisition of stimulus-evoked exocytosis at early developmental stages occurs independent of both postsynaptic receptor and synaptic responses in zebrafish.
Inhibiting the Expression of a Classically Conditioned Behavior Prevents Its Extinction
Authors: Krupa David J. , Thompson Richard F.
Published: April 2018

The underlying neuronal substrates and behavioral properties that might mediate extinction of the classically conditioned eye-blink response (CR) were examined. Four groups of rabbits were trained to perform the CR. Two of the groups then received either three or six sessions of tone-alone extinction training while the motor nuclei that mediate expression of the CR (facial nucleus and accessory abducens) were reversibly inactivated with microinjections of the GABA agonist muscimol. After these inactivation extinction sessions, rabbits received four more extinction sessions without inactivation. Two groups of controls received either three or six extinction sessions while saline vehicle was infused into the motor nuclei, followed by four sessions with no infusions. Saline infusions had no effect on extinction, and controls extinguished the CR normally over the first three to four sessions. In contrast, muscimol inactivation of the motor nuclei completely prevented any performance of CRs during the three or six inactivation extinction sessions. At the start of the four extinction sessions without inactivation, rabbits performed CRs at the same rate and amplitude as controls on their first extinction sessions. The muscimol rabbits then extinguished the CR normally over the four sessions without inactivation. In short, inactivation of the motor nuclei completely prevented any extinction of the eye-blink CR with no effect on subsequent extinction without inactivation. These results are discussed in terms of possible neuroanatomical loci that might mediate the extinction process as well as how effects of manipulating CR performance during extinction may affect the extinction process.
Perisynaptic Localization of δ Subunit-Containing GABAAReceptors and Their Activation by GABA Spillover in the Mouse Dentate Gyrus
Authors: Wei Weizheng , Zhang Nianhui , Peng Zechun , Houser Carolyn R. , Mody Istvan
Published: April 2018

In cerebellar granule cells, δ subunit-containing GABAAreceptors are found exclusively at extrasynaptic sites, but their subcellular distribution in other brain areas is poorly understood. We examined the anatomical localization and physiological activation of these receptors in adult mouse dentate gyrus granule cells. Immunocytochemistry revealed a high density of δ subunits in the molecular layer and a much lower density in the cell body layer. At the ultrastructural level, immunogold-labeled δ subunits were found at the edge of symmetric synapses on granule cell dendrites. Functional correlates of this perisynaptic localization were obtained by comparing inhibitory responses in δ subunit-deficient (δ-/-) and wild-type (wt) mice. In whole-cell recordings at 22°C, the weighted decay time constants (τw) of spontaneous IPSCs (sIPSCs) were significantly longer in wt mice but were similar at 34°C, reflecting the role of temperature-dependent GABA uptake in shaping sIPSC decay. IPSCs evoked by minimal stimulation (eIPSCs) near the somata had similar τwin δ-/- and wt mice, but eIPSCs elicited from dendritic sites decayed significantly more slowly in wt mice, consistent with a higher density of δ subunit-containing receptors in the molecular layer. The τwof dendritic eIPSCs of wt mice were shortened by ZnCl2(10 μm), reflecting the high Zn2+sensitivity of δ subunit-containing GABAAreceptors, and were prolonged by the GAT-1 GABA transporter inhibitor NO711 (10 μm). Our results demonstrate a perisynaptic localization of δ subunit-containing GABAAreceptors and indicate that these receptors can be activated by GABA overspill in the molecular layer.
Intracellular Domains of NMDA Receptor Subtypes Are Determinants for Long-Term Potentiation Induction
Authors: Köhr Georg , Jensen Vidar , Koester Helmut J. , Mihaljevic Andre L. A. , Utvik Jo K. , Kvello Ane , Ottersen Ole P. , Seeburg Peter H. , Sprengel Rolf , Hvalby Øivind
Published: April 2018

NMDA receptors (NMDARs) are essential for modulating synaptic strength at central synapses. At hippocampal CA3-to-CA1 synapses of adult mice, different NMDAR subtypes with distinct functionality assemble from NR1 with NR2A and/or NR2B subunits. Here we investigated the role of these NMDA receptor subtypes in long-term potentiation (LTP) induction. Because of the higher NR2B contribution in the young hippocampus, LTP of extracellular field potentials could be enhanced by repeated tetanic stimulation in young but not in adult mice. Similarly, NR2B-specific antagonists reduced LTP in young but only marginally in adult wild-type mice, further demonstrating that in mature CA3-to-CA1 connections LTP induction results primarily from NR2A-type signaling. This finding is also supported by gene-targeted mutant mice expressing C-terminally truncated NR2A subunits, which participate in synaptic NMDAR channel formation and Ca2+signaling, as indicated by immunopurified synaptic receptors, postembedding immunogold labeling, and spinous Ca2+transients in the presence of NR2B blockers. These blockers abolished LTP in the mutant at all ages, revealing that, without the intracellular C-terminal domain, NR2A-type receptors are deficient in LTP signaling. Without NR2B blockade, CA3-to-CA1 LTP was more strongly reduced in adult than young mutant mice but could be restored to wild-type levels by repeated tetanic stimulation. Thus, besides NMDA receptor-mediated Ca2+influx, subtype-specific signaling is critical for LTP induction, with the intracellular C-terminal domain of the NR2 subunits directing signaling pathways with an age-dependent preference.
Long-Term K+Channel-Mediated Dampening of Dopamine Neuron Excitability by the Antipsychotic Drug Haloperidol
Authors: Hahn Junghyun , Tse Tonia E. , Levitan Edwin S.
Published: April 2018

Antipsychotic drugs require days of treatment to begin to produce therapeutic effects. We report thatin vivotreatment with the antipsychotic drug haloperidol acts with a delay of days to slow spontaneous repetitive firing by isolated midbrain dopamine neurons. The decreased excitability is caused by an increased number of functional A-type K+channels without any change in gating properties. Upregulation of dopamine neuron Kv4.3 mRNA accounts for this effect, demonstrating a role for channel gene expression in this delayed drug action. The resultant long-term dampening of dopamine neuron excitability may serve to tone down the dopamine system.
Sleep-Dependent θ Oscillations in the Human Hippocampus and Neocortex
Authors: Cantero Jose L. , Atienza Mercedes , Stickgold Robert , Kahana Michael J. , Madsen Joseph R. , Kocsis Bernat
Published: April 2018

Hippocampal θ waves recorded during rapid eye movement (REM) sleep are thought to play a critical role in memory consolidation in lower mammals, but previous attempts to detect similar θ oscillations in the human hippocampus have been unsuccessful. Using subdural and depth recordings from epileptic patients, we now report the first evidence of state-dependent hippocampal θ waves (4-7 Hz) in humans. Unlike the continuous θ in rodents, however, these oscillations were consistently observed during REM sleep in short (∼1 sec) bursts and during transitions to wake in longer epochs. θ waves were also observed in the basal temporal lobe and frontal cortex during transitions from sleep to wake and in quiet wakefulness but not in REM, and they were not coherent with hippocampal θ oscillations. The absence of functional coupling between neocortex and hippocampus during θ periods indicates that multiple θ generators exist in the human brain, and that they are dynamically regulated by brain state. γ oscillations were also present during REM θ bursts, but the fluctuations in γ power were not associated with θ phase, pointing out another significant difference between rodent and human θ properties. Together, these findings suggest that the generation mechanisms of θ oscillations in humans might have evolved from tonic to phasic in hippocampus during REM sleep and extended from hippocampus to cortex, where they appear in certain wakefulness-related states.
Distinct GABAergic Targets of Feedforward and Feedback Connections Between Lower and Higher Areas of Rat Visual Cortex
Authors: Gonchar Yuri , Burkhalter Andreas
Published: April 2018

Processing of visual information is performed in different cortical areas that are interconnected by feedforward (FF) and feedback (FB) pathways. Although FF and FB inputs are excitatory, their influences on pyramidal neurons also depend on the outputs of GABAergic neurons, which receive FF and FB inputs. Rat visual cortex contains at least three different families of GABAergic neurons that express parvalbumin (PV), calretinin (CR), and somatostatin (SOM) (Gonchar and Burkhalter, 1997). To examine whether pathway-specific inhibition (Shao and Burkhalter, 1996) is attributable to distinct connections with GABAergic neurons, we traced FF and FB inputs to PV, CR, and SOM neurons in layers 1-2/3 of area 17 and the secondary lateromedial area in rat visual cortex. We found that in layer 2/3 maximally 2% of FF and FB inputs go to CR and SOM neurons. This contrasts with 12-13% of FF and FB inputs onto layer 2/3 PV neurons. Unlike inputs to layer 2/3, connections to layer 1, which contains CR but lacks SOM and PV somata, are pathway-specific: 21% of FB inputs go to CR neurons, whereas FF inputs to layer 1 and its CR neurons are absent. These findings suggest that FF and FB influences on layer 2/3 pyramidal neurons mainly involve disynaptic connections via PV neurons that control the spike outputs to axons and proximal dendrites. Unlike FF input, FB input in addition makes a disynaptic link via CR neurons, which may influence the excitability of distal pyramidal cell dendrites in layer 1.
Long-Lasting Functional Disabilities in Middle-Aged Rats with Small Cerebral Infarcts
Authors: Lindner Mark D. , Gribkoff Valentin K. , Donlan Nicole A. , Jones Theresa A.
Published: April 2018

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies.
Dual Regulation of Calcium Oscillation in Astrocytes by Growth Factors and Pro-Inflammatory Cytokines via the Mitogen-Activated Protein Kinase Cascade
Authors: Morita Mitsuhiro , Higuchi Chitose , Moto Takanori , Kozuka Nagisa , Susuki Jinichi , Itofusa Rurika , Yamashita Jiro , Kudo Yoshihisa
Published: April 2018

In response to neurotransmitters, astrocytes show various types of calcium increase (transient, oscillatory, and complex), the physiological significance of which is still controversial. To explore this variability, we examined factors affecting the calcium increase pattern in cultured astrocytes and investigated the consequences of the astrocytic calcium response in slice preparations. We found that growth factors (GFs) (EGF plus basic FGF) promoted calcium oscillation in response to glutamate, ATP, or thimerosal (which directly activates the inositol-1,4,5 triphosphate receptor) and that this effect was suppressed by pro-inflammatory cytokines (interleukin-1β or tumor necrosis factor-α), lipopolysaccharide, or a MEK (mitogen-activated protein kinase kinase) inhibitor, suggesting dual regulation of calcium oscillation in astrocytes by factors affecting brain function and pathology via the mitogen-activated protein kinase (MAPK) cascade. The calcium oscillation was accompanied by enlargement of the calcium store, cell proliferation, and the development of a hypertrophic morphology. The cytokines suppressed GF-induced MAPK-dependent immediate early gene promoter activation, but not phosphorylation of extracellular signal-regulated kinase (ERK), showing that they affected gene regulation by acting on the MAPK cascade downstream of ERK. In slice preparations, a metabotropic glutamate receptor agonist converted the spontaneous neuronal calcium increase, attributable to synaptic transmission, to an oscillatory response similar to that seen in astrocytes in culture, indicating that the calcium response in astrocytes acted as a feedback mechanism on the activity of neighboring neurons. This is the first evidence for a dual regulation of calcium oscillation by physiological factors and for the control of calcium dynamics actually being used in physiological processes.
Mediolateral Compartmentalization of the Cerebellum Is Determined on the “Birth Date” of Purkinje Cells
Authors: Hashimoto Mitsuhiro , Mikoshiba Katsuhiko
Published: April 2018

The adult cerebellum is functionally compartmentalized into clusters along the mediolateral axis (M-L clusters), and a variety of molecular makers are expressed in specific subsets of M-L clusters. These M-L clusters appear to be the basic structure in which cerebellar functions are performed, but the mechanisms by which cerebellar mediolateral compartmentalization is established are still unclear. To address these questions, we examined the development of M-L clusters using replication-defective adenoviral vectors. The adenoviral vectors effectively introduced foreign genes into the neuronal progenitor cells of the cerebellum in a birth date-specific manner, allowing us to observe the native behavior of each cohort of birth date-related progenitor cells. When the adenoviral vectors were injected into the midbrain ventricle of mouse embryos on embryonic days 10.5 (E10.5), E11.5, and E12.5, the virally infected cerebellar progenitor cells developed into Purkinje cells. Notably, the Purkinje cells that shared the same birth date formed specific subsets of M-L clusters in the cerebellum. Each subset of M-L clusters displayed nested and, in part, mutually complementary patterns, and these patterns were unchanged from the late embryonic stage to adulthood, suggesting that Purkinje cell progenitors are fated to form specific subsets of M-L clusters after their birth between E10.5 and E12.5. This study represents the first such direct observation of Purkinje cell development. Moreover, we also show that there is a correlation between the M-L clusters established by the birth date-related Purkinje cells and the domains ofengrailed-2, Wnt-7B, L7/pcp2, and EphA4 receptor tyrosine kinase expression.
Plasticity of GABABReceptor-Mediated Heterosynaptic Interactions at Mossy Fibers After Status Epilepticus
Authors: Chandler Kate E. , Princivalle Alessandra P. , Fabian-Fine Ruth , Bowery Norman G. , Kullmann Dimitri M. , Walker Matthew C.
Published: April 2018

Several neurotransmitters, including GABA acting at presynaptic GABABreceptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABABreceptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABABreceptor agonist baclofen. Autoradiography revealed a reduction in GABABreceptor binding in the stratum lucidum after status epilepticus. Failure of GABABreceptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus.
Effects of Spontaneous Eye Movements on Spatial Memory in Macaque Periarcuate Cortex
Authors: Balan Puiu F. , Ferrera Vincent P.
Published: April 2018

Persistent activity in prefrontal cortex during delayed response tasks is a putative neural correlate of spatial working memory. We tested whether this activity was sensitive to eye movements made during the memory interval by recording from prefrontal neurons while monkeys performed a delayed spatial matching saccade task in which they were allowed to make eye movements freely. We found that eye movements degraded the spatial tuning of persistent activity even as there was an improvement in behavioral performance. Although the strength of the memory signal decreased, delay activity continued to signal the location of cue. The results suggest that free eye movements reduce neuronal gain rather than add variability. The saccades performed during the delay suggest the existence of a rehearsal mechanism that could contribute to working memory maintenance. The results do not provide support for a segregation of storage and executive functions in the periarcuate cortex.
Treadmill Locomotion in the Intact and Spinal Mouse
Authors: Leblond Hugues , L'Espérance Marion , Orsal Didier , Rossignol Serge
Published: April 2018

Because the genetic characteristics of several inbred strains of mice are well identified, their use is becoming increasingly popular in spinal cord injury research. In this context, it appears particularly important to document adequately motor patterns, such as locomotion in normal mice, to establish some baseline values of locomotor characteristics. It also seems crucial to determine the extent to which mice can express a locomotor pattern after a complete spinal transection to establish a baseline on which one can evaluate the effects of treatments after spinal injury. Therefore, we have used conventional techniques to document the kinematics of treadmill locomotion in intact mice (n= 11) and in mice with a complete section of the spinal cord at T8 (n= 12). The results show that the kinematics and EMG of adult normal mice can be adequately monitored with such conventional equipment and that mice can re-express hindlimb locomotion within 14 d after spinalization, without any pharmacological treatments. The angular excursions of the hip, knee, and ankle are similar to those of the intact mice, although the joints are sometimes more flexed. After spinal cord transection, out-of-phase alternation between the homologous limbs recovered, whereas the timing between homolateral limbs was completely lost. This remarkable ability of mice to express hindlimb locomotion after a complete spinalization should be taken into account in the evaluation of various procedures aimed at promoting the functional recovery of locomotion after spinal lesions.
Enigmas of the Third Space: Mingus and Varèse at Greenwich House, 1957
Authors: Cohen Brigid
Published: April 2018

In 1957 Edgard Varèse led a series of improvisation sessions in Greenwich Village with jazz musicians who included Charles Mingus, Art Farmer, Don Butterfield, Teo Macero, and Ed Shaughnessy. Few scholars have explored this episode, a lacuna that speaks to a wider, racially inflected rift in historiographies of jazz and non-jazz musical avant-gardes. Against this tendency I bring new light to the sessions as a messy and fleeting exchange characterized by mutual curiosity and crossed signals, drawing on analysis of session recordings, original interviews, and archival research. Within the larger ensemble of musicians I focus on Edgard Varèse and Charles Mingus in particular, in order to address dilemmas of race and citizenship in downtown New York during a period of postwar American cultural ascendency and national canon formation. To this end I claim Homi Bhabha's notion of “third space” as the most promising sign under which to construe the sessions, a concept that foregrounds ambivalent and transient cultural crossings that play out across an uneven field of power.
Gênero e sexualidade: entre a explosão do pluralismo e os embates da normalização
Authors: Seffner Fernando , Borrillo Daniel , Ribeiro Fernanda Bittencourt
Published: April 2018

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Effects of the Methanol Leaf Extract Of Chromolaena Odorata on Blood Lipids and the Histology of the Kidney in Salmonella Typhi Infected Wistar Rats
Authors: Charles Isirima, Joshua , Minakiri Siminialayi, Iyeopu
Published: April 2018

Infection with Salmonella typhi, the causative agent of typhoid fever is said to be associated with dyslipidemia. This study evaluated the effects of Chromolaena odorata on the lipid profile and histology of the kidneys in Salmonella typhi infected Wistar rats. The animals were divided into six groups: group 1 was normal control, group 2 was infected with Salmonella typhi without treatment, groups 3, 4 and 5 were Salmonella typhi infected and treated with 100mg/kg, 200mg/kg and 400mg/kg of the extract, respectively, and group 6 was infected and treated with 500mg/70kg of ciprofloxacin. The animals were inoculated with a single infectious dose of Salmonella typhi bacteria and were subsequently, treated with graded doses of the methanol leaf extract of Chromolaena odorata and 500mg/70kg dose of ciprofloxacin for a period of seventeen days, when the animals were confirmed infected. The animals were humanely sacrificed using diethyl ether anesthesia and blood sample was collected for lipid profile investigation and the kidneys were harvested for histological examination. Chromolaena odorata administration reversed the dyslipidemia and histological changes induced by Salmonella typhi.