bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical Regions Involved in Perceiving Object Shape
Authors: Kourtzi Zoe , Kanwisher Nancy
Published: April 2018

The studies described here use functional magnetic resonance imaging to test whether common or distinct cognitive and/or neural mechanisms are involved in extracting object structure from the different image cues defining an object's shape, such as contours, shading, and monocular depth cues. We found overlapping activations in the lateral and ventral occipital cortex [known as the lateral occipital complex (LOC)] for objects defined by different visual cues (e.g., grayscale photographs and line drawings) when each was compared with its own scrambled-object control. In a second experiment we found a reduced response when objects were repeated, independent of whether they appeared in the same or a different format (i.e., grayscale images vs line drawings). A third experiment showed that activation in the LOC was no stronger for three-dimensional shapes defined by contours or monocular depth cues, such as occlusion, than for two-dimensional shapes, suggesting that these regions are not selectively involved in processing three-dimensional shape information. These results suggest that common regions in the LOC are involved in extracting and/or representing information about object structure from different image cues.
Classical Conditioning of Feeding inAplysia: II. Neurophysiological Correlates
Authors: Lechner Hilde A. , Baxter Douglas A. , Byrne John H.
Published: April 2018

Feeding behavior inAplysia californicacan be classically conditioned using tactile stimulation of the lips as conditional stimulus (CS) and food as unconditional stimulus (US) [Lechner et al., 2000 (companion paper)]. Conditioning resulted in an increase in the number of CS-evoked bites that persisted for at least 24 hr after training. In this study, neurophysiological correlates of classical conditioning training were identified and characterized in anin vitropreparation of the cerebral and buccal ganglia. Stimulation of a lip nerve (AT4), which mediates mechanosensory information, resulted in a greater number of buccal motor patterns (BMPs) in ganglia isolated from animals that had received paired training than in ganglia from control animals. The majority of the evoked BMPs were classified as ingestion-like patterns. Intracellular recordings from pattern-initiating neuron B31/32 revealed that stimulation of AT4evoked greater excitatory input in B31/32 in preparations from animals that had received paired training than from control animals. In contrast, excitatory input to buccal neuron B4/5 in response to stimulation of AT4was not significantly increased by paired training. Moreover, correlates of classical conditioning were specific to stimulation of AT4. The number of spontaneously occurring BMPs and the intrinsic properties of two buccal neurons (B4/5 and B31/32) did not differ between groups. These results suggest that appetitive classical conditioning of feeding resulted in the pairing-specific strengthening of the polysynaptic pathway between afferent fibers and pattern-initiating neurons of the buccal central pattern generator.
Reversal of Dopamine D2Receptor Responses by an Anandamide Transport Inhibitor
Authors: Beltramo Massimiliano , de Fonseca Fernando Rodrı́guez , Navarro Miguel , Calignano Antonio , Gorriti Miguel Angel , Grammatikopoulos Gerasimos , Sadile Adolfo G. , Giuffrida Andrea , Piomelli Daniele
Published: April 2018

We characterized the pharmacological properties of the anandamide transport inhibitorN-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D2family receptors. Rat brain slices accumulated [3H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alonein vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D2family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines.
Coregulation of Voltage-Dependent Kinetics of Na+and K+Currents in Electric Organ
Authors: McAnelly M. Lynne , Zakon Harold H.
Published: April 2018

The electric organ cells ofSternopygusgenerate action potentials whose durations vary over a fourfold range. This variation in action potential duration is the basis for individual variation in a communication signal. Thus, action potential duration must be precisely regulated in these cells. We had observed previously that the inactivation kinetics of the electrocyte Na+current show systematic individual variation. In this study, using a two-electrode voltage clamp, we found that the voltage-dependent activation and deactivation kinetics of the delayed rectifying K+current in these cells covary in a graded and predictable manner across fish. Furthermore, when Na+and K+currents were recorded in the same cell, their voltage-dependent kinetics were highly correlated. This finding illustrates an unprecedented degree of coregulation of voltage-dependent properties in two molecularly distinct ionic channels. Such a coregulation of ionic channels is uniquely observable in a cell specialized to generate individual differences in electrical activity and in which the results of biophysical control mechanisms are evident in behaving animals. We propose that the precise coregulation of the voltage-dependent kinetics of multiple ionic currents may be a general mechanism for regulation of membrane excitability.
Activity-Dependent Plasticity of Descending Synaptic Inputs to Spinal Motoneurons in anIn VitroTurtle Brainstem–Spinal Cord Preparation
Authors: Johnson Stephen M. , Mitchell Gordon S.
Published: April 2018

Anin vitrobrainstem–spinal cord preparation from adult turtles was used to test the hypothesis that descending synaptic inputs to multifunctional spinal motoneurons (i.e., involved in respiration and locomotion) express activity-dependent depression or potentiation. The tissue was placed in a chamber that allowed for separate superfusion of the brainstem, spinal segments C2–C4, and C5–D1. Action potential conduction between the brainstem and spinal segments C5–D1was blocked by superfusing C2–C4with Na+-free solution. With C5–D1at [K+] = 10 mm, electrical stimulation at C5every 2 min evoked potentials in intact pectoralis (expiratory, inward rotation of shoulder) and serratus (inspiratory, outward rotation of shoulder) nerves that were stable for at least 2 hr. Application of conditioning stimulation (900 pulses at 1 or 10 Hz) at C5decreased pectoralis evoked potential amplitudes by ∼40% initially and by 20% after 90 min; serratus evoked potentials were unaltered. Conditioning stimulation (100 Hz, 900 pulses) transiently depressed pectoralis evoked potential amplitude by <20% but produced a delayed 72% increase in serratus evoked potential amplitude after ∼80 min. Conditioning stimulation (10 Hz) at C5also reduced the amplitude of sensory afferent evoked potentials in pectoralis produced by stimulating ipsilateral dorsal roots at C8. Thus, long-lasting changes in descending synaptic inputs to multifunctional spinal motoneurons were frequency-dependent and heterosynaptic. We hypothesize that activity-dependent plasticity may modulate descending synaptic drive to spinal motoneurons involved in both respiration and locomotion.
Dual Effects of d-Amphetamine on Dopamine Neurons Mediated by Dopamine and Nondopamine Receptors
Authors: Shi Wei-Xing , Pun Chen-Lun , Zhang Xue-Xiang , Jones Michelle D. , Bunney Benjamin S.
Published: April 2018

By increasing dopamine (DA) release and activating feedback mechanisms, amphetamine and related psychostimulants are known to inhibit DA cell firing. Here, we report thatd-amphetamine also has an excitatory effect on DA cells, which under control conditions, is masked by the inhibitory effect ofd-amphetamine and is revealed when D2-like receptors are blocked. Thus, usingin vivosingle-unit recording in rats, we found that the selective D2 antagonist raclopride not only blocked the inhibition induced byd-amphetamine but also enabledd-amphetamine to excite DA cells. The excitation, expressed as an increase in both firing rate and bursting, persisted when both D1- and D2-like receptors were blocked by SCH23390 and eticlopride, suggesting that it is not mediated by DA receptors. The norepinephrine uptake blocker nisoxetine mimicked the effect ofd-amphetamine, especially the increase in bursting, whereas the 5-HT uptake blocker fluoxetine produced no significant effect. Adrenergic α1 antagonists prazosin and WB4101 and the nonselective α antagonist phenoxybenzamine completely blocked increase in bursting induced byd-amphetamine and partially blocked the increase in firing rate. The α2 antagonist idazoxan and the β antagonist propranolole, however, failed to preventd-amphetamine from producing the excitation. Thus, revising the traditional concept, this study suggests thatd-amphetamine has two effects on DA cells, a DA-mediated inhibition and a non-DA-mediated excitation. The latter is mediated in part through adrenergic α1 receptors.
Light Transduction in Invertebrate Hyperpolarizing Photoreceptors: Possible Involvement of a Go-Regulated Guanylate Cyclase
Authors: Gomez Maria del Pilar , Nasi Enrico
Published: April 2018

The hyperpolarizing receptor potential of scallop ciliary photoreceptors is attributable to light-induced opening of K+-selective channels. Having previously demonstrated the activation of this K+current by cGMP, we examined upstream events in the transduction cascade. GTP-γ-S produced persistent excitation after a flash, accompanied by decreased sensitivity and acceleration of the photocurrent, whereas GDP-β-S only inhibited responsiveness, consistent with the involvement of a G-protein. Because Go(but not Gtnor Gq) recently has been detected in the ciliary retinal layer of a related species, we tested the effects of activators of Go; mastoparan peptides induced an outward current suppressible by blockers of the light-sensitive conductance such asl-cis-diltiazem. In addition, intracellular dialysis with the A-protomer of pertussis toxin (PTX) depressed the photocurrent. The mechanisms that couple G-protein stimulation to changes in cGMP were investigated. Intracellular IBMX enhanced the photoresponse with little effect on the baseline current, a result that argues against regulation by light of phosphodiesterase activity. LY83583, an inhibitor of guanylate cyclase (GC), exerted a reversible, dose-dependent suppression of the photocurrent. By contrast, ODQ, an antagonist of NO-sensitive GC, and YC-1, an activator of NO-sensitive GC, failed to alter the light response or the holding current; furthermore, the NO synthase inhibitorN-methyl-l-arginine was inert, indicating that the NO signaling pathway is not implicated. Taken together, these results suggest a novel type of phototransduction cascade in which stimulation of a PTX-sensitive Gomay activate a membrane GC to induce an increase in cGMP and the consequent opening of light-dependent channels.
Properties and Plasticity of Paired-Pulse Depression at a Central Synapse
Authors: Waldeck Robert F. , Pereda Alberto , Faber Donald S.
Published: April 2018

Synaptic depression was studied at the axo-axonic connection between the goldfish Mauthner axon and identified cranial relay interneurons using simultaneous presynaptic and postsynaptic recordings and a paired-pulse stimulus paradigm. We used interstimulus intervals (ISIs) ranging from 10 msec to 1 sec and a cycle time of ∼5 sec. Depression (Δ EPSP/EPSP1) was maximal at the shorter intervals (80%) and decreased exponentially with a τ ∼ 400 msec (360 ± 107 msec, mean ± SD). We found the amplitudes of the first and second EPSP were not correlated, indicating the magnitude of depression does not depend on the amount of transmitter released by the conditioning stimulus. At short ISIs, the latency of EPSP2 was 23% longer than that of EPSP1 and recovered to control with τ ∼ 400 msec, whereas rise time and decay time were not altered significantly. The latency distribution, which is determined by the timing of the first quantum released each trial, was used to derive α(t), the rate of evoked exocytosis after an action potential. α(t) was biphasic, and both components were consistently delayed during depression. Presynaptic manipulations of putative intracellular regulatory pathways, such as Ca2+and GTPγS injections, preferentially affected the amplitude of EPSP1 or EPSP2. These results are not consistent with simple depletion of the available pool of synaptic vesicles as the major mechanism underlying depression. They rather suggest that it is attributable to a modification or refractoriness of the release process and that there may be multiple pathways subserving evoked exocytosis.
Selective Alterations in GABAAReceptor Subtypes in Human Temporal Lobe Epilepsy
Authors: Loup Fabienne , Wieser Heinz-Gregor , Yonekawa Yasuhiro , Aguzzi Adriano , Fritschy Jean-Marc
Published: April 2018

Temporal lobe epilepsy (TLE) is associated with impaired inhibitory neurotransmission. Studies in animal models suggest that GABAAreceptor dysfunction contributes to epileptogenesis. To understand the mechanisms underlying TLE in humans, it is fundamental to determine whether and how GABAAreceptor subtypes are altered. Furthermore, identifying novel receptor targets is a prerequisite for developing selective antiepileptic drugs. We have therefore analyzed subunit composition and distribution of the three major GABAAreceptor subtypes immunohistochemically with subunit-specific antibodies (α1, α2, α3, β2,3, and γ2) in surgical specimens from TLE patients with hippocampal sclerosis (n= 16). Profound alterations in GABAAreceptor subtype expression were observed when compared with control hippocampi (n= 10). Although decreased GABAAreceptor subunit staining, reflecting cell loss, was observed in CA1, CA3, and hilus, the distinct neuron-specific expression pattern of the α-subunit variants observed in controls was markedly changed in surviving neurons. In granule cells, prominent upregulation mainly of the α2-subunit was seen on somata and apical dendrites with reduced labeling on basal dendrites. In CA2, differential rearrangement of all three α-subunits occurred. Moreover, there was layer-specific loss of α1-subunit-immunoreactive interneurons in hippocampus proper, whereas surviving interneurons exhibited extensive changes in dendritic morphology. Throughout, expression patterns of β2,3- and γ2-subunits largely followed those of α-subunit variants. These results demonstrate unique subtype-specific expression of GABAAreceptors in human hippocampus. The significant reorganization of distinct receptor subtypes in surviving hippocampal neurons of TLE patients with hippocampal sclerosis underlines the potential for synaptic plasticity in the human GABA system.
Synaptic Interactions between Thalamic Inputs to Simple Cells in Cat Visual Cortex
Authors: Usrey W. Martin , Alonso Jose-Manuel , Reid R. Clay
Published: April 2018

We performed experiments in the cat geniculocortical pathway,in vivo,to examine how presynaptic spikes interact to influence the firing of postsynaptic targets. In particular, we asked (1) how do multiple spikes from a single presynaptic neuron interact to influence the firing of a postsynaptic target (homosynaptic interactions), (2) how do spikes from two different presynaptic neurons interact (heterosynaptic interactions), and (3) what is the time course of homosynaptic and heterosynaptic interactions? We found that both homosynaptic and heterosynaptic interactions increase the likelihood of driving a postsynaptic spike, although with different time courses. For two spikes traveling down a single geniculate axon, the second spike is more effective than the first for ∼15 msec. For two spikes on separate axons, the interaction is faster (∼7 msec duration, ∼2.5 msec time constant). Thus changes in firing rate are perhaps best relayed by homosynaptic interactions, whereas heterosynaptic interactions may help detect coincident spikes from different thalamic inputs.
Firing Rate of Nucleus Accumbens Neurons Is Dopamine-Dependent and Reflects the Timing of Cocaine-Seeking Behavior in Rats on a Progressive Ratio Schedule of Reinforcement
Authors: Nicola Saleem M. , Deadwyler Sam A.
Published: April 2018

The progressive ratio (PR) schedule of reinforcement is used to determine the reinforcing properties of rewards such as drugs of abuse. In this schedule, the animal is required to press a lever a progressively increasing number of times to receive a reward; the highest ratio obtained before the animal ceases responding is termed “breakpoint.” We recorded neuronal spike activity from cells in the nucleus accumbens (NAc) of rats responding on a PR schedule for cocaine reinforcement. A common subtype of NAc cells demonstrated firing rates that varied according to the time between cocaine deliveries. The firing rate was inversely related to the NAc cocaine level predicted by a pharmacokinetic model. At higher response-to-reward ratios, inter-reward intervals were increased, resulting in a decrease in modeled cocaine level and a concomitant increase in firing rate over the session. The final increase in firing rate above a threshold value suggests a neural correlate of breakpoint. The effects of preadministration of dopamine D1 or D2 antagonists on the animals' behavior were similar in that both reduced breakpoint; however, each antagonist had markedly different effects on NAc cell firing. The D1 antagonist SCH23390 reduced firing rates, even at low cocaine levels, whereas the D2 antagonist eticlopride induced a rightward shift in the dose dependence of NAc cell firing relative to modeled cocaine level. Our results suggest that the firing of NAc cells reflects changes in cocaine levels and thereby contributes to the temporal spacing of self-administration and to the cessation of responding at breakpoint.
Perinatal Distress Leads to Lateralized Medial Prefrontal Cortical Dopamine Hypofunction in Adult Rats
Authors: Brake Wayne G. , Sullivan Ron M. , Gratton Alain
Published: April 2018

Obstetric complications involving anoxia or prolonged hypoxia are suspected to increase the risk for such mental disorders as schizophrenia and attention deficit–hyperactivity disorder. In previous studies, we reported evidence of enhanced nucleus accumbens (NAcc) dopamine (DA) function in adult rats subjected to intrauterine anoxia during cesarean (C) section birth. In the present study, we used voltammetry and monoamine-sensitive electrodes to investigate the possibility that this functional hyperactivity of the meso-NAcc system is attributable to a loss of inhibitory control from the medial prefrontal cortex (PFC). We monitored the DA responses to repeated once-daily stress in the right or left PFC of adult male rats born vaginally (VAG) or by C-section, either with (C + 15) or without (C + 0) an additional 15 min of intrauterine anoxia. In C + 15 animals, we observed a pronounced and persistent blunting of stress-induced DA release in the right PFC but not in the left; with repeated testing, a similar pattern of dampened right PFC DA stress responses emerged in C + 0 animals. In addition, C + 15 animals were spontaneously more active than VAG and C + 0 animals and displayed an increase in PFC DA transporter density that was also lateralized to the right hemisphere. There was no evidence, however, that PFC D1and D2receptor levels differed between birth groups or hemisphere. These findings suggest a mechanism by which perinatal complications involving anoxia might contribute to the etiology of mental disorders that have been linked to disturbances in central DA transmission and lateralized PFC dysfunction.
Mechanism of Interleukin-1- and Tumor Necrosis Factor α-Dependent Regulation of the α1-Antichymotrypsin Gene in Human Astrocytes
Authors: Kordula Tomasz , Bugno Marcin , Rydel Russell E. , Travis James
Published: April 2018

The expression of α1-antichymotrypsin (ACT) is significantly enhanced in affected brain regions in Alzheimer's disease. This serine proteinase inhibitor specifically colocalizes with filamentous β-amyloid deposits and recently has been shown to influence both formation and destabilization of β-amyloid fibrils. In the brain, ACT is expressed in astrocytes, and interleukin-1 (IL-1), tumor necrosis factor α (TNF), oncostatin M (OSM), and IL-6/soluble IL-6 receptor complexes control synthesis of this inhibitor. Here, we characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5′ distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5′ NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. In addition, we demonstrate that the 5′ untranslated region of the ACT mRNA does not contribute to cytokine-mediated activation. Finally, we find that overexpression of the NF-kB inhibitor (IkB) totally inhibits any activation mediated by the newly identified IL-1/TNF enhancer of the ACT gene.
Abnormal GABAAReceptor-Mediated Currents in Dorsal Root Ganglion Neurons Isolated from Na–K–2Cl Cotransporter Null Mice
Authors: Sung Ki-Wug , Kirby Michael , McDonald Michael P. , Lovinger David M. , Delpire Eric
Published: April 2018

We have recently disruptedSlc12a2, the gene encoding the secretory Na–K–2Cl cotransporter in mice (NKCC1) (Delpire et al., 1999). Gramicidin perforated-patch and whole-cell recordings were performed to study GABA-induced currents in dorsal root ganglion (DRG) neurons isolated from wild-type and homozygote NKCC1 knock-out mice. In wild-type DRG neurons, strong GABA-evoked inward current was observed at the resting membrane potential, suggesting active accumulation of Cl−in these cells. This GABA-induced current was blocked by picrotoxin, a GABAAreceptor blocker. The strong Cl−accumulation that gives rise to depolarizing GABA responses is caused by Na–K–2Cl cotransport because reduction of external Cl−or application of bumetanide induced a decrease in [Cl−]i, whereas an increase in external K+caused an apparent [Cl−]iaccumulation. In contrast to control neurons, little or no net current was observed at the resting membrane potential in homozygote NKCC1 mutant DRG neurons.EGABAwas significantly more negative, demonstrating the absence of Cl−accumulation in these cells. Application of bumetanide induced a positive shift ofEGABA, suggesting the presence of an outward Cl−transport mechanism. In agreement with an absence of GABA depolarization in DRG neurons, behavioral analysis revealed significant alterations in locomotion and pain perception in the knock-out mouse. Our results clearly demonstrate that the Na–K–2Cl cotransporter is responsible for [Cl−]iaccumulation in DRG neurons and that via regulation of intracellular Cl−, the Na–K–2Cl cotransporter participates in the modulation of GABA neurotransmission and sensory perception.
Differential Localization of Divalent Metal Transporter 1 with and without Iron Response Element in Rat PC12 and Sympathetic Neuronal Cells
Authors: Roth Jerome A. , Horbinski Craig , Feng Li , Dolan Kevin G. , Higgins Dennis , Garrick Michael D.
Published: April 2018

Two isoforms of divalent metal transporter 1 (DMT1) (Nramp2 and DCT1) are encoded by two mRNA species, one of which contains an iron response element (IRE) motif in the 3′-noncoding region. The subcellular distribution of the two isoforms of DMT1 is distinct, and the −IRE species accumulates in the nucleus of neuronal or neuronal-like cells. Reverse transcription-PCR and Western blot analysis of PC12 cells reveals that these cells express both forms of DMT1. Immunofluorescence and immunoblotting studies, using immunospecific antibodies to the −IRE form of DMT1, demonstrate that this form of the transporter, in PC12 cells, is predominantly localized in the nucleus, cell membrane, and neurites with only weak staining of the cell body. Studies using antibodies to the +IRE form indicate that this species of DMT1 is distributed within vesicles in the cell body and neurite projections, with minimal nuclear staining. Similar staining patterns are observed for the two forms of DMT1 in cultures of sympathetic ganglion neurons isolated from perinatal rat pups. To determine whether nuclear localization of the −IRE form of DMT1 is constrained to neuronal or neuronal-like cells, immunocytochemical studies were performed with human embryonic kidney 293T (HEK293T), HEP2G hepatoma and medulloblastoma, and rat Schwann cells. The −IRE-specific antibodies stained nuclei from medulloblastoma, whereas little nuclear staining was observed with HEK293T, hepatoma, or Schwann cells. The unexpected finding that the −IRE species of DMT1 selectively accumulates in the nucleus of neuronal and neuronal-like cells leads us to postulate that the two proteins may have different functionsin vivo.
Dual Roles for c-Jun N-Terminal Kinase in Developmental and Stress Responses in Cerebellar Granule Neurons
Authors: Coffey Eleanor T. , Hongisto Vesa , Dickens Martin , Davis Roger J. , Courtney Michael J.
Published: April 2018

c-Jun N-terminal kinases (JNKs) typically respond strongly to stress, are implicated in brain development, and are believed to mediate neuronal apoptosis. Surprisingly, however, JNK does not respond characteristically to stress in cultured cerebellar granule (CBG) neurons, a widely exploited CNS model for studies of death and development, despite the regulation of its substrate c-Jun. To understand this anomaly, we characterized JNK regulation in CBG neurons. We find that the specific activity of CBG JNK is elevated considerably above that from neuron-like cell lines (SH-SY5Y, PC12); however, similar elevated activities are found in brain extracts. This activity does not result from cellular stress because the stress-activated protein kinase p38 is not activated. We identify a minor stress-sensitive pool of JNK that translocates with mitogen-activated protein kinase kinase-4 (MKK4) into the nucleus. However, the major pool of total activity is cytoplasmic, residing largely in the neurites, suggesting a non-nuclear role for JNK in neurons. A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease. A role for JNK during differentiation is supported by modulation of neuritic architecture after expression of dominant inhibitory regulators of the JNK pathway. Channeling of JNK signaling away from c-Jun during differentiation is consistent with the presence in the nucleus of the JNK/MKK7 scaffold protein JNK-interacting protein, which inhibits JNK–c-Jun interaction. We propose a model in which distinct pools of JNK serve different functions, providing a basis for understanding multifunctional JNK signaling in differentiating neurons.
p75 Is Important for Axon Growth and Schwann Cell Migration during Development
Authors: Bentley Cornelia A. , Lee Kuo-Fen
Published: April 2018

Mice lacking the low-affinity neurotrophin receptor p75 have multiple peripheral neural deficits. Here we examined the developmental nature of these deficiencies. Peripheral axons in p75 −/− embryos were severely stunted and poorly arborized from embryonic day 11.5 (E11.5) to E14.5.In vitro, neurite outgrowth from the dorsal root ganglia was significantly decreased in the p75 −/− embryos at E12.5, suggesting that stunted axonal growth in the embryo may result in part from defects in neurite elongation. Additionally, Schwann cell marker S100β immunoreactivity was decreased or absent along the growing axons of the ophthalmic branch from the trigeminal ganglia in p75 −/− embryos. Electron microscopy studies of the axons of the trigeminal ganglion at E13.5 revealed that in the p75 mutant embryo, nerve bundles were highly impaired and that coverage of the growing axons by Schwann cell cytoplasm was substantially reduced.In vitro, Schwann cell migration from the dorsal root ganglia was significantly decreased in the p75 −/− embryos at E12.5, suggesting that the lack of S100β staining and Schwann cell coverage in the p75 mutant results from a deficit in Schwann cell migration. These results provide evidence that p75 is important in the developing embryo for regulating axon growth and arborization and for Schwann cell migration.
Corticotropin-Releasing Factor IncreasesIn VitroFiring Rates of Serotonergic Neurons in the Rat Dorsal Raphe Nucleus: Evidence for Activation of a Topographically Organized Mesolimbocortical Serotonergic System
Authors: Lowry Christopher A. , Rodda Joanne E. , Lightman Stafford L. , Ingram Colin D.
Published: April 2018

In vivostudies suggest that the stress-related neuropeptide corticotropin-releasing factor (CRF) modulates serotonergic neurotransmission. To investigate the underlying mechanisms for this interaction, the present study examined the effects of CRFin vitroon dorsal raphe neurons that displayed electrophysiological and pharmacological properties consistent with a serotonergic phenotype. In the presence of either 1 or 2 mmCa2+, perfusion of ovine CRF or rat/human CRF rapidly and reversibly increased firing rates of a subpopulation (19 of 70, 27%) of serotonergic neurons predominantly located in the ventral portion of the dorsal raphe nucleus. For a given responsive neuron, the excitatory effects of CRF were reproducible, and there was no tachyphylaxis. Excitatory effects were dose-dependent (over the range of 0.1–1.6 μm) and were completely absent after exposure to the competitive CRF receptor antagonists α-helical CRF9–41or rat/human [d-Phe12, Nle21,38, α-Me-Leu37]-CRF12–41. Both the proportion of responsive neurons and the magnitude of excitatory responses to CRF in the ventral portion of the caudal dorsal raphe nucleus were markedly potentiated in slices prepared from animals previously exposed to isolation and daily restraint stress for 5 d. Immunohistochemical staining of the recorded slices revealed close associations between CRF-immunoreactive varicose axons and tryptophan hydroxylase-immunoreactive neurons in the area of the recordings, providing anatomical evidence for potential direct actions of CRF on serotonergic neurons. The electrophysiological properties and the distribution of responsive neurons within the dorsal raphe nucleus are consistent with the hypothesis that endogenous CRF activates a topographically organized mesolimbocortical serotonergic system.
Nav2/NaG Channel Is Involved in Control of Salt-Intake Behavior in the CNS
Authors: Watanabe Eiji , Fujikawa Akihiro , Matsunaga Haruyuki , Yasoshima Yasunobu , Sako Noritaka , Yamamoto Takashi , Saegusa Chika , Noda Masaharu
Published: April 2018

Nav2/NaG is a putative sodium channel, whose physiological role has long been an enigma. We generatedNav2gene-deficient mice by inserting thelacZgene. Analysis of the targeted mice allowed us to identify Nav2-producing cells by examining thelacZexpression. Besides in the lung, heart, dorsal root ganglia, and Schwann cells in the peripheral nervous system,Nav2was expressed in neurons and ependymal cells in restricted areas of the CNS, particularly in the circumventricular organs, which are involved in body-fluid homeostasis. Under water-depleted conditions,c-fosexpression was markedly elevated in neurons in the subfornical organ and organum vasculosum laminae terminalis compared with wild-type animals, suggesting a hyperactive state in theNav2-null mice. Moreover, the null mutants showed abnormal intakes of hypertonic saline under both water- and salt-depleted conditions. These findings suggest that the Nav2 channel plays an important role in the central sensing of body-fluid sodium level and regulation of salt intake behavior.
Functional Magnetic Resonance Imaging (fMRI) Activity in the Hippocampal Region during Recognition Memory
Authors: Stark Craig E. L. , Squire Larry R.
Published: April 2018

Neuroimaging studies have often failed to observe activity in the hippocampal region during memory retrieval. Recently, two functional magnetic resonance imaging studies reported activity in the hippocampal region associated with recollective success. In both, participants studied pictures of objects and were given a recognition memory test with words that either did or did not name the studied objects. The recognition test was therefore cross-modal or associative in nature. These findings raise the question of what circumstances are required to observe activity in the hippocampal region during memory retrieval. Here, we report that robust hippocampal activity for targets relative to foils occurred during retrieval in a recognition memory task when single words were used at both study and test, as well as when pictures of single nameable objects were used at both study and test. The hippocampal region is involved not just in overtly associative tasks but more broadly in the recollection of recently occurring facts and events.
Persistent Alterations in Dendrites, Spines, and Dynorphinergic Synapses in the Nucleus Accumbens Shell of Rats with Neuroleptic-Induced Dyskinesias
Authors: Meredith Gloria E. , De Souza Ian E. J. , Hyde Thomas M. , Tipper Geoffrey , Wong Mai Luen , Egan Michael F.
Published: April 2018

Chronic treatment of humans or experimental animals with classical neuroleptic drugs can lead to abnormal, tardive movements that persist long after the drugs are withdrawn. A role in these neuroleptic-induced dyskinesias may be played by a structural change in the shell of the nucleus accumbens where the opioid peptide dynorphin is upregulated in treated rats that show vacuous chewing movements (VCMs). The shell of the nucleus accumbens normally contains a dense plexus of dynorphinergic fibers especially in its caudomedial part. After 27 weeks of haloperidol administration and 18 weeks of withdrawal, the immunoreactive labeling of this plexus is intensified when compared with that after vehicle treatment. In addition, medium spiny neurons here show a significant increase in spine density, dendritic branching, and numbers of terminal segments. In the VCM-positive animals, the dendritic surface area is reduced, and dynorphin-positive terminals contact more spines and form more asymmetrical specializations than do those in animals without the syndrome (VCM-negative and vehicle-treated groups). Persistent, neuroleptic-induced oral dyskinesias could therefore be caused by incontrovertible alterations, involving terminal remodeling or sprouting, to the synaptic connectivity of the accumbal shell.
Spatial Generalization from Learning Dynamics of Reaching Movements
Authors: Shadmehr Reza , Moussavi Zahra M. K.
Published: April 2018

When subjects practice reaching movements in a force field, they learn a new sensorimotor map that associates desired trajectories to motor commands. The map is formed in the brain with elements that allow for generalization beyond the region of training. We quantified spatial generalization properties of these elements by training in one extreme of the reachable space and testing near another. Training resulted in rotations in the preferred direction (PD) of activation of some arm muscles. We designed force fields that maintained a constant rotation in muscle PDs as the shoulder joint rotated in the horizontal plane. In such fields, training in a small region resulted in generalization to near and far work spaces (80 cm). In one such field, the forces on the hand reversed directions for a given hand velocity with respect to the location of original training. Despite this, there was generalization. However, if the field was such that the change in the muscle PDs reversed as the work spaces changed, then performance was worse than performance of naive subjects. We suggest that the sensorimotor map of arm dynamics is represented in the brain by elements that globally encode the position of the arm but locally encode its velocity. The elements have preferred directions of movement but are modulated globally by the position of the shoulder joint. We suggest that tuning properties of cells in the motor system influence behavior and that this influence is reflected in the way that we learn dynamics of reaching movements.
Differential cAMP Gating of Glutamatergic Signaling Regulates Long-Term State Changes in the Suprachiasmatic Circadian Clock
Authors: Tischkau Shelley A. , Gallman Eve A. , Buchanan Gordon F. , Gillette Martha U.
Published: April 2018

We investigated a role for cAMP/protein kinase A (PKA) in light/glutamate (GLU)-stimulated state changes of the mammalian circadian clock in the suprachiasmatic nucleus (SCN). Nocturnal GLU treatment elevated [cAMP]; however, agonists of cAMP/PKA did not mimic the effects of light/GLU. Coincident activation of cAMP/PKA enhanced GLU-stimulated state changes in early night but blocked light/GLU-induced state changes in the late night, whereas inhibition of cAMP/PKA reversed these effects. These responses are distinct from those mediated by mitogen-activated protein kinase (MAPK). MAPK inhibitors attenuated both GLU-induced state changes. Although GLU inducedmPer1mRNA in both early and late night, inhibition of PKA blocked this event only in early night, suggesting that cellular mechanisms regulatingmPer1are gated by the suprachiasmatic circadian clock. These data support a diametric gating role for cAMP/PKA in light/GLU-induced SCN state changes: cAMP/PKA promotes the effects of light/GLU in early night, but opposes them in late night.
In SituCa2+Imaging Reveals Neurotransmitter Receptors for Glutamate in Taste Receptor Cells
Authors: Caicedo Alejandro , Jafri M. Samir , Roper Stephen D.
Published: April 2018

The neurotransmitters at synapses in taste buds are not yet known with confidence. Here we report a new calcium-imaging technique for taste buds that allowed us to test for the presence of glutamate receptors (GluRs) in living isolated tissue preparations. Taste cells of rat foliate papillae were loaded with calcium green dextran (CaGD). Lingual slices containing CaGD-labeled taste cells were imaged with a scanning confocal microscope and superfused with glutamate (30 μmto 1 mm), kainate (30 and 100 μm), AMPA (30 and 100 μm), or NMDA (100 μm). Responses were observed in 26% of the cells that were tested with 300 μmglutamate. Responses to glutamate were localized to the basal processes and cell bodies, which are synaptic regions of taste cells. Glutamate responses were dose-dependent and were induced by concentrations as low as 30 μm. The non-NMDA receptor antagonists CNQX and GYKI 52466 reversibly blocked responses to glutamate. Kainate, but not AMPA, also elicited Ca2+responses. NMDA stimulated increases in [Ca2+]iwhen the bath medium was modified to optimize for NMDA receptor activation. The subset of cells that responded to glutamate was either NMDA-unresponsive (54%) or NMDA-responsive (46%), suggesting that there are presumably two populations of glutamate-sensitive taste cells—one with NMDA receptors and the other without NMDA receptors. The function of GluRs in taste buds is not yet known, but the data suggest that glutamate is a neurotransmitter there. GluRs in taste cells might be presynaptic autoreceptors or postsynaptic receptors at afferent or efferent synapses.
Apoptosis Has a Prolonged Role in the Neurodegeneration after Hypoxic Ischemia in the Newborn Rat
Authors: Nakajima Wako , Ishida Akira , Lange Mary S. , Gabrielson Kathleen L. , Wilson Mary Ann , Martin Lee J. , Blue Mary E. , Johnston Michael V.
Published: April 2018

Birth asphyxia can cause moderate to severe brain injury. It is unclear to what degree apoptotic or necrotic mechanisms of cell death account for damage after neonatal hypoxia–ischemia (HI). In a 7-d-old rat HI model, we determined the contributions of apoptosis and necrosis to neuronal injury in adjacent Nissl-stained, hematoxylin and eosin-stained, and terminal deoxynucleotidyl transferase-mediated UTP nick end-labeled sections. We found an apoptotic–necrotic continuum in the morphology of injured neurons in all regions examined. Eosinophilic necrotic neurons, typical in adult models, were rarely observed in neonatal HI. Electron microscopic analysis showed “classic” apoptotic and necrotic neurons and “hybrid” cells with intermediate characteristics. The time course of apoptotic injury varied regionally. In CA3, dentate gyrus, medial habenula, and laterodorsal thalamus, the density of apoptotic cells was highest at 24–72 hr after HI and then declined. In contrast, densities remained elevated from 12 hr to 7 d after HI in most cortical areas and in the basal ganglia. Temporal and regional patterns of neuronal death were compared with expression of caspase-3, a cysteine protease involved in the execution phase of apoptosis. Immunocytochemical and Western blot analyses showed increased caspase-3 expression in damaged hemispheres 24 hr to 7 d after HI. A p17 peptide fragment, which results from the proteolytic activation of the caspase-3 precursor, was detected in hippocampus, thalamus, and striatum but not in cerebral cortex. The continued expression of activated caspase-3 and the persistence of cells with an apoptotic morphology for days after HI suggests a prolonged role for apoptosis in neonatal hypoxic ischemic brain injury.
A Purine-Sensitive Pathway Regulates Multiple Genes Involved in Axon Regeneration in Goldfish Retinal Ganglion Cells
Authors: Petrausch Barbara , Tabibiazar Raymond , Roser Timo , Jing Yun , Goldman Daniel , Stuermer Claudia A. O. , Irwin Nina , Benowitz Larry I.
Published: April 2018

In lower vertebrates, retinal ganglion cells (RGCs) can regenerate their axons and reestablish functional connections after optic nerve injury. We show here that in goldfish RGCs, the effects of several trophic factors converge on a purine-sensitive signaling mechanism that controls axonal outgrowth and the expression of multiple growth-associated proteins. In culture, goldfish RGCs regenerate their axons in response to two molecules secreted by optic nerve glia, axogenesis factor-1 (AF-1) and AF-2, along with ciliary neurotrophic factor. The purine analog 6-thioguanine (6-TG) blocked outgrowth induced by each of these factors. Previous studies in PC12 cells have shown that the effects of 6-TG on neurite outgrowth may be mediated via inhibition of a 47 kDa protein kinase. Growth factor-induced axogenesis in RGCs was accompanied by many of the molecular changes that characterize regenerative growthin vivo, e.g., increased expression of GAP-43 and certain cell surface glycoproteins. 6-TG inhibited all of these changes but not those associated with axotomy per se, e.g., induction of jun family transcription factors, nor did it affect cell survival. Additional studies using RGCs from transgenic zebrafish showed that expression of Tα-1 tubulin is likewise stimulated by AF-1 and blocked by 6-TG. The purine nucleoside inosine had effects opposite to those of 6-TG. Inosine stimulated outgrowth and the characteristic pattern of molecular changes in RGCs and competitively reversed the inhibitory effects of 6-TG. We conclude that axon regeneration and the underlying program of gene expression in goldfish RGCs are mediated via a common, purine-sensitive pathway.
Parallel Instabilities of Long-Term Potentiation, Place Cells, and Learning Caused by Decreased Protein Kinase A Activity
Authors: Rotenberg Alexander , Abel Ted , Hawkins Robert D. , Kandel Eric R. , Muller Robert U.
Published: April 2018

To further elucidate the links among synaptic plasticity, hippocampal place cells, and spatial memory, place cells were recorded from wild-type mice and transgenic “R(AB)” mice with reduced forebrain protein kinase A (PKA) activity after introduction into a novel environment. Place cells in both strains were similar during the first exposure and were equally stable for recording sessions separated by 1 hr. Place cell stability in wild-type mice was unchanged for sessions separated by 24 hr but was reduced in R(AB) mice over the longer interval. This stability pattern parallels both the reduced late-phase long-term potentiation in hippocampal slices from R(AB) mice and the amnesia for context fear conditioning seen in R(AB) mice 24 but not 1 hr after training. The similar time courses of synaptic, network, and behavioral instability suggest that the genetic reduction of PKA activity is responsible for the defects at each level and support the idea that hippocampal synaptic plasticity is important in spatial memory.
Antagonism of the Melanocortin System Reduces Cold and Mechanical Allodynia in Mononeuropathic Rats
Authors: Vrinten Dorien H. , Gispen Willem Hendrik , Groen Gerbrand J. , Adan Roger A. H.
Published: April 2018

The presence of both pro-opiomelanocortin-derived peptides and melanocortin (MC) receptors in nociception-associated areas in the spinal cord suggests that, at the spinal level, the MC system might be involved in nociceptive transmission. In the present study, we demonstrate that a chronic constriction injury (CCI) to the rat sciatic nerve, a lesion that produces neuropathic pain, results in changes in the spinal cord MC system, as shown by an increased binding of125I-NDP-MSH to the dorsal horn. Furthermore, we investigated whether intrathecal administration (in the cisterna magna) of selective MC receptor ligands can affect the mechanical and cold allodynia associated with the CCI. Mechanical and cold allodynia were assessed by measuring withdrawal responses of the affected limb to von Frey filaments and withdrawal latencies upon immersion in a 4.5°C water bath, respectively. We show that treatment with the MC receptor antagonist SHU9119 has a profound anti-allodynic effect, suggesting that the endogenous MC system has a tonic effect on nociception. In contrast, administration of the MC4 receptor agonists MTII andd-Tyr-MTII primarily increases the sensitivity to mechanical and cold stimulation. No antinociceptive action was observed after administration of the selective MC3 receptor agonist Nle-γ-MSH. Together, our data suggest that the spinal cord MC system is involved in neuropathic pain and that the effects of MC receptor ligands on the responses to painful stimuli are exerted through the MC4 receptor. In conclusion, antagonism of the spinal melanocortin system might provide a new approach in the treatment of neuropathic pain.