bluuebunny/crossref_metadata_2025 huggingface dataset:
Rats with fimbria-fornix lesions display a place response in a swimming pool: a dissociation between getting there and knowing where
Authors: Whishaw IQ , Cassel JC , Jarrad LE
Published: April 2018

Some theories of hippocampal formation function postulate that it is involved in using the relationships between distal cues for spatial navigation. That rats with damage to the hippocampal formation are impaired in learning place responses of escaping to a platform hidden just below the surface of the water of a swimming pool, supports this view. Using rats with fimbria-fornix (FF) lesions, we examined whether their impairment is related to an inability to learn how to reach the platform as opposed to learning its location. In a first experiment, the FF rats were impaired in learning to swim to a hidden platform but could swim to a visible platform. In a second experiment, after being pretrained to swim to a visible platform, the FF rats swam to, paused, and searched the vicinity of the platform's previous location when it was removed. This finding showed that the FF rats expected to find the platform at that location. Additional tests confirmed that they had learned a place response. Despite having acquired a place response, they still could not acquire new place responses when only the hidden platform training procedure was used. Thus, these results in dissociating the processes of “getting there” and “knowing where” suggest that the FF rats' impairment may be in some process of motoric control, such as path integration, rather than in learning the location of the platform in relation to ambient cues. The results are discussed in relation to relevant theories of hippocampal function.
Cloning of rat interleukin-3 receptor beta-subunit from cultured microglia and its mRNA expression in vivo
Authors: Appel K , Buttini M , Sauter A , Gebicke-Haerter PJ
Published: April 2018

The high-affinity receptors for interleukin-3 (IL-3), GM-CSF, and IL-5 are composed of a ligand binding (alpha-) and a transducing (beta-) subunit. Two distinct transducing subunits (clones AIC2A and AIC2B) have been cloned from mouse, whereas in humans, only one (common) beta- subunit (beta c) has been found. A PCR-based cloning strategy was used to obtain a full-length cDNA sequence from rat microglia including 5′- untranslated regions. Sequence analysis revealed a number of features indicative of the presence of only one beta-subunit in the rat. Most likely, the new rIL-3R beta cDNA is the rat equivalent of human respective murine (AIC2B) beta c subunits. Regulation of rIL-3R beta mRNA expression was investigated in cultured microglia and in vivo. Purified microglia expressed significant amounts of rIL-3R beta mRNA. Addition of lipopolysaccharide (LPS) resulted in a marked upregulation of rIL-3R beta mRNA within approximately 4 hr. No downregulation was observed within 1 week's treatment. No rIL-3R beta mRNA was detectable in normal rat brain. However, 3 hr after a single injection of LPS into the tail vein of a rat, a marked induction of receptor mRNA occurred in a variety of brain regions. Transcriptional rates subsided significantly after 24 hr. rIL-3R beta mRNA was visualized by in situ hybridizations with cRNA antisense probes in ramified cells formerly characterized as microglial cells. rIL-3R beta mRNA was also induced in rat brain after occlusion of middle cerebral artery (MCAO).
The role of free radicals and p53 in neuron apoptosis in vivo
Authors: Wood KA , Youle RJ
Published: April 2018

Apoptosis is a mechanism of cell death operative in the normal development and regulation of vertebrate tissues and organ cellularity. During the postnatal development of the mouse cerebellum, extensive granule neuron apoptosis occurs that may regulate the final granule cell to Purkinje cell stoichiometry observed in the adult. Cerebellar granule cells are highly sensitive to genotoxic agents such as gamma- irradiation and methylazoxymethanol during the first 2 weeks of postnatal development. We demonstrate that ionizing radiation induces extensive cerebellar granule cell death via apoptosis in vivo. In p53 null mice, however, the cerebellar granule cells do not undergo apoptosis in response to gamma-irradiation. In mice heterozygous for the p53 allele, the granule cells apoptosis is delayed, indicating an intermediate response. The developmental apoptosis of cerebellar granule cells, however, occurs similarly in wild-type and p53 null mice. Therefore, neurons undergo p53-dependent and p53-independent apoptosis, depending upon the initiating stimulus that triggers DNA fragmentation. In contrast to x-ray damage, the extensive death of cerebellar granule cells induced by methylazoxymethanol was found to be independent of the DNA fragmentation characteristic of apoptosis, and was also independent of expression of p53. Ablation of neuron progenitor cells with genotoxic agents may occur by p53-dependent apoptosis or by p53-independent mechanisms not associated with DNA fragmentation.
Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differs significantly from those projecting to ventral tegmental area
Authors: Oakman SA , Faris PL , Kerr PE , Cozzari C , Hartman BK
Published: April 2018

Locations of pontomesencephalic cholinergic projection neurons from the laterodorsal tegmental (LDTg) and pedunculopontine tegmental (PPTg) nuclei to midbrain dopaminergic nuclei were mapped. Stereotaxic microinjections of Fluoro-Gold- or rhodamine-labeled microspheres were made either to substantia nigra (SN) or ventral tegmental area (VTA) in rat. Choline acetyltransferase was visualized immunohistochemically. Labeled cells were digitally mapped at multiple levels of the nuclei using an interactive computer/microscope system. SN-projecting neurons were distributed predominantly ipsilaterally in distinct regions of the PPTg: either at its rostral pole or caudally in an area ventromedial to the superior cerebellar peduncle. Few SN-projecting neurons were found in LDTg. VTA-projecting neurons were distributed bilaterally throughout the cholinergic group, primarily in the densest regions of the LDTg and caudal PPTg. Neurons were not strictly segregated into these patterns. Scattered cells belonging to either projection could be found throughout the cholinergic group on either side. Hierarchical log- linear analysis showed these differences in topographic distribution to be statistically significant. Subtraction of cell density images demonstrated well delineated regions of the cholinergic group where the projections were predominately either to SN or VTA. These data indicate a high degree of internal organization within the pontomesencephalic cholinergic group based on the location of efferent projections to SN or VTA. These findings support the concept that this cholinergic group is functionally organized in a manner which selectively innervates motor (SN) and limbic (VTA) dopaminergic nuclei.
A selective toxicity toward cultured mesencephalic dopaminergic neurons is induced by the synergistic effects of energetic metabolism impairment and NMDA receptor activation
Authors: Marey-Semper I , Gelman M , Levi-Strauss M
Published: April 2018

Numerous observations strongly support the hypothesis that dopaminergic neurons could be particularly vulnerable to an impairment of their energetic metabolism. In order to demonstrate the existence of such a selective vulnerability, the toxic effects of rotenone, an inhibitor of complex I of the respiratory chain, and of glutamate, which is very likely involved in the neurotoxicity induced by an energetic stress, were analyzed on cultured mouse mesencephalic neurons. Toxicity toward dopaminergic and GABAergic neurons was compared by measuring the residual uptakes of dopamine and GABA. Exposure to 5 nM rotenone for 6 hr or to a low concentration of glutamate (100 microM) for 1 hr did not lead to a high selective toxic effect on dopaminergic neurons. In contrast, dopaminergic neurons were three times less resistant to the sequential exposure to rotenone and glutamate than GABAergic neurons. A particular resistance of mesencephalic GABAergic neurons to the synergistic toxic effects of rotenone and glutamate was ruled out since two other neuronal types, the striatal cholinergic and GABAergic neurons, displayed the same weak vulnerability as the mesencephalic GABAergic neurons. This selective toxic effect of glutamate on rotenone- pretreated dopaminergic neurons was blocked by either AMPA or NMDA receptor antagonists and mimicked by combined treatment with AMPA and NMDA, or by NMDA alone when the medium was deprived of Mg2+ ions. Moreover, this NMDA-selective neurotoxicity was critically dependent on the presence of a physiological extracellular sodium concentration, since the use of choline chloride instead of sodium chloride had a protective effect on dopaminergic neurons.
Depolarization-induced neurite outgrowth in PC12 cells requires permissive, low level NGF receptor stimulation and activation of calcium/calmodulin-dependent protein kinase
Authors: Solem M , McMahon T , Messing RO
Published: April 2018

Neuronal activity is required for normal neural development. Excessive activity can cause abnormal growth of neural processes and may contribute to formation of epileptic foci. Using PC12 cells, we investigated mechanisms by which depolarization regulates neurite growth. Depolarization with 45 mM KCl induced neurite outgrowth only if NGF receptors were partly activated by overexpression of p140trkA or by treatment with a low concentration of NGF that alone was insufficient to stimulate neurite formation. Depolarization-induced neurite growth was reduced by inhibitors of L-type Ca2+ channels, Ca2+/calmodulin- dependent protein (CaM) kinases II and IV, and transcription. These results identify a novel mechanism by which depolarizing stimuli synergize with subthreshold activation of NGF receptors to induce neurite growth through a Ca2+ and CaM kinase-dependent signal transduction pathway.
Structural and functional evolution of the vasopressin/oxytocin superfamily: vasopressin-related conopressin is the only member present in Lymnaea, and is involved in the control of sexual behavior
Authors: Van Kesteren RE , Smit AB , De Lange RP , Kits KS , Van Golen FA , Van Der Schors RC , De With ND , Burke JF , Geraerts WP
Published: April 2018

It has been suggested that the gene duplication that led to the formation of the vasopressin/oxytocin two-gene family occurred early during vertebrate evolution. However, the existence of both vasopressin- and oxytocin-related peptides in invertebrates suggests that this duplication may have occurred much earlier, although there is no evidence for the co-occurrence of vasopressin- and oxytocin-related peptides in the same invertebrate species. We report here that in Lymnaea only the vasopressin-related peptide Lys-conopressin, but not an oxytocin-related peptide, is present. Moreover, it is very likely that an oxytocin-like cDNA or gene is absent. The conopressin gene is expressed in neurons that control male sexual behavior, and its gene products are present in the penis nerve and the vas deferens. Conopressin induces muscular contractions of the vas deferens and inhibits central neurons that control female reproductive behavior. Thus, although structurally related to vasopressin, conopressin has functional and behavioral characteristics typical for oxytocin. Physiological and receptor binding data suggest that conopressin and [Ile8]-conopressin, a synthetic oxytocin-like analog of conopressin, are functionally equivalent in Lymnaea, and that the chemical nature of the amino acid residue at position 8 does not result in a functional difference. Therefore, we suggest that invertebrates contain only a single member of the vasopressin/oxytocin gene family and that the amino acid change that distinguishes vasopressin from oxytocin is functionally neutral in invertebrates.
Enhancement of high threshold calcium currents in rat primary afferent neurons by constitutively active protein kinase C
Authors: Hall KE , Browning MD , Dudek EM , Macdonald RL
Published: April 2018

Protein kinase C has been implicated in the modulation of calcium channel function. However, controversy exists concerning the actions of agents such as phorbol esters or diacylglycerol (DAG) that activate endogenous PKC, with both enhancement and inhibition of Ca2+ currents described. In this article we report the effects of direct intracellular application of a constitutively active form of PKC (PKM) on whole cell calcium currents in acutely dissociated rat dorsal root ganglion neurons. PKM application significantly enhanced high threshold voltage-activated calcium currents elicited from holding potentials of - 80 mV and -40 mV. The rate of current rundown in PKM-treated cells was not significantly different from controls. The enhancement observed with PKM was not due to a shift in the voltage dependence of the peak current. Synthetic PKC inhibitor peptide (PKC-I) added to recording solutions containing PKM (PKM+PKC-I) abolished the PKM-associated enhancement. The rate of current rundown was significantly increased in the presence of PKM+PKC-I, and PKC-I alone, suggesting that substantial enhancement of voltage-activated calcium currents by endogenous PKC occurred in this preparation of rat dorsal root ganglion neurons. The portions of current attributable to N-, L-, and non-N,L-type currents [determined by applying the N- and L-type calcium antagonists omega- conotoxin GVIA and nifedipine (3–10 microM)] were not affected by PKM, suggesting that both N and L current components were enhanced by PKM.
Resolution and pharmacological analysis of the voltage-dependent calcium channels of Drosophila larval muscles
Authors: Gielow ML , Gu GG , Singh S
Published: April 2018

Voltage-dependent calcium channels play a role in many cellular phenomena. Very little is known about Ca2+ channels in Drosophila, especially those in muscles. Existing literature on neuronal Ca2+ channels of Drosophila suggests that their pharmacology may be distinct from that of vertebrate Ca2+ channels. This raises questions on the pharmacology and diversity of Ca2+ channels in Drosophila muscles. Here we show that the Ca2+ channel current in the body-wall muscles of Drosophila larvae consists of two main components. One component is sensitive to 1,4-dihydropyridines and diltiazem, which block vertebrate L-type Ca2+ channels. The second component is sensitive to amiloride, which blocks vertebrate T-type Ca2+ channels. In contrast to Drosophila brain membrane preparations in which a majority of the Ca2+ channels are phenylalkylamine-sensitive but dihydropyridine-insensitive, the major current in the muscles was dihydropyridine-sensitive but relatively less sensitive to verapamil. This might indicate an underlying tissue specific distribution of distinct subtypes of dihydropyridine/phenylalkylamine-sensitive Ca2+ channels in Drosophila. Low verapamil sensitivity of the dihydropyridine-sensitive current of Drosophila muscles also set it apart from the vertebrate L-type channels which are sensitive to 1,4-dihydropyridines, benzothiazepines as well as phenylalkylamines. The dihydropyridine-sensitive current in Drosophila muscles activated in a similar voltage range as the vertebrate L-type current. As with the vertebrate current, blockade by dihydropyridines was voltage dependent.
Long-term maintenance of presynaptic function in the absence of target muscle fibers
Authors: Dunaevsky A , Connor EA
Published: April 2018

Here we have investigated the role of the muscle fiber in the maintenance of presynaptic function at frog motor nerve terminals. Muscle fibers were selectively damaged and prevented from regenerating while leaving the motor innervation intact. Presynaptic activity of the resulting target-deprived nerve terminals was assayed using the fluorescent dye, FM1–43. FM1–43 stains nerve terminals in an activity- dependent fashion in that it incorporates into synaptic vesicles and can be released upon stimulation. We demonstrate that nerve terminals permanently deprived of target for 1 to 5 months maintain the ability to release and recycle synaptic vesicles in response to stimulation. The level of presynaptic function of target-deprived nerve terminals was not detectably different from that of nerve terminals in contact with muscle fibers. The remarkable maintenance of presynaptic function in these target-deprived nerve terminals indicates that the molecular machinery required for vesicular release is maintained in a functional state for long periods without target muscle fibers.
Nerve growth factor in Alzheimer's disease: increased levels throughout the brain coupled with declines in nucleus basalis
Authors: Scott SA , Mufson EJ , Weingartner JA , Skau KA , Crutcher KA
Published: April 2018

The current study analyzed NGF protein levels in the brains of patients with Alzheimer's disease (AD) as compared with aged neurologically normal individuals. An established two-site ELISA was used to measure NGF-like immunoreactivity in the hippocampus, superior temporal gyrus, superior frontal gyrus, inferior parietal lobule, frontal and occipital cortical poles, cerebellum, amygdala, putamen, and nucleus basalis of Meynert (nbM). ChAT activity was assayed in adjacent tissue samples. NGF levels were also evaluated in Parkinson's disease for comparison with both AD and age-matched control cases. Regardless of the brain bank (University of Cincinnati, Rush Presbyterian St. Luke's Medical Center in Chicago, or University of Alabama at Birmingham), NGF-like activity was at least moderately increased with AD in virtually every brain region examined except for the nbM, in which significant declines were observed. NGF levels were also increased when compared with age- matched Parkinson's cases (frontal cortex). NGF-like activity was not related to age at onset or disease duration in AD cases, nor did NGF levels correlate with age at death in the control or AD groups. Correlations between ChAT and NGF-like activity across brains varied considerably and were generally not significant. The present findings indicate that AD is characterized by a widespread increase in cortical and subcortical NGF. Although a correlation with ChAT activity was not observed in cortex, the AD-related decline in NGF found in nbM is consistent with the possibility of impaired retrograde transport of NGF to this region.
P13suc1 associates with a cdc2-like kinase in a multimeric cytoskeletal complex in squid axoplasm
Authors: Takahashi M , Amin N , Grant P , Pant HC
Published: April 2018

P13suc1 sepharose-conjugated beads were used to extract the kinases that phosphorylate neurofilaments in the squid giant axon. Using Western blots and in vitro kinase assays, we demonstrated the presence of an active cdc2-like kinase and its putative regulators such as cyclin E, p13, and p67 in axoplasm and a P13-axoplasm complex (P13-Ax). Protein kinase A (PKA) and casein kinase (CK) I and II were also found in the P13-Ax. Western blot analysis of the P13-Ax also demonstrated several axonal cytoskeletal components; e.g., neurofilaments (NFs; NF 60, 70, and 220), tubulin, actin, and microtubule-associated proteins. NF 220 and tubulin were phosphorylated by the kinases in the P13-Ax. To determine whether NFs bound directly to the P13 beads, or bound indirectly by association with cdc2 kinase, a washed, axon-derived neurofilament preparation that contained NFs, PKA, CKl, and tubulin, but no cdc2-like kinase, yielded no bound proteins after incubation with P13suc1. The wash supernatant from the neurofilament preparation, however, containing the cdc2-like kinase, did yield cytoskeletal components that bound to P13suc1. Moreover, a bacterial-expressed cdk5 associated with P13 beads was able to complex with selected cytoskeletal components in the washed neurofilament preparation. These data indicate that direct binding of P13 beads with a cdc2-like kinase could extract active multimeric complexes composed of axonal cytoskeletal proteins and kinases. Application of P13 chromatography may be useful in characterizing the network of functional interactions among cytoskeletal elements and protein kinases in neurons.
Tissue-specific expression of a Drosophila calcium-activated potassium channel
Authors: Becker MN , Brenner R , Atkinson NS
Published: April 2018

The Drosophila slowpoke (slo) gene encodes a subunit of a CAK channel homologous to the vertebrate BK channel. We have examined slo expression throughout development. It is expressed in muscle cells, neurons of the CNS and PNS, mushroom bodies, a limited number of cells in embryonic and larval midgut and in epithelial-derived tracheal cells. The promoter has been cloned and shown to direct expression in the same pattern as the endogenous gene in both neural and epithelial- derived cells. During pupariation and embryogenesis, slo is expressed in muscles many hours prior to the appearance of functional channels.
Anticipatory head direction signals in anterior thalamus: evidence for a thalamocortical circuit that integrates angular head motion to compute head direction
Authors: Blair HT , Sharp PE
Published: April 2018

Several regions in the rat brain contain neurons known as head- direction cells, which fire only when the rat's head is facing in a specific direction. Head-direction cells are influenced only by the direction of the head with respect to the static environmental surroundings, and not by the position of the head relative to the body. Each head-direction cell has its own preferred direction of firing, so that together, the population of cells provides a continuous signal of momentary directional heading. Here, head-direction cells were recorded from the post-subicular cortex (PSC) and anterodorsal nucleus (ADN) of the thalamus of freely moving rats. Cell activity was analyzed in relation to both momentary head direction, and the angular velocity of head turns. Head-direction cells in PSC maintained the same directional firing preference, regardless of the angular head velocity. By contrast, head-direction cells in ADN systematically shifted their directional firing preference, as a function of angular head velocity. The ADN cells always shifted their directional tuning peak to the left during clockwise head turns, and to the right during counterclockwise head turns. These results suggest that ADN neurons anticipate the future direction of the head, whereas PSC neurons encode the present direction of the head. Based on these findings, we hypothesize that neurons in PSC and ADN are reciprocally connected to form a thalamocortical circuit, which computes the directional position of the rat's head by integrating the angular motion of the head over time.
Moving effortlessly in three dimensions: does Donders' law apply to arm movement?
Authors: Soechting JF , Buneo CA , Herrmann U , Flanders M
Published: April 2018

Donders' law, as applied to the arm, predicts that to every location of the hand in space there corresponds a unique posture of the arm as defined by shoulder and elbow angles. This prediction was tested experimentally by asking human subjects to make pointing movements to a select number of target locations starting from a wide range of initial hand locations. The posture of the arm was measured at the start and end of every movement by means of video cameras. It was found that, in general, the posture of the arm at a given hand location does depend on the starting location of the movement and that, consequently, Donders' law is violated in this experimental condition. Kinematic and kinetic factors that could account for the variations in arm posture were investigated. It proved impossible to predict the final posture of the arm purely from kinematics, based on the initial posture of the arm. One hypothesis was successful in predicting final arm postures, namely that the final posture minimizes the amount of work that must be done to transport the arm from the starting location.
Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate
Authors: Dugan LL , Sensi SL , Canzoniero LM , Handran SD , Rothman SM , Lin TS , Goldberg MP , Choi DW
Published: April 2018

Increasing evidence suggests that glutamate neurotoxicity is partly mediated by reactive oxygen species, formed as a consequence of several processes, including arachidonic acid metabolism and nitric oxide production. Here we used an oxidation-sensitive indicator, dihydrorhodamine 123, in combination with confocal microscopy, to examine the hypothesis that electron transport by neuronal mitochondria may be an important source of glutamate-induced reactive oxygen species (ROS). Exposure to NMDA, but not kainate, ionomycin, or elevated potassium stimulated oxygen radical production in cultured murine cortical neurons, demonstrated by oxidation of nonfluorescent dihydrorhodamine 123 to fluorescent rhodamine 123. Electron paramagnetic resonance spectroscopy studies using 5,5-dimethyl-1- pyrroline-N-oxide (DMPO) as a radical-trapping agent, also showed production of ROS by cortical neurons after NMDA but not kainate exposure. NMDA-induced ROS production depended on extracellular Ca2+, and was not affected by inhibitors of nitric oxide synthase or arachidonic acid metabolism. The increased production of ROS was blocked by inhibitors of mitochondrial electron transport, rotenone or antimycin, and mimicked by the electron transport uncoupler, carbonyl cyanide p-trifluoromethoxyphenylhydrazone. These data support the possibility that NMDA receptor-mediated, Ca(2+)-dependent uncoupling of neuronal mitochondrial electron transport may contribute to the oxidative stress initiated by glutamate exposure.
The first retinal axon growth in the mouse optic chiasm: axon patterning and the cellular environment
Authors: Marcus RC , Mason CA
Published: April 2018

The retinofugal pathway is a useful model for axon guidance because fibers from each eye project to targets on both sides of the brain. Studies using static and real time analyses in mice at E15-17 demonstrated that uncrossed axons from ventrotemporal retina diverge from crossed axons in the optic chiasm, where specialized resident cells may direct divergence. Other studies, however, suggest that pioneering uncrossed retinal axons derive from a different retinal region, take a different course, and enter the ipsilateral optic tract independent of fiber-fiber interactions. We examine these differences by dye-labeling the earliest optic axons and immunocytochemically identifying cells in their path. The first optic axons arising from dorsocentral retina, enter the diencephalon at E12.5. All axons initially grow caudally, lateral to a radial glial palisade. In contrast to later growing axons, early uncrossed axons enter the ipsilateral optic tract directly. Crossed axons enter the glial palisade and course medially, then anteriorly, in a pathway corresponding to the border of an early neuronal population that expresses SSEA-1, CD44, and beta-tubulin. Axon patterning occurs independent of fiber-fiber interactions from both eyes, as the first uncrossed axons enter the optic tract before crossed ones from opposite eye. These analysis, in conjunction with our previous studies during the principal period of retinal axon growth in the diencephalon, suggest that the adult visual projection arises from age-dependent variations in the types and relative contribution of cues along the path through the emerging optic chiasm.
The nicotinic blocking agents d-tubocurare and alpha-bungarotoxin save motoneurons from naturally occurring death in the absence of neuromuscular blockade
Authors: Hory-Lee F , Frank E
Published: April 2018

Motoneurons undergo a phase of target-dependent cell death during development. In chick embryos, motoneuronal death is blocked by the application of the nicotinic antagonists d-tubocurare (dTC) or alpha- bungarotoxin (alpha BTX). Paralytic doses of these drugs also increase intramuscular nerve branch formation. To investigate the possibility that a neuronal rather than a muscle-type nicotinic ACh receptor (nAChR) might be responsible for the toxin-induced arrest of naturally occurring motoneuronal death, we compared the doses of dTC and alpha- BTX required for paralysis with those needed to protect motoneurons from cell death. We also measured the effects of dTC on the survival of retrogradely labeled motoneurons in culture, and of various doses of dTC on intramuscular nerve branch formation. Subparalytic doses of dTC caused small but significant increases in nerve branch number, while higher doses produced larger effects. In contrast, motoneuronal survival was already maximal at doses of dTC or alpha-BTX below those needed for a visible effect on limb movement. Moreover, dTC increased motoneuron survival in culture, in the absence of muscle cells and muscle-type nAChRs. Nicotinic blocking agents can therefore rescue motoneurons with minimal depression of neuromuscular transmission, suggesting that this effect may be mediated through neuronal, rather than muscle-type.
Transfer of coded information from sensory to motor networks
Authors: Salinas E , Abbott LF
Published: April 2018

During sensory-guided motor tasks, information must be transferred from arrays of neurons coding target location to motor networks that generate and control movement. We address two basic questions about this information transfer. First, what mechanisms assure that the different neural representations align properly so that activity in the sensory network representing target location evokes a motor response generating accurate movement toward the target? Coordinate transformations may be needed to put the sensory data into a form appropriate for use by the motor system. For example, in visually guided reaching the location of a target relative to the body is determined by a combination of the position of its image on the retina and the direction of gaze. What assures that the motor network responds to the appropriate combination of sensory inputs corresponding to target position in body- or arm-centered coordinates? To answer these questions, we model a sensory network coding target position and use it to drive a similarly modeled motor network. To determine the actual motor response we use decoding methods that have been developed and verified in experimental work. We derive a general set of conditions on the sensory-to-motor synaptic connections that assure a properly aligned and transformed response. The accuracy of the response for different numbers of coding cells is computed. We show that development of the synaptic weights needed to generate the correct motor response can occur spontaneously through the observation of random movements and correlation-based synaptic modification. No error signal or external teaching is needed during this process. We also discuss nonlinear coordinate transformations and the presence of both shifting and nonshifting receptive fields in sensory/motor systems.
Light removes inactivation of the A-type potassium channels in scallop hyperpolarizing photoreceptors
Authors: Shimatani Y , Katagiri Y
Published: April 2018

The properties of light-activated and voltage dependent conductances in the hyperpolarizing photoreceptors of the isolated retina of the giant scallop (Patinopecten yessoensis) have been studied in whole-cell voltage-clamp recordings. Resting membrane potential of the cells was - 35 to -60 mV in the dark. Large outward current was maintained during illumination when the cell was voltage clamped at the resting potential. Previous reports have shown that the hyperpolarizing response to light and the light-activated outward current are mediated by an increase of a conductance of K+ channels in the plasma membrane (Gorman and McReynolds, 1974; Gomez and Nasi, 1994a). This report shows that the light-activated K+ channels of this photoreceptor cell generate the voltage-dependent transient outward current in response to depolarizing voltage steps in the dark. The characteristic of this current resembles the typical voltage-dependent transient current (A- current) of molluscan neurons in the kinetics of activation and inactivation, and in the blockage by 4-aminopyridine (4-AP). However, the voltage-dependent transient current during illumination becomes a flat stable form which inactivation process disappeared. We report here that light removes inactivation of the K+ channels which generate the voltage-dependent transient outward currents in the dark.
In a rat model of parkinsonism, lesions of the subthalamic nucleus reverse increases of reaction time but induce a dramatic premature responding deficit
Authors: Baunez C , Nieoullon A , Amalric M
Published: April 2018

Lesions of the subthalamic nucleus (STN) have been found to reduce the severe akinetic motor symptom produced in animal models of Parkinson's disease, such as in monkeys treated with 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) or in monoamine-depleted rats. However, little is known about the effect of STN exclusion on subtle motor deficits induced by moderate dopaminergic lesions in complex motor tasks. The present study was thus performed on rats trained in a reaction time (RT) task known to be extremely sensitive to variations of dopamine transmission in the striatum. Animals were trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Discrete dopamine depletion produced by infusing the neurotoxin 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal part of the striatum, produced motor initiation deficits which were revealed by an increase in the number of delayed responses (lever release after the time limit) and a lengthening of RTs. In contrast, bilateral excitotoxic lesion of the STN with ibotenic acid induced severe behavioral deficits which were opposite to those produced by the dopaminergic lesion, as shown by an increase in the number of premature responses (lever release before the onset of the visual stimulus) and a decrease of RTs. Surprisingly, the performance of the animals bearing a double lesion (striatal dopaminergic lesion followed 14 d later by STN ibotenic lesion) was still impaired 40 d after the ibotenic lesion. As expected, the 6-OHDA-induced motor initiation deficits were reversed by a subsequent STN lesion. However, the dramatic increase of premature responses contributing to major behavioral deficits induced by the STN lesion remained unchanged. Thus, the bilateral lesion of the STN was found to alleviate the motor deficits in this model of parkinsonism, but essentially produced over time, long lasting deficits that might be related to dyskinesia or cognitive impairment. The present results strongly support the recent concept of a predominant control of the STN on basal ganglia output structures.
Subthalamic nucleus lesions: widespread effects on changes in gene expression induced by nigrostriatal dopamine depletion in rats
Authors: Delfs JM , Ciaramitaro VM , Parry TJ , Chesselet MF
Published: April 2018

Lesions of the subthalamic nucleus block behavioral effects of nigrostriatal dopamine depletion in rats and primates, but the contribution of this region to the molecular effects of dopaminergic lesions is unknown. The effects of subthalamic nucleus lesions alone or in combination with a 6-hydroxydopamine-induced lesion of the substantia nigra were examined in adult rats. Unilateral subthalamic nucleus lesions caused ipsiversive rotation after peripheral administration of apomorphine and a small decrease in glutamic acid decarboxylase (GAD) mRNA in the ipsilateral globus pallidus (external pallidum). Confirming previous results, nigrostriatal dopaminergic lesions caused contraversive rotation after apomorphine injection, and increased enkephalin mRNA in the striatum, GAD mRNA in the globus pallidus, and somatostatin mRNA in the entopeduncular nucleus (internal pallidum) ipsilateral to the lesion. In addition, the lesion decreased substance P mRNA in the ipsilateral striatum compared to the contralateral side, and GAD mRNA in the contralateral entopeduncular nucleus. These effects were abolished in rats with lesions of the subthalamic nucleus and substantia nigra on the same side. Thus, the subthalamic lesions prevented changes in gene expression induced by dopamine depletion, not only in regions receiving a direct input from the subthalamic nucleus (ipsilateral pallidum), but also in regions which do not (striatum and contralateral pallidum). This suggests that polysynaptic pathways regulated by the subthalamic nucleus contribute to the effects of dopaminergic lesions in many regions of the basal ganglia. This pivotal role of the subthalamic nucleus may account for the beneficial effects of subthalamic nucleus lesions on motor symptoms resulting from dopamine depletion.
Inhibitors of cyclic-GMP phosphodiesterase alter excitation of Limulus ventral photoreceptors in Ca(2+)-dependent fashion
Authors: Johnson EC , O'Day PM
Published: April 2018

We have examined the hypothesis that Ca(2+)-dependent cyclic-GMP metabolism may play a role in visual transduction in Limulus photoreceptors. Although phosphoinositide hydrolysis is central to phototransduction and phosphoinositide-dependent Ca(2+)-mobilization seems to be required for transduction, the subsequent steps leading to ion channel gating (the immediate cause of excitation) are not understood. Channels normally opened in response to light can be opened in excised membrane patches by cGMP but not by Ca2+, suggesting that cGMP acts as a channel ligand in excitation. Using phosphodiesterase inhibitors, we investigated whether changes in cGMP metabolism could affect excitation. We report that zaprinast and IBMX increased the amplitudes and retarded the kinetics of physiological light responses. These effects were maximal for brightest stimuli. The effects were markedly enhanced in low Ca2+ conditions. In contrast, excitation induced by direct IP3-injection and by direct Ca(2+)-injection were inhibited. These observations suggest that PI-induced excitation is dependent on cGMP metabolism in a Ca(2+)-dependent manner, and they support the possibility that transduction involves modification of cGMP metabolism by Ca(2+)-release resulting from phosphoinositide hydrolysis.
Hippocampal CA1 interneurons: an in vivo intracellular labeling study
Authors: Sik A , Penttonen M , Ylinen A , Buzsaki G
Published: April 2018

Fast spiking interneurons in the CA1 area of the dorsal hippocampus were recorded from and filled with biocytin in anesthetized rats. The full extent of their dendrites and axonal arborizations as well as their calcium binding protein content were examined. Based on the spatial extent of axon collaterals, local circuit cells (basket and O- LM neurons) and long-range cells (bistratified, trilaminar, and backprojection neurons) could be distinguished. Basket cells were immunoreactive for parvalbumin and their axon collaterals were confined to the pyramidal layer. A single basket cell contacted more than 1500 pyramidal neurons and 60 other parvalbumin-positive interneurons. Commissural stimulation directly discharged basket cells, followed by an early and late IPSPs, indicating interneuronal inhibition of basket cells. The dendrites of another local circuit neuron (O-LM) were confined to stratum oriens and it had a small but high-density axonal terminal field in stratum lacunosum-moleculare. The fastest firing cell of all interneurons was a calbindin-immunoreactive bistratified neuron with axonal targets in stratum oriens and radiatum. Two neurons with their cell bodies in the alveus innervated the CA3 region (backprojection cells), in addition to rich axon collaterals in the CA1 region. The trilaminar interneuron had axon collaterals in strata radiatum, oriens and pyramidale with its dendrites confined to stratum oriens. Commissural stimulation evoked an early EPSP-IPSP-late depolarizing potential sequence in this cell. All interneurons formed symmetric synapses with their targets at the electron microscopic level. These findings indicate that interneurons with distinct axonal targets have differential functions in shaping the physiological patterns of the CA1 network.
The adult CNS retains the potential to direct region-specific differentiation of a transplanted neuronal precursor cell line
Authors: Shihabuddin LS , Hertz JA , Holets VR , Whittemore SR
Published: April 2018

The chronic survival and differentiation of the conditionally immortalized neuronal cell line, RN33B, was examined following transplantation into the adult and neonatal rat hippocampus and cerebral cortex. In clonal culture, differentiated RN33B cells express p75NTR and trkB mRNA and protein, and respond to brain-derived neurotrophic factor treatment by inducing c-fos mRNA. Transplanted cells, identified using immunohistochemistry to detect beta- galactosidase expression, were seen in most animals up to 24 weeks posttransplantation (the latest time point examined). Stably integrated cells with various morphologies consistent with their transplantation site were observed. In the cerebral cortex, many RN33B cells differentiated with morphologies similar to pyramidal neurons and stellate cells. In the hippocampal formation, many RN33B cells assumed morphologies similar to pyramidal neurons characteristic of CA1 and CA3 regions, granular cell layer neurons of the dentate gyrus, and polymorphic neurons of the hilar region. Identical morphologies were observed in both adult and neonatal hosts, although a greater percentage of beta-galactosidase immunoreactive cells had differentiated in the neonatal brains. These results suggest that RN33B cells have the developmental plasticity to respond to local microenvironmental signals and that the adult brain retains the capacity to direct the differentiation of neuronal precursor cells in a direction that is consistent with that of endogenous neurons.
Consequences and mechanisms of spike broadening of R20 cells in Aplysia californica
Authors: Ma M , Koester J
Published: April 2018

We studied frequency-dependent spike broadening in the two electrically coupled R20 neurons in the abdominal ganglion of Aplysia. The peptidergic R20 cells excite the R25/L25 interneurons (which trigger respiratory pumping) and inhibit the RB cells. When fired at 1–10 Hz, the duration of the falling phase of the action potential in R20 neurons increases 2-10 fold during a spike train. Spike broadening recorded from the somata of the R20 cells affected synaptic transmission to nearby follower cells. Chemically mediated synaptic output was reduced by approximately 50% when recorded trains of nonbroadened action potentials were used as command signals for a voltage-clamped R20 cell. Electrotonic EPSPs between the R20 cells, which normally facilitated by two- to fourfold during a high frequency spike train, showed no facilitation when spike broadening was prevented under voltage-clamp control. To examine the mechanism of frequency- dependent spike broadening, we applied two-electrode voltage-clamp and pharmacological techniques to the somata of R20 cells. Several voltage- gated ionic currents were isolated, including INa, a multicomponent ICa, and three K+ currents--a high threshold, fast transient A-type K+ current (IAdepol), a delayed rectifier K+ current (IK-V), and a Ca(2+)- sensitive K+ current (IK-Ca), made up of two components. The influences of different currents on spike broadening were determined by using the recorded train of gradually broadening action potentials as the command for the voltage clamp. We found the following. (1) IAdepol is the major outward current that contributes to repolarization of nonbroadened spikes. It undergoes pronounced cumulative inactivation that is a critical determinant of spike broadening. (2) Activity-dependent changes in IK-V, IK-Ca, and ICa have complex effects on the kinetics and extent of broadening. (3) The time integral of ICa during individual action potentials increases approximately threefold during spike broadening.
Tissue- and age-specific expression patterns of alternatively spliced agrin mRNA transcripts in embryonic rat suggest novel developmental roles
Authors: Stone DM , Nikolics K
Published: April 2018

Agrin is an extracellular matrix protein that mediates the nerve- induced clustering of nicotinic acetylcholine receptors on target muscle cells, and thus plays a key role in development of the neuromuscular synapse. Alternative exon usage within the rat agrin gene predicts numerous protein isoforms, which differ by the inclusion or exclusion of small inserts at three sites in the C-terminal half of the molecule; the insert status at two of these sites, termed Y and Z, profoundly influences the acetylcholine receptor clustering activity. We have examined the cellular expression patterns of agrin messenger RNA transcripts during rat embryogenesis by in situ hybridization with isoform-specific probes. Six 36-mer oligonucleotide probes were designed to distinguish between mRNA isoforms at either the Y site: the encoded protein contains either no insert (Y0) or a 4-amino acid insert (Y4), or the Z site: the encoded protein contains either no insert or one of 8 (Z8), 11 (Z11), or 19 (Z19) amino acids. Strikingly different expression patterns were observed for the individual Y- and Z-site encoding messages. While optional exon usage predicts the possibility of eight different agrin isoforms at the two splice sites, we detected only four isoforms in vivo: Y4Z0, Y0Z0, Y4Z8, and Y4Z19. The Y4Z0 transcript, which comprised the majority of the agrin expressed, was localized exclusively to nervous tissue and exhibited a distribution profile suggestive of a potential role in neurogenesis and/or neural differentiation. From embryonic day 13 to birth, Y4Z0 was found in mitotic ventricular zones, spinal, cranial, and sympathetic ganglia, and diffusely throughout the brain. In contrast, Y0Z0 was not expressed in neurons, but specifically labeled capillary endothelial cells within the developing nervous system. Y4Z8 and Y4Z19, the forms most active in acetylcholine receptor aggregation, were expressed at low levels only in spinal and brainstem motor neurons; Z19 expression declined from embryonic day 15 to adulthood, whereas Z8 expression increased slightly during this period. Transcripts encoding the Z11 insert could not be detected. These data suggest potential novel biological roles for agrin beyond that originally proposed in synapse formation.
Forebrain contribution to the induction of a cellular correlate of conditioned taste aversion in the nucleus of the solitary tract
Authors: Schafe GE , Seeley RJ , Bernstein IL
Published: April 2018

A conditioned taste aversion (CTA) is a form of classical conditioning in which animals avoid a taste (conditioned stimulus; CS) which has been previously paired with a treatment (unconditioned stimulus; US) that produces transient illness. Recently, a reliable cellular correlate of the behavioral expression of a CTA was identified using c- Fos immunostaining as a marker of neuronal activation. Exposure to a saccharin solution (CS) which had previously been paired with lithium chloride (LiCl; US) induced significant c-Fos-like immunoreactivity (c- FLI) in the intermediate zone of the nucleus of the solitary tract (NTS), a response that was quite similar to that displayed following administration of LiCl alone. The present studies employed a variant of the chronic decerebrate rat preparation to explore whether circuitry intrinsic to the brainstem is sufficient for the induction of c-FLI in both as an unconditioned response to the LiCl and as a conditioned response to the saccharin. Using chronic hemidecerebrate rats, which have a unilateral brain transection at the level of the superior colliculus, we found that the unconditioned c-FLI to LiCI was unaltered by the transection, while the conditioned expression of c-FLI to the CS taste was evident only on the side of the NTS which retained neural connections with the forebrain. These findings strongly implicate forebrain input in this cellular correlate of CTA learning and also indicate that the pathways mediating the response to the US (LiCl) and the CS (saccharin) differ.