bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Change of NMDA Receptors Related to Enhancement of Susceptibility to Neurotoxicity in the Developing Pontine Nucleus
Authors: Mitani Akira , Watanabe Masahiko , Kataoka Kiyoshi
Published: April 2018

The developing neurons have been reported to be extremely susceptible to toxicity of NMDA during a restricted developmental period. Pontosubicular neuronal necrosis is a typical type of perinatal human brain lesion and often coexists with other forms of cerebral hypoxic and ischemic injuries. To determine whether functional changes of NMDA receptors related to the susceptibility to NMDA toxicity are involved in developing neurons in the pontine nucleus, we have examined the lesion produced byin vivodirect injection of NMDA into the pontine nucleus of rats at postnatal days 1–30, recorded NMDA-induced whole-cell currents from neurons in the pontine nucleus in the developing rat brainstem slices, and performedin situhybridization for NMDA receptor subunit mRNAs in the pontine nucleus. The susceptibility to NMDA neurotoxicity peaked near postnatal day 15, and the NMDA-induced currents showed prominent reduction of the voltage-dependent block by Mg2+near postnatal day 15. The pontine nucleus near postnatal day 15 showed distinct expression of the NMDA receptor subunit NR2C mRNA. These results suggest that the susceptibility to NMDA neurotoxicity that is enhanced in the rat pontine nucleus near postnatal day 15 is mediated by the NMDA receptor channels that are relatively insensitive to Mg2+and that the reduction in the sensitivity of NMDA receptors to Mg2+correlates with the expression of the NR2C. We present the possibility that functional changes in the NMDA receptor channels play a crucial role in the occurrence of developmentally specific neuronal injury.
Active Membrane Properties and Signal Encoding in Graded Potential Neurons
Authors: Haag Juergen , Borst Alexander
Published: April 2018

We investigated the influence of active membrane properties on the precision by which the stimulus velocity is encoded in the membrane potential of a motion-sensitive interneuron in the blowfly. The so-called HS-cells respond to visual motion stimuli with a graded shift in membrane potential. Superimposed on this graded response are small spike-like events. This “mixed” visual response mode can be modified by current injection in two different ways. (1) By ongoing injection of hyperpolarizing current, the spike-like events are turned into full-blown action potentials, and (2) by injection of depolarizing current, the spike-like events become completely suppressed. The visual response then consists of a graded shift of membrane potential only. As a measure of the fidelity, we calculated the coherence between the motion stimulus and the response of the cell elicited with different electrical manipulations of the cell. We found that the coherence was highest for the cell at rest. Any electrical manipulation resulted in a reduced coherence. This was attributable partly to a lower signal-to-noise ratio and partly to an increased nonlinearity in the response. By applying a threshold operation we transformed the analog membrane response into an all-or-none spike train. A comparison between these two ways of signal representation revealed that more information about the stimulus velocity is inherent in the analog membrane potential than in the spike train.
Removal of Cholinergic Input to Rat Posterior Parietal Cortex Disrupts Incremental Processing of Conditioned Stimuli
Authors: Bucci David J. , Holland Peter C. , Gallagher Michela
Published: April 2018

Recent research suggests that the basal forebrain cholinergic neurons innervating the cortex play a role in attentional functions in both primates and rodents. Among the cortical targets of these projections in primates is the posterior parietal cortex (PPC), a region shown to be critically involved in the regulation of attention. Recent anatomical studies have defined a cortical region in the rat that may be homologous to the PPC of primates. In the present study, cholinergic innervation of the PPC was depleted by intracortical infusion of the immunotoxin 192 IgG-saporin. Control and lesioned rats were then tested in two associative learning paradigms designed to increase attentional processing of conditioned stimuli (CSs). In one experiment, attention was manipulated by shifting a predictive relation between a light CS and another CS to a less predictive relation. Unlike control rats, lesioned rats failed to increase attention when the predictive relation was modified. In a second experiment, attentional processing of a tone CS was increased when its introduction during training coincided with a change in the value of the unconditioned stimulus, a phenomenon referred to as unblocking. Unlike control rats, lesioned rats failed to exhibit unblocking. In both paradigms, lesioned rats conditioned normally when the training procedures did not encourage increased attentional processing. These findings, across different behavioral paradigms and stimulus modalities, provide converging evidence that intact cholinergic innervation of the PPC is important for changes in attention that can increase the processing of certain cues.
Functional and Molecular Differences between Voltage-Gated K+Channels of Fast-Spiking Interneurons and Pyramidal Neurons of Rat Hippocampus
Authors: Martina Marco , Schultz Jobst H. , Ehmke Heimo , Monyer Hannah , Jonas Peter
Published: April 2018

We have examined gating and pharmacological characteristics of somatic K+channels in fast-spiking interneurons and regularly spiking principal neurons of hippocampal slices. In nucleated patches isolated from basket cells of the dentate gyrus, a fast delayed rectifier K+current component that was highly sensitive to tetraethylammonium (TEA) and 4-aminopyridine (4-AP) (half-maximal inhibitory concentrations <0.1 mm) predominated, contributing an average of 58% to the total K+current in these cells. By contrast, in pyramidal neurons of the CA1 region a rapidly inactivating A-type K+current component that was TEA-resistant prevailed, contributing 61% to the total K+current. Both types of neurons also showed small amounts of the K+current component mainly found in the other type of neuron and, in addition, a slow delayed rectifier K+current component with intermediate properties (slow inactivation, intermediate sensitivity to TEA). Single-cell RT-PCR analysis of mRNA revealed that Kv3 (Kv3.1, Kv3.2) subunit transcripts were expressed in almost all (89%) of the interneurons but only in 17% of the pyramidal neurons. In contrast, Kv4 (Kv4.2, Kv4.3) subunit mRNAs were present in 87% of pyramidal neurons but only in 55% of interneurons. Selective block of fast delayed rectifier K+channels, presumably assembled from Kv3 subunits, by 4-AP reduced substantially the action potential frequency in interneurons. These results indicate that the differential expression of Kv3 and Kv4 subunits shapes the action potential phenotypes of principal neurons and interneurons in the cortex.
Neurotransmitter Activation of Inwardly Rectifying Potassium Current in Dissociated Hippocampal CA3 Neurons: Interactions among Multiple Receptors
Authors: Sodickson Deborah L. , Bean Bruce P.
Published: April 2018

We characterized potassium current activated by G-protein-coupled receptors in acutely dissociated hippocampal CA3 neurons. Agonists for serotonin, adenosine, and somatostatin receptors reliably activated a potassium-selective conductance that was inwardly rectifying and that was blocked by 1 mmexternal Ba2+. The conductance had identical properties to that activated by GABABreceptors in the same cells. In one-half of the CA3 neurons that were tested, the metabotropic glutamate agonist 1S,3R-ACPD also activated inwardly rectifying Ba2+-sensitive potassium current. Activation of the current by serotonin and adenosine agonists occurred with a time constant of 200–700 msec after a lag of 50–100 msec; on removal of agonist the current deactivated with a time constant of 1–2 sec after a lag of 200–400 msec. These kinetics are similar to GABAB-activated current and consistent with a direct action of G-protein on the channels. For somatostatin, both activation and deactivation were approximately fourfold slower, probably limited by agonist binding and unbinding. The half-maximally effective agonist concentrations were ∼75 nmfor somatostatin, ∼100 nmfor serotonin, and ∼400 nmfor 2-chloroadenosine. Dose–response relationships had Hill coefficients of 1.2–1.9, suggesting cooperativity in the receptor-to-channel coupling mechanism. At saturating concentrations of agonists, the combined application of baclofen and either somatostatin, serotonin, or 2-chloroadenosine produced effects that were subadditive and often completely occlusive. However, at subsaturating concentrations the effects of baclofen and 2-chloroadenosine were supra-additive. Thus, low levels of different transmitters can act synergistically in activating inwardly rectifying potassium current.
Regulation of Tyrosine Hydroxylase Gene Expression during Transdifferentiation of Striatal Neurons: Changes in Transcription Factors Binding the AP-1 Site
Authors: Guo Zheng , Du Xinyu , Iacovitti Lorraine
Published: April 2018

We have shown previously that the synergistic interaction of acidic fibroblast growth factor (aFGF) and a coactivator (dopamine, protein kinase A, or protein kinase C activator) will induce the novel expression of tyrosine hydroxylase (TH) in neurons of the developing striatum. In this study we sought to determine whether, concomitant with TH expression, there were unique changes in transcription factors binding the AP-1 regulatory element on the TH gene. Indeed, we found a significant recruitment of proteins into TH–AP-1 complexes as well as a shift from low- to high-affinity binding. Supershift experiments further revealed dramatic changes in the proteins comprising the AP-1 complexes, including recruitment of the transcriptional activators c-Fos, a novel Fos protein, Fos-B, and Jun-D. Concomitantly, there was a decrease in repressor-type factors ATF-2 and CREM-1. aFGF appeared to play a central but insufficient role, requiring the further participation of at least one of the coactivating substances. Experiments examining the signal transduction pathway involved in mediating these nuclear events demonstrated that the presence of only an FGF (1, 2, 4, 9) competent to induce TH caused the phosphorylation of mitogen-activated protein kinase (MAPK). Moreover, the treatment of cells with MEK/ERK inhibitors (apigenin or PD98059) eliminated TH expression and the associated AP-1 changes, suggesting that MAPK was a critical mediator of these events. We conclude that, during transdifferentiation, signals may be transmitted via MAPK to the TH–AP-1 site to increase activators and reduce repressors, helping to shift the balance in favor of TH gene expression at this and possibly other important regulatory sites on the gene.
The Endogenous Calcium Buffer and the Time Course of Transducer Adaptation in Auditory Hair Cells
Authors: Ricci A. J. , Wu Y-C. , Fettiplace R.
Published: April 2018

Mechanoelectrical transducer currents in turtle auditory hair cells adapt to maintained stimuli via a Ca2+-dependent mechanism that is sensitive to the level of internal calcium buffer. We have used the properties of transducer adaptation to compare the effects of exogenous calcium buffers in the patch electrode solution with those of the endogenous buffer assayed with perforated-patch recording. The endogenous buffer of the hair bundle was equivalent to 0.1–0.4 mmBAPTA and, in a majority of cells, supported adaptation in an external Ca2+concentration of 70 μmsimilar to that in turtle endolymph. The endogenous buffer had a higher effective concentration, and the adaptation time constant was faster in cells at the high-frequency end than at the low-frequency end of the cochlea. Experiments using buffers with different Ca2+-binding rates or dissociation constants indicated that the speed of adaptation and the resting open probability of the transducer channels could be differentially regulated and imply that the endogenous buffer must be a fast, high-affinity buffer. In some hair cells, the transducer current did not decay exponentially during a sustained stimulus but displayed damped oscillations at a frequency (58–230 Hz) that depended on external Ca2+concentration. The gradient in adaptation time constant and the tuned transducer current at physiological levels of calcium buffer and external Ca2+suggest that transducer adaptation may contribute to hair cell frequency selectivity. The results are discussed in terms of feedback regulation of transducer channels mediated by Ca2+binding at two intracellular sites.
Overexpression of SOD1 in Transgenic Rats Protects Vulnerable Neurons Against Ischemic Damage After Global Cerebral Ischemia and Reperfusion
Authors: Chan Pak H. , Kawase Makoto , Murakami Kensuke , Chen Sylvia F. , Li Yibing , Calagui Bernard , Reola Liza , Carlson Elaine , Epstein Charles J.
Published: April 2018

Transient global cerebral ischemia resulting from cardiac arrest is known to cause selective death in vulnerable neurons, including hippocampal CA1pyramidal neurons. It is postulated that oxygen radicals, superoxide in particular, are involved in cell death processes. To test this hypothesis, we first usedin situimaging of superoxide radical distribution by hydroethidine oxidation in vulnerable neurons. We then generated SOD1 transgenic (Tg) rats with a five-fold increase in copper zinc superoxide dismutase activity. The Tg rats and their non-Tg wild-type littermates were subjected to 10 min of global ischemia followed by 1 and 3 d of reperfusion. Neuronal damage, as assessed by cresyl violet staining and DNA fragmentation analysis, was significantly reduced in the hippocampal CA1region, cortex, striatum, and thalamus in SOD1 Tg rats at 3 d, as compared with the non-Tg littermates. There were no changes in the hippocampal CA3subregion and dentate gyrus, resistant areas in both SOD1 Tg and non-Tg rats. Quantitative analysis of the damaged CA1subregion showed marked neuroprotection against transient global cerebral ischemia in SOD1 Tg rats. These results suggest that superoxide radicals play a role in the delayed ischemic death of hippocampal CA1neurons. Our data also indicate that SOD1 Tg rats are useful tools for studying the role of oxygen radicals in the pathogenesis of neuronal death after transient global cerebral ischemia.
Autocrine Hepatocyte Growth Factor Provides a Local Mechanism for Promoting Axonal Growth
Authors: Yang Xiu-Ming , Toma Jean G. , Bamji Shernaz X. , Belliveau Daniel J. , Kohn Judi , Park Morag , Miller Freda D.
Published: April 2018

In this report, we describe a novel local mechanism necessary for optimal axonal growth that involves hepatocyte growth factor (HGF). Sympathetic neurons of the superior cervical ganglion coexpress bioactive HGF and its receptor, the Met tyrosine kinase, bothin vivoandin vitro. Exogenous HGF selectively promotes the growth but not survival of cultured sympathetic neurons; the magnitude of this growth effect is similar to that observed with exogenous NGF. Conversely, HGF antibodies that inhibit endogenous HGF decrease sympathetic neuron growth but have no effect on survival. This autocrine HGF is required locally by sympathetic axons for optimal growth, as demonstrated using compartmented cultures. Thus, autocrine HGF provides a local, intrinsic mechanism for promoting neuronal growth without affecting survival, a role that may be essential during developmental axogenesis or after neuronal injury.
Spatial Firing Properties of Hippocampal CA1 Populations in an Environment Containing Two Visually Identical Regions
Authors: Skaggs William E. , McNaughton Bruce L.
Published: April 2018

Populations of 10-39 CA1 pyramidal cells were recorded from four rats foraging for food reward in an environment consisting of two nearly identical boxes connected by a corridor. For each rat, a higher-than-chance fraction of cells had similarly shaped spatial firing fields in both boxes, but other cells had completely different fields in the two boxes. The level of correlation of fields in the two boxes differed greatly across rats and, for three of the four rats, across recording sessions. Thus, the factors controlling the level of correlation are likely to be subtle. Two control manipulations were performed. First, the two boxes were physically interchanged. In no case did firing fields move along with the boxes. Second, on the final session of recording, the rat was started in the south box, after having been started in the north box for every previous session. For at least two of the four rats, the north fields from the previous session were instantiated in the south during the first visit of the second session, but thereafter reverted. Thus neither differences between the physical boxes nor sensory input from outside the apparatus could account for the differences in firing fields: most likely they were caused by a combination of learned expectations and a neural mechanism for remembering movements. These findings could be explained either by hypothesizing a more sophisticated attractor-map architecture than has been proposed previously, or by hypothesizing that the hippocampus conjunctively encodes both map information and some other type of information.
Mice Lacking the β3Subunit of the GABAAReceptor Have the Epilepsy Phenotype and Many of the Behavioral Characteristics of Angelman Syndrome
Authors: DeLorey T. M. , Handforth A. , Anagnostaras S. G. , Homanics G. E. , Minassian B. A. , Asatourian A. , Fanselow M. S. , Delgado-Escueta A. , Ellison G. D. , Olsen R. W.
Published: April 2018

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from a deletion/mutation in maternal chromosome 15q11–13. The genes in 15q11–13 contributing to the full array of the clinical phenotype are not fully identified. This study examines whether a loss or reduction in the GABAAreceptor β3subunit (GABRB3) gene, contained within the AS deletion region, may contribute to the overall severity of AS. Disrupting the gabrb3 gene in mice produces electroencephalographic abnormalities, seizures, and behavior that parallel those seen in AS. The seizures that are observed in these mice showed a pharmacological response profile to antiepileptic medications similar to that observed in AS. Additionally, these mice exhibited learning and memory deficits, poor motor skills on a repetitive task, hyperactivity, and a disturbed rest–activity cycle, features all common to AS. The loss of the single gene, gabrb3, in these mice is sufficient to cause phenotypic traits that have marked similarities to the clinical features of AS, indicating that impaired expression of the GABRB3 gene in humans probably contributes to the overall phenotype of Angelman syndrome. At least one other gene, the E6-associated protein ubiquitin-protein ligase (UBE3A) gene, has been implicated in AS, so the relative contribution of the GABRB3 gene alone or in combination with other genes remains to be established.
Computational Properties of Peri-Dendritic Calcium Fluctuations
Authors: Egelman David M. , Montague P. Read
Published: April 2018

Using a model of the extracellular space, we show how external calcium fluctuations, engendered during normal neural activity, can act as a rapid information-bearing signal in nervous systems. We demonstrate that action potentials propagating along a dendrite can induce large peri-dendritic calcium fluctuations, lowering significantly the external calcium available to overlying presynaptic terminals. The geometrical distribution of active calcium sinks critically influences the time and spatial extent of fluctuations in external calcium. In particular, clusters of coactive dendrites can prolong and amplify an external calcium fluctuation. This latter effect provides a natural substrate for a computational mechanism that locates specific volumes of neural tissue on rapid time scales. Such an interpretation suggests that the detailed structure of the extracellular space, in combination with the three-dimensional distribution of active calcium sinks, may play a role in neural information processing.
The Localization of the Brain-Specific Inorganic Phosphate Transporter Suggests a Specific Presynaptic Role in Glutamatergic Transmission
Authors: Bellocchio Elizabeth E. , Hu Hailan , Pohorille Alicia , Chan June , Pickel Virginia M. , Edwards Robert H.
Published: April 2018

Molecular cloning has recently identified a vertebrate brain-specific Na+-dependent inorganic phosphate transporter (BNPI). BNPI has strong sequence similarity to EAT-4, aCaenorhabditis elegansprotein implicated in glutamatergic transmission. To characterize the physiological role of BNPI, we have generated an antibody to the protein. Immunocytochemistry of rat brain sections shows a light microscopic pattern that is suggestive of reactivity in nerve terminals. Excitatory projections are labeled prominently, and ultrastructural analysis confirms that BNPI localizes almost exclusively to terminals forming asymmetric excitatory-type synapses. Although BNPI depends on a Na+gradient and presumably functions at the plasma membrane, both electron microscopy and biochemical fractionation show that BNPI associates preferentially with the membranes of small synaptic vesicles. The results provide anatomic evidence of a specific presynaptic role for BNPI in glutamatergic neurotransmission, consistent with the phenotype ofeat-4mutants. Because an enzyme known as the phosphate-activated glutaminase produces glutamate for release as a neurotransmitter, BNPI may augment excitatory transmission by increasing cytoplasmic phosphate concentrations within the nerve terminal and hence increasing glutamate synthesis. Expression of BNPI on synaptic vesicles suggests a mechanism for neural activity to regulate the function of BNPI.
Lampetra fluviatilisNeurotrophin Homolog, Descendant of a Neurotrophin Ancestor, Discloses the Early Molecular Evolution of Neurotrophins in the Vertebrate Subphylum
Authors: Hallböök Finn , Lundin Lars-Gustav , Kullander Klas
Published: April 2018

We have isolated a neurotrophin from the lamprey that permitted us to perform a phylogenetic analysis of the neurotrophin gene family that dates back more than 460 million years to the early vertebrate ancestors. The results show that the neurotrophin gene family was originally formed by two subsequent duplications. The duplication that formed nerve growth factor, neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5 occurred after the split of lampreys but before the split of cartilaginous fish from the main vertebrate lineage. Compilation of chromosomal gene maps around the neurotrophins shows that they are located in paralogous regions, suggesting that the genes were formed at major duplication events possibly by complete genome doubling. Analysis of two isolated Trk receptor sequences shows similar results as for the lamprey neurotrophin. Multiple neurotrophin and Trk genes, including neurotrophin-6 and -7, have been found in bony fish, and we suggest that the extra genes were formed by an additional duplication in the bony fish lineage. Analysis of lamprey Trk mRNA expression in the adult brain shows that the genes are expressed in all regions analyzed so far. Together, the results suggest that the duplications of ancestral neurotrophin and Trk genes at an early vertebrate stage have permitted evolution to bring about differential neurotrophin and Trk expression, thereby allowing the formation of specific functions in selective neuronal populations.
Localization of Postsynaptic Density-93 to Dendritic Microtubules and Interaction with Microtubule-Associated Protein 1A
Authors: Brenman Jay E. , Topinka J. Rick , Cooper Edward C. , McGee Aaron W. , Rosen Joel , Milroy Toni , Ralston Henry J. , Bredt David S.
Published: April 2018

Postsynaptic density-93 (PSD-93)/Chapsyn-110 is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ domain-containing proteins. MAGUKs are widely expressed in the brain and are critical elements of the cytoskeleton and of certain synapses. In the ultrastructural studies that are described here, PSD-93 localizes to both postsynaptic densities and dendritic microtubules of cerebellar Purkinje neurons. The microtubule localization is paralleled by a high-affinityin vivointeraction of PSD-93 via its guanylate kinase (GK) domain with microtubule-associated protein 1A (MAP1A). GK domain truncations that mimic genetically identified mutations of aDrosophilaMAGUK,discs-large, disrupt the GK/MAP-1A interaction. Additional biochemical experiments demonstrate that intact MAGUKs do not bind to MAP1A as effectively as do isolated GK domains. This appears to be attributable to an intramolecular inhibition of the GK domain by the PDZs, because GK binding activity of full-length MAGUKs is partially restored by a variety of PDZ ligands, including the C termini of NMDA receptor 2B, adenomatous polyposis coli (APC), and CRIPT. Beyond demonstrating a novel cytoskeletal link for PSD-93, these experiments support a model in which intramolecular interactions between the multiple domains of MAGUKs regulate intermolecular associations and thereby may play a role in the proper targeting and function of MAGUK proteins.
A Specific Role for the Thalamus in Mediating the Interaction of Attention and Arousal in Humans
Authors: Portas C. M. , Rees G. , Howseman A. M. , Josephs O. , Turner R. , Frith C. D.
Published: April 2018

The physiological basis for the interaction of selective attention and arousal is not clearly understood. Here we present evidence in humans that specifically implicates the thalamus in this interaction. We used functional magnetic resonance imaging to measure brain activity during the performance of an attentional task under different levels of arousal. Activity evoked in the ventrolateral thalamus by the attentional task changed as a function of arousal. The highest level of attention-related thalamic activity is seen under conditions of low arousal (secondary to sleep deprivation) compared with high arousal (secondary to caffeine administration). Other brain regions were also active during the attentional task, but these areas did not change their activity as a function of arousal. Control experiments establish that this pattern of changes in thalamic activity cannot be accounted for by nonspecific effects of arousal on cerebral hemodynamics. We conclude that the thalamus is involved in mediating the interaction of attention and arousal in humans.
Mediodorsal Thalamus Plays a Critical Role in the Development of Limbic Motor Seizures
Authors: Cassidy Robert M. , Gale Karen
Published: April 2018

Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex.

A GABAAreceptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAAagonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures.
Firing Properties of Rat Lateral Mammillary Single Units: Head Direction, Head Pitch, and Angular Head Velocity
Authors: Stackman Robert W. , Taube Jeffrey S.
Published: April 2018

Many neurons in the rat anterodorsal thalamus (ADN) and postsubiculum (PoS) fire selectively when the rat points its head in a specific direction in the horizontal plane, independent of the animal’s location and ongoing behavior. The lateral mammillary nuclei (LMN) are interconnected with both the ADN and PoS and, therefore, are in a pivotal position to influence ADN/PoS neurophysiology. To further understand how the head direction (HD) cell signal is generated, we recorded single neurons from the LMN of freely moving rats. The majority of cells discharged as a function of one of three types of spatial correlates: (1) directional heading, (2) head pitch, or (3) angular head velocity (AHV). LMN HD cells exhibited higher peak firing rates and greater range of directional firing than that of ADN and PoS HD cells. LMN HD cells were modulated by angular head velocity, turning direction, and anticipated the rat’s future HD by a greater amount of time (∼95 msec) than that previously reported for ADN HD cells (∼25 msec). Most head pitch cells discharged when the rostrocaudal axis of the rat’s head was orthogonal to the horizontal plane. Head pitch cell firing was independent of the rat’s location, directional heading, and its body orientation (i.e., the cell discharged whenever the rat pointed its head up, whether standing on all four limbs or rearing). AHV cells were categorized as fast or slow AHV cells depending on whether their firing rate increased or decreased in proportion to angular head velocity. These data demonstrate that LMN neurons code direction and angular motion of the head in both horizontal and vertical planes and support the hypothesis that the LMN play an important role in processing both egocentric and allocentric spatial information.
Partial Inactivation of the Primary Motor Cortex Hand Area: Effects on Individuated Finger Movements
Authors: Schieber Marc H. , Poliakov Andrew V.
Published: April 2018

After large lesions of the primary motor cortex (M1), voluntary movements of affected body parts are weak and slow. In addition, the relative independence of moving one body part without others is lost; attempts at individuated movements of a given body part are accompanied by excessive, unintended motion of contiguous body parts. The effects of partial inactivation of the M1 hand area are comparatively unknown, however. If the M1 hand area contains the somatotopically ordered finger representations implied by the classic homunculus or simiusculus, then partial inactivation might produce weakness, slowness, and loss of independence of one or two adjacent digits without affecting other digits. But if control of each finger movement is distributed in the M1 hand area as many studies suggest, then partial inactivation might produce dissociation of weakness, slowness, and relative independence of movement, and which fingers movements are impaired might be unrelated to the location of the inactivation along the central sulcus.

To investigate the motoric deficits resulting from partial inactivation of the M1 hand area, we therefore made single intracortical injections of muscimol as trained monkeys performed visually cued, individuated flexion–extension movements of the fingers and wrist. We found little if any evidence that which finger movements were impaired after each injection was related to the injection location along the central sulcus. Unimpaired fingers could be flanked on both sides by impaired fingers, and the flexion movements of a given finger could be unaffected even though the extension movements were impaired, or vice versa. Partial inactivation also could produce dissociated weakness and slowness versus loss of independence in a given finger movement. These findings suggest that control of each individuated finger movement is distributed widely in the M1 hand area.
Zebrafish Touch-Insensitive Mutants Reveal an Essential Role for the Developmental Regulation of Sodium Current
Authors: Ribera Angeles B. , Nüsslein-Volhard Christiane
Published: April 2018

Developmental changes in neuronal connectivity and membrane properties underlie the stage-specific appearance of embryonic behaviors. The behavioral response of embryonic zebrafish to tactile stimulation first appears at 27 hr postfertilization. Because the touch response requires the activation of mechanosensory Rohon–Beard neurons, we have used whole-cell recordings in semi-intact preparations to characterize Rohon–Beard cell electrical membrane properties in several touch-insensitive mutants and then to correlate the development of excitability in these cells with changes in wild-type behavior. Electrophysiological analysis of mechanosensory neurons of touch-insensitive zebrafish mutants indicates that in three mutant lines that have been examined the sodium current amplitudes are reduced, and action potentials either have diminished overshoots or are not generated. Inmachomutants the action potential never overshoots, and the sodium current remains small;alligatorandsteifftiershow similar but weaker effects. The effects are specific to sodium channel function; resting membrane potentials are unaffected, and outward currents of normal amplitude are present. Developmental analysis of sodium current expression in mechanosensory neurons of wild-type embryos indicates that, during the transition from a touch-insensitive to a touch-sensitive embryo, action potentials acquire larger overshoots and briefer durations as both sodium and potassium currents increase in amplitude. However, inmachotouch-insensitive mutants, developmental changes in action potential overshoot and sodium current are absent despite the normal regulation of action potential duration and potassium current. Thus, the maturation of a voltage-dependent sodium current promotes a behavioral response to touch. A study of these mutants will allow insight into the genes controlling the maturation of the affected sodium current.
Na,K-ATPase Subunit β1knock-inPrevents Lethality of β2 Deficiency in Mice
Authors: Weber Philipp , Bartsch Udo , Schachner Melitta , Montag Dirk
Published: April 2018

The β2 subunit of the Na,K-ATPase displays functional properties of both an integral constituent of an ion pump and an adhesion and neurite outgrowth-promoting moleculein vitro. To investigate whether the β1 subunit of the Na,K-ATPase can functionally substitute for the β2 isoformin vivo, we have generated β2/β1knock-inmice by homologous recombination in embryonic stem cells. In β2/β1knock-inmice, expression of β2 was abolished, whereas β1 mRNA expression from the mutated gene amounted to ∼15% of the normal expression of β2 in the adult mouse brain and prevented the juvenile lethality observed for β2 null mutant mice. In contrast to β2 null mutant mice, the overall morphological structure of all analyzed brain regions was normal. By immunohistochemical analysis, β1 expression was detected in photoreceptor cells in the retina ofknock-inmice at an age when expression of β1 and β2, respectively, is downregulated and persisting in the wild-type mice. Morphological analysis by light and electron microscopy revealed a progressive degeneration of photoreceptor cells. Apoptotic death of photoreceptor cells determined quantitatively by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis increased in β2/β1knock-inmice with age. These observations suggest that the β1 subunit of the Na,K-ATPase can substitute sufficiently, at least in certain cell types, for the role of the β2 subunit as a component of a functional Na,K-ATPase, but they do not allow us to determine the possible role of the β2 subunit as an adhesion moleculein vivo.
Persyn, a Member of the Synuclein Family, Has a Distinct Pattern of Expression in the Developing Nervous System
Authors: Buchman Vladimir L. , Hunter Hamish J. A. , Pinõn Luzia G. P. , Thompson Jane , Privalova Eugenia M. , Ninkina Natalia N. , Davies Alun M.
Published: April 2018

The synucleins are a unique family of small intracellular proteins that have recently attracted considerable attention because of their involvement in human neurodegenerative diseases. We have cloned a new member of the synuclein family called persyn. In contrast to other synucleins, which are presynaptic proteins of CNS neurons, persyn is a cytosolic protein that is expressed predominantly in the cell bodies and axons of primary sensory neurons, sympathetic neurons, and motoneurons. Northern blotting,in situhybridization, Western blotting, and immunohistochemistry revealed that persyn mRNA and protein are expressed in these neurons from the earliest stages of axonal outgrowth and are maintained at a high level throughout life. Persyn also becomes detectable in evolutionary recent regions of the brain by adulthood.
Granule Cell Raphes and Parasagittal Domains of Purkinje Cells: Complementary Patterns in the Developing Chick Cerebellum
Authors: Lin John C. , Cepko Constance L.
Published: April 2018

The extensive migration of granule cells and the parasagittal organization of Purkinje cells are two prominent features of cerebellar development. Using granule cell markers, we observed that the inward migration of a subset of granule cells occurs in streams that appear to be restricted to specific areas in the developing chick cerebellum. These streams are organized into a stereotypical series of parasagittal linear arrays, similar to the “granule cell raphes” described previously by Feirabend (1990). Similar raphes were found in the developing cerebellum of other avian species but not in the mouse cerebellum. During the period when granule cell raphes are apparent, Purkinje cells appear to be segregated into discrete parasagittal domains, interrupted by Purkinje cell-poor areas that correspond to the granule cell raphes. Purkinje cells in each domain exhibit a domain-specific expression profile of genes, includingBmp-7,EphA5/Cek-7,EphA4/Cek-8, and several chick homologs ofDrosophilasegmentation genes. From embryonic day 12 (E12) to E15, most of these genes gradually cease to be expressed differentially in parasagittal stripes, concurrent with the disappearance of the granule cell raphes by E15–E16. The spatial and temporal correlations of granule cell raphes and Purkinje cell parasagittal domains suggest a novel interaction between these two cell types and a potentially critical period of parasagittal patterning of the chick cerebellum.
Schwann Cells Proliferate at Rat Neuromuscular Junctions during Development and Regeneration
Authors: Love Flora M. , Thompson Wesley J.
Published: April 2018

Terminal Schwann cells (TSCs) cover neuromuscular junctions and are important in the repair and maintenance of these synapses. We have examined how these cells are generated at developing junctions and how their number is regulated during repair of nerve injury. At birth, approximately half of the junctions in rat soleus and extensor digitorum longus muscles have one TSC soma. Somata are absent from the remainder, although Schwann cell (SC) processes arising from somata along the preterminal axon cover almost all of these synapses. By 2 months of age, junctions have gained an additional two to three TSCs. Most of this gain occurs during the first 2 postnatal weeks and largely precedes the expansion of endplate size. Although the initial addition is caused by cell migration, mitotic labeling shows extensive division of TSCs at junctions. A slower addition of TSCs occurs in adult muscles, and TSC number in the adult is correlated with endplate size.

During repair of nerve injury, TSC number is regulated by a combination of signals from motor neurons and denervated tissue. As shown previously (Connor et al., 1987), denervation of adult muscles did not, in itself, cause TSC mitosis. However, TSCs became mitotic during reinnervation. Partial denervation induced division of TSCs at innervated but not denervated endplates. A disproportionate number of these mitotic cells were found at endplates contacted by TSC processes extended from nearby denervated endplates, contacts known to promote nerve sprouting. These results show an association between TSC mitotic activity and alterations in synaptic structure during development, sprouting, and reinnervation.
Sustained Activity in the Medial Wall during Working Memory Delays
Authors: Petit Laurent , Courtney Susan M. , Ungerleider Leslie G. , Haxby James V.
Published: April 2018

We have taken advantage of the temporal resolution afforded by functional magnetic resonance imaging (fMRI) to investigate the role played by medial wall areas in humans during working memory tasks. We demarcated the medial motor areas activated during simple manual movement, namely the supplementary motor area (SMA) and the cingulate motor area (CMA), and those activated during visually guided saccadic eye movements, namely the supplementary eye field (SEF). We determined the location of sustained activity over working memory delays in the medial wall in relation to these functional landmarks during both spatial and face working memory tasks. We identified two distinct areas, namely the pre-SMA and the caudal part of the anterior cingulate cortex (caudal-AC), that showed similar sustained activity during both spatial and face working memory delays. These areas were distinct from and anterior to the SMA, CMA, and SEF. Both the pre-SMA and caudal-AC activation were identified by a contrast between sustained activity during working memory delays as compared with sustained activity during control delays in which subjects were waiting for a cue to make a simple manual motor response. Thus, the present findings suggest that sustained activity during working memory delays in both the pre-SMA and caudal-AC does not reflect simple motor preparation but rather a state of preparedness for selecting a motor response based on the information held on-line.
A Lateralized Deficit in Morphine Antinociception after Unilateral Inactivation of the Central Amygdala
Authors: Manning Barton H.
Published: April 2018

The amygdala is a forebrain region that is receiving increasing attention as a modulator of pain sensation. The amygdala contributes to antinociception elicited by both psychological factors (e.g., fear) and exogenous opioid agonists. Unlike the midbrain periaqueductal gray matter (PAG) or rostral ventromedial medulla, the amygdala is a pain-modulating region that has clear bilateral representation in the brain, making it possible to determine whether pain-modulating effects of this region arelateralizedwith respect to the peripheral origin of noxious stimulation. Unilateral inactivation of the central nucleus of the amygdala (Ce) plus adjacent portions of the basolateral amygdaloid complex (with either the excitotoxin NMDA or the GABAAagonist muscimol) reduced the ability of morphine to suppress prolonged, formalin-induced pain derived from the hindpaw ipsilateral, but not contralateral, to the inactivated region. This effect was evident regardless of the nociceptive scoring method used (weighted scores or flinch-frequency method) and wasnotaccompanied by a concurrent reduction in morphine-induced hyperlocomotion. Unilateral lesions restricted to the basolateral amygdaloid complex (i.e., not including the Ce) did not reduce the ability of morphine to suppress formalin-induced pain derived from either hindpaw. The results constitute the first report of a lateralized deficit in opioid antinociception after unilateral inactivation of a specific brain area and show the first clear neuroanatomical dissociation between antinociceptive and motor effects of systemically administered morphine in the rat. The amygdala appears to modulate nociceptive signals entering the ipsilateral spinal dorsal horn, probably through monosynaptic connections with ipsilateral portions of the PAG.
Heteromultimeric Potassium Channels Formed by Members of the Kv2 Subfamily
Authors: Blaine Judith T. , Ribera Angeles B.
Published: April 2018

Four α-subunits are thought to coassemble and form a voltage-dependent potassium (Kv) channel. Kvα-subunits belong to one of four major subfamilies (Kv1, Kv2, Kv3, Kv4). Within a subfamily up to eight different genetic isotypes exist (e.g., Kv1.1, Kv1.2). Different isotypes within the Kv1 or Kv3 subfamily coassemble. It is not known, however, whether the only two members of the vertebrate Kv2 subfamily identified thus far, Kv2.1 and Kv2.2, heteromultimerize. This might account for the lack of detection of heteromultimeric Kv2 channelsin situdespite the coexpression of Kv2.1 and Kv2.2 mRNAs within the same cell. To probe whether Kv2 isotypes can form heteromultimers, we developed a dominant-negative mutant Kv2.2 subunit to act as a molecular poison of Kv2 subunit-containing channels. The dominant-negative Kv2.2 suppresses formation of functional channels when it is coexpressed in oocytes with either wild-type Kv2.2 or Kv2.1 subunits. These results indicate that Kv2.1 and Kv2.2 subunits are capable of heteromultimerization. Thus, in native cells either Kv2.1 and Kv2.2 subunits are targeted at an early stage to different biosynthetic compartments or heteromultimerization otherwise is inhibited.
Stoichiometry of the Glial Glutamate Transporter GLT-1 Expressed Inducibly in a Chinese Hamster Ovary Cell Line Selected for Low Endogenous Na+-Dependent Glutamate Uptake
Authors: Levy Line M. , Warr Orpheus , Attwell David
Published: April 2018

Glutamate transport across the plasma membrane of neurons and glia is powered by the transmembrane electrochemical gradients for sodium, potassium, and pH, but there is controversy over the number of Na+cotransported with glutamate. The stoichiometry of glutamate transporters is important because it determines a lower limit to the extracellular glutamate concentration, [glu]o, in both normal and pathological conditions. We used whole-cell clamping to study the stoichiometry of the glial transporter GLT-1, the most abundant glutamate transporter in the brain, expressed under control of the Tet-On system in a Chinese hamster ovary (CHO) cell line selected for low endogenous glutamate transport. After the induction of GLT-1 expression with doxycycline, glutamate evoked a Na+-dependent inward current with the voltage dependence and pharmacology of GLT-1 and acidified the cell cytoplasm. Raising [K+]oaround cells clamped with electrodes containing sodium and glutamate evoked an outward reversed uptake current. These responses were reduced by the specific GLT-1 blocker dihydrokainate (DHK). DHK evoked an outward current with NO3−, but not with Cl−, as the main intracellular anion, suggesting that the anion conductance of the transporter is active even without external glutamate but generates little current in the absence of highly permeable anions like NO3−. Measuring the reversal potential of the transporter current in various ionic conditions suggested that the transport of one glutamate anion is coupled to the cotransport of three Na+and one H+and to the countertransport of one K+. This suggests that in ischemia, when [K+]orises to 60 mm, the reversal of glutamate transporters will raise [glu]oto >50 μm.