bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAergic Neurons in Barrel Cortex Show Strong, Whisker-Dependent Metabolic Activation during Normal Behavior
Authors: McCasland James S. , Hibbard Lyndon S.
Published: April 2018

Electrophysiological data from the rodent whisker/barrel cortex indicate that GABAergic, presumed inhibitory, neurons respond more vigorously to stimulation than glutamatergic, presumed excitatory, cells. However, these data represent very small neuronal samples in restrained, anesthetized, or narcotized animals or in cortical slices. Histochemical data from primate visual cortex, stained for the mitochondrial enzyme cytochrome oxidase (CO) and for GABA, show that GABAergic neurons are more highly reactive for CO than glutamatergic cells, indicating that inhibitory neurons are chronically more active than excitatory neurons but leaving doubt about the short-term stimulus dependence of this activation. Taken together, these results suggest that highly active inhibitory neurons powerfully influence relatively inactive excitatory cells but do not demonstrate directly the relative activities of excitatory and inhibitory neurons in the cortexduring normal behavior.

We used a novel double-labeling technique to approach the issue of excitatory and inhibitory neuronal activation during behavior. Our technique combines high-resolution 2-deoxyglucose (2DG), immunohistochemical staining for neurotransmitter-specific antibodies, and automated image analysis to collect the data. We find that putative inhibitory neurons in barrel cortex of behaving animals are, on average, much more heavily 2DG-labeled than presumed excitatory cells, a pattern not seen in animals anesthetized at the time of 2DG injection. This metabolic activation is dependent specifically on sensory inputs from the whiskers, because acute trimming of most whiskers greatly reduces 2DG labeling in both cell classes in columns corresponding to trimmed whiskers. Our results provide confirmation of the active GABAergic cell hypothesis suggested by CO and single-unit data. We conclude that strong activation of inhibitory cortical neurons must confer selective advantages that compensate for its inherent energy inefficiency.
Expression of LIM Protein GenesLmo1, Lmo2,andLmo3in Adult Mouse Hippocampus and Other Forebrain Regions: Differential Regulation by Seizure Activity
Authors: Hinks G. L. , Shah B. , French S. J. , Campos L. S. , Staley K. , Hughes J. , Sofroniew M. V.
Published: April 2018

The LIM domain is a zinc-binding amino acid motif that characterizes various proteins which function in protein–protein interactions and transcriptional regulation. Expression patterns of several LIM protein genes are compatible with roles in vertebrate CNS development, but little is known about the expression, regulation, or function of LIM proteins in the mature CNS.Lmo1, Lmo2,andLmo3are LIM-only genes originally identified as putative oncogenes that have been implicated in the control of cell differentiation and are active during CNS development. Usingin situhybridization for mRNA and immunohistochemical detection of reporter protein expression in transgenic mice, we found thatLmo1, Lmo2, andLmo3show individually unique but partially overlapping patterns of expression in several regions of the adult mouse forebrain, including hippocampus, caudate putamen, medial habenula, thalamus, amygdala, olfactory bulb, hypothalamus, and cerebral cortex. In the hippocampal formation,Lmo1, Lmo2, andLmo3show different combinatorial patterns of expression levels in CA pyramidal and dentate granule neurons, andLmo1is present in topographically restricted subpopulations of astrocytes. Kainic acid-induced limbic seizures differentially regulatedLmo1, Lmo2,andLmo3mRNA levels in hippocampal pyramidal and granule neurons, such thatLmo1mRNA increased, whereasLmo2andLmo3mRNAs decreased significantly, with maximal changes at 6 hr after seizure onset and return to baseline by 24 hr. These findings show thatLmo1, Lmo2, andLmo3continue to be expressed in the adult mammalian CNS in a cell type-specific manner, are differentially regulated by neuronal activity, and may thus be involved in cell phenotype-specific regulatory functions.
Adrenergic Receptors in Alzheimer’s Disease Brain: Selective Increases in the Cerebella of Aggressive Patients
Authors: Russo-Neustadt Amelia , Cotman Carl W.
Published: April 2018

In this study, the distribution and concentration of β1, β2, and α2adrenergic receptors were examined in the frontal cortex, hypothalamus, and cerebellum of Alzheimer’s disease (AD) and age-matched control human brains by receptor autoradiography. The purpose of this study was to detect changes in adrenergic receptor concentrations in key areas of the brain known to affect behavior. For these studies, [125I]iodopindolol ([125I]IPIN) was used to visualize total β adrenergic sites (with ICI-89,406 and ICI-118,551 as subtype-selective antagonists to visualize β2and β1receptors, respectively). [3H]UK-14,304 was used to localize the α2sites. Essentially no significant difference in adrenergic receptor concentration was found between total AD cases taken together and control patients. It was found, however, that there were important distinctions within the AD group when cases were subdivided according to the presence or absence of aggression, agitation, and disruptive behavior. Aggressive AD patients had markedly increased (by ∼70%) concentrations of α2receptors in the cerebellar cortex compared with nonaggressive patients with similar levels of cognitive deficit. The levels of cerebellar α2receptors in aggressive AD patients were slightly above the healthy elderly controls, suggesting that these receptors are preserved and perhaps increased in this subgroup of AD. β1And β2adrenergic receptors of the cerebellar cortex showed smaller but significant (∼25%) increases in concentration in aggressive AD subjects versus both nonaggressive AD patients and controls. No significant differences were found in adrenergic receptor concentrations within the frontal cortex or hypothalamus. These results point out the importance of distinguishing behavioral subgroups of AD when looking for specific neurochemical changes. These autoradiographic results may reflect the importance of the cerebellum in behavioral control.
Temporal Dynamics of Graded Synaptic Transmission in the Lobster Stomatogastric Ganglion
Authors: Manor Yair , Nadim Farzan , Abbott L. F. , Marder Eve
Published: April 2018

Synaptic transmission between neurons in the stomatogastric ganglion of the lobsterPanulirus interruptusis a graded function of membrane potential, with a threshold for transmitter release in the range of −50 to −60 mV. We studied the dynamics of graded transmission between the lateral pyloric (LP) neuron and the pyloric dilator (PD) neurons after blocking action potential-mediated transmission with 0.1 μmtetrodotoxin. We compared the graded IPSPs (gIPSPs) from LP to PD neurons evoked by square pulse presynaptic depolarizations with those potentials evoked by realistic presynaptic waveforms of variable frequency, amplitude, and duty cycle. The gIPSP shows frequency-dependent synaptic depression. The recovery from depression is slow, and as a result, the gIPSP is depressed at normal pyloric network frequencies. Changes in the duration of the presynaptic depolarization produce nonintuitive changes in the amplitude and time course of the postsynaptic responses, which are again frequency-dependent. Taken together, these data demonstrate that the measurements of synaptic efficacy that are used to understand neural network function are best made using presynaptic waveforms and patterns of activity that mimic those in the functional network.
Neural Agrin Induces Ectopic Postsynaptic Specializations in Innervated Muscle Fibers
Authors: Meier Thomas , Hauser Dominik M. , Chiquet Matthias , Landmann Lukas , Ruegg Markus A. , Brenner Hans R.
Published: April 2018

Neural agrin, in the absence of a nerve terminal, can induce the activity-resistant expression of acetylcholine receptor (AChR) subunit genes and the clustering of synapse-specific adult-type AChR channels in nonsynaptic regions of adult skeletal muscle fibers. Here we show that, when expression plasmids for neural agrin are injected into the extrasynaptic region of innervated muscle fibers, the following components of the postsynaptic apparatus are aggregated and colocalized with ectopic agrin-induced AChR clusters: laminin-β2, MuSK, phosphotyrosine-containing proteins, β-dystroglycan, utrophin, and rapsyn. These components have been implicated to play a role in the differentiation of neuromuscular junctions. Furthermore, ErbB2 and ErbB3, which are thought to be involved in the regulation of neurally induced AChR subunit gene expression, were colocalized with agrin-induced AChR aggregates at ectopic nerve-free sites. The postsynaptic muscle membrane also contained a high concentration of voltage-gated Na+channels as well as deep, basal lamina-containing invaginations comparable to the secondary synaptic folds of normal endplates. The ability to induce AChR aggregationin vivowas not observed in experiments with a muscle-specific agrin isoform. Thus, a motor neuron-specific agrin isoform is sufficient to induce a full ectopic postsynaptic apparatus in muscle fibers kept electrically active at their original endplate sites.
Glutamate Receptor Subunits GluR5 and KA-2 Are Coexpressed in Rat Trigeminal Ganglion Neurons
Authors: Sahara Yoshinori , Noro Nobuhiro , Iida Yutaka , Soma Kunimichi , Nakamura Yoshio
Published: April 2018

To determine the subunit composition of high-affinity kainate receptors in native neurons is a challenging problem because of the expression of more than one GluR subunit. In the present study the question of whether GluR5 and/or GluR6 subunits combine with KA-1 or KA-2 subunitsin vivois addressed by performing detailed physiological, pharmacological, and molecular characterization of functional kainate receptor channels in acutely dissociated trigeminal ganglion (TG) neurons. The results show that (1) smaller diameter TG neurons (<30 μm) respond tol-glutamate and kainate, and the currents gated by kainate desensitize with prolonged agonist exposure; (2) all kainate receptor subunits are detected to some extent by reverse transcriptase-PCR, whereas glutamate receptor subunits GluR5 and KA-2 are expressed at high levels in the TG; (3) there is an obvious similarity between the features of native kainate receptor channels in TG neurons and of heteromeric recombinant GluR5(R)/KA-2 channels in pharmacological properties, desensitization, rectification, ion permeability, and mean channel conductance; and (4) the age-dependent increase in GluR5 and KA-2 RNA levels in the TG is correlated well with an increased number of kainate-sensitive cells during postnatal development. Our data suggest that the heteromeric GluR5/KA2 combination actually occurs in TG neurons and give a clue as to the subunit composition of native kainate receptor channels.
Subunit Composition, Kinetic, and Permeation Properties of AMPA Receptors in Single Neocortical Nonpyramidal Cells
Authors: Angulo Marı́a Cecilia , Lambolez Bertrand , Audinat Etienne , Hestrin Shaul , Rossier Jean
Published: April 2018

Native AMPA receptors (AMPARs) were investigated in neocortical fast-spiking (FS) and regular-spiking nonpyramidal (RSNP) cells. The onset of and recovery from desensitization as well as current rectification and single-channel conductance were studied by using fast glutamate application to outside-out patches. The GluR1–4 subunit, flip/flop splicing, and R/G editing expression patterns of functionally characterized cells were determined by single-cell reverse transcription-PCR to correlate the subunit composition of native AMPARs with their functional properties. Our sample, mostly constituted by RSNP neurons, predominantly expressed GluR3 flip and GluR2 flop. In individual cells, flip/flop splicing of each subunit appeared to be regulated independently, whereas for R/G editing all subunits were either almost fully edited or unedited. We confirmed that the relative GluR2 expression controls the permeation properties of native AMPARs, whereas none of the single molecular parameters considered appeared to be a key determinant of the kinetics. FS neurons displayed AMPARs with relatively homogeneous functional properties characterized by fast desensitization, slow recovery from desensitization, marked inward rectification, and large single-channel conductance. In contrast, these parameters varied over a wide range in RSNP neurons, and their combination resulted in various AMPAR functional patterns. Indeed, in different cells, fast or slow desensitization was found to be associated with either slow or fast recovery from desensitization. Similarly, fast or slow kinetics was associated with either strong or weak rectification. Our results suggest that kinetic and permeation properties of native AMPARs can be regulated independently in cortical neurons and probably do not have the same molecular determinants.
Differential Expression of Distinct Members of Rho Family GTP-Binding Proteins during Neuronal Development: Identification ofRac1B, a New Neural-Specific Member of the Family
Authors: Malosio Maria Luisa , Gilardelli Daniela , Paris Simona , Albertinazzi Chiara , de Curtis Ivan
Published: April 2018

Previous studies on small GTP-binding proteins of the Rho family have revealed their involvement in the organization of cell actin cytoskeleton. The function of these GTPases during vertebrate development is not known. With the aim of understanding the possible role of these proteins during neuronal development, we have cloned and sequenced five members expressed in developing chick neural retinal cells. We have identified four chicken genes, cRhoA, cRhoB, cRhoC, andcRac1A, homologous to known human genes, and a novelRacgene,cRac1B. Analysis of the distribution of four of the identified transcripts in chicken embryos shows for the first time high levels of expression of Rho family genes in the vertebrate developing nervous system, with distinct patterns of distribution for the different transcripts. In particular,cRhoAandcRac1Agene expression appeared ubiquitous in the whole embryo, and thecRhoBtranscript was more prominent in populations of neurons actively extending neurites, whereas the newly identifiedcRac1Bgene was homogeneously expressed only in the developing nervous system. Temporal analysis of the expression of the five genes suggests a correlation with the morphogenetic events occurring within the developing retina and the retinotectal pathway. Expression of an epitope-tagged cRac1B in retinal neurons showed a diffuse distribution of the protein in the cell body and along neurites.

Taken as a whole, our results suggest important roles for ubiquitous and neural-specific members of the Rho family in the acquisition of the mature neuronal phenotype.
The Response of Subthalamic Nucleus Neurons to Dopamine Receptor Stimulation in a Rodent Model of Parkinson’s Disease
Authors: Kreiss Deborah S. , Mastropietro Christopher W. , Rawji Saima S. , Walters Judith R.
Published: April 2018

Overactivity in the subthalamic nucleus (STN) is believed to contribute to the pathophysiology of Parkinson’s disease. It is hypothesized that dopamine receptor agonists reduce neuronal output from the STN. The present study tests this hypothesis by usingin vivoextracellular single unit recording techniques to measure neuronal activity in the STN of rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway (a model of Parkinson’s disease). As predicted, firing rates of STN neurons in lesioned rats were tonically elevated under basal conditions and were decreased by the nonselective dopamine receptor agonists apomorphine andl-3,4-dihydroxyphenylalanine (l-DOPA). STN firing rates were also decreased by the D2 receptor agonist quinpirole when administered after the D1 receptor agonist (±)- 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393). Results of the present study challenge the prediction that dopaminergic agonists reduce STN activity predominantly through actions at striatal dopamine D2 receptors. Firing rates of STN neurons were not altered by selective stimulation of D2 receptors and were increased by selective stimulation of D1 receptors. Moreover, there was a striking difference between the responses of the STN to D1/D2 receptor stimulation in the lesioned and intact rat; apomorphine inhibited STN firing in the lesioned rat and increased STN firing in the intact rat. These findings support the premise that therapeutic efficacy in the treatment of Parkinson’s disease is associated with a decrease in the activity of the STN, but challenge assumptions about the roles of D1 and D2 receptors in the regulation of neuronal activity of the STN in both the intact and dopamine-depleted states.
Modulation of Force during Locomotion: Differential Action of Crustacean Cardioactive Peptide on Power-Stroke and Return- Stroke Motor Neurons
Authors: Mulloney Brian , Namba Hisaaki , Agricola Hans-Jürgen , Hall Wendy M.
Published: April 2018

Crustacean cardioactive peptide (CCAP) elicited expression of the motor pattern that drives coordinated swimmeret beating in crayfish and modulated this pattern in a dose-dependent manner. In each ganglion that innervates swimmerets, neurons with CCAP-like immunoreactivity sent processes to the lateral neuropils, which contain branches of swimmeret motor neurons and the local pattern-generating circuits.

CCAP affected each of the four functional groups of motor neurons, power-stroke excitors (PSE), return-stroke excitors (RSE), power-stroke inhibitors (PSI), and return-stroke inhibitors (RSI), that innervate each swimmeret. When CCAP was superfused, the membrane potentials of these neurons began to oscillate periodically about their mean potentials. The mean potentials of PSE and RSI neurons depolarized, and some of these neurons began to fire during each depolarization. Both intensity and durations of PSE bursts increased significantly. The mean potentials of RSE and PSI neurons hyperpolarized, and these neurons were less likely to fire during each depolarization. When CCAP was superfused in a low Ca2+saline that blocked chemical transmission, these changes in mean potential persisted, but the periodic oscillations disappeared.

These results are evidence that CCAP acts at two levels: activation of local premotor circuits and direct modulation of swimmeret motor neurons. The action on motor neurons is differential; PSEs and RSIs are excited, but RSEs and PSIs are inhibited. The consequences of this selectivity are to increase intensity of bursts of impulses that excite power-stroke muscles.
Linearized Buffered Ca2+Diffusion in Microdomains and Its Implications for Calculation of [Ca2+] at the Mouth of a Calcium Channel
Authors: Naraghi Mohammad , Neher Erwin
Published: April 2018

Immobile and mobile calcium buffers shape the calcium signal close to a channel by reducing and localizing the transient calcium increase to physiological compartments. In this paper, we focus on the impact of mobile buffers in shaping steady-state calcium gradients in the vicinity of an open channel, i.e. within its “calcium microdomain.” We present a linear approximation of the combined reaction–diffusion problem, which can be solved explicitly and accounts for an arbitrary number of calcium buffers, either endogenous or added exogenously. It is valid for small saturation levels of the present buffers and shows that within a few hundred nanometers from the channel, standing calcium gradients develop in hundreds of microseconds after channel opening. It is shown that every buffer can be assigned a uniquely defined length-constant as a measure of its capability to buffer calcium close to the channel. The length-constant clarifies intuitively the significance of buffer binding and unbinding kinetics for understanding local calcium signals. Hence, we examine the parameters shaping these steady-state gradients. The model can be used to check the expected influence of single channel calcium microdomains on physiological processes such as excitation–secretion coupling or excitation–contraction coupling and to explore the differential effect of kinetic buffer parameters on the shape of these microdomains.
Functional Analysis of V3A and Related Areas in Human Visual Cortex
Authors: Tootell Roger B. H. , Mendola Janine D. , Hadjikhani Nouchine K. , Ledden Patrick J. , Liu Arthur. K. , Reppas John B. , Sereno Martin I. , Dale Anders M.
Published: April 2018

Using functional magnetic resonance imaging (fMRI) and cortical unfolding techniques, we analyzed the retinotopy, motion sensitivity, and functional organization of human area V3A. These data were compared with data from additional human cortical visual areas, including V1, V2, V3/VP, V4v, and MT (V5). Human V3A has a retinotopy that is similar to that reported previously in macaque: (1) it has a distinctive, continuous map of the contralateral hemifield immediately anterior to area V3, including a unique retinotopic representation of the upper visual field in superior occipital cortex; (2) in some cases the V3A foveal representation is displaced from and superior to the confluent foveal representations of V1, V2, V3, and VP; and (3) inferred receptive fields are significantly larger in human V3A, compared with those in more posterior areas such as V1. However, in other aspects human V3A appears quite different from its macaque counterpart: human V3A is relatively motion-selective, whereas human V3 is less so. In macaque, the situation is qualitatively reversed: V3 is reported to be prominently motion-selective, whereas V3A is less so. As in human and macaque MT, the contrast sensitivity appears quite high in human areas V3 and V3A.
Modulation of the Parieto-Occipital Alpha Rhythm during Object Detection
Authors: Vanni Simo , Revonsuo Antti , Hari Riitta
Published: April 2018

Changes in the human neuromagnetic alpha rhythm were monitored during an object detection task to study the effects of visual shape processing on the parieto-occipital activity. Pictures of coherent meaningful objects, which the observers had to detect, and of disorganized meaningless non-objects were presented briefly between masks. The non-objects were systematically followed by a higher level of alpha than the objects, the difference emerging on average 400 msec after the stimulus, with a median delay of 130 msec after evoked response onsets in the occipital, temporal, and parietal cortices. Without attention to visual shape, the alpha levels did not differ between objects and non-objects. The alpha level was higher after non-objects than missed objects, and higher after missed than correctly detected objects, suggesting that the alpha level is inversely related to saliency or familiarity of the object and does not directly reflect visual awareness.

The reactive alpha rhythm was generated in the parieto-occipital sulcus, which in several primate species includes areas belonging to the dorsal visual pathway. According to current views, the parietal cortex produces attentional signals that filter out irrelevant information in the ventral visual stream. Our results reinforce the idea of bidirectional interaction: information derived from visual shape can rapidly modify activity in the parieto-occipital region. The synchronized alpha oscillations may reflect attenuation of occipito-parietal information transfer and disengagement of parietal cortex from object selection.
Activity-Dependent Changes to the Brain and Behavior of the Honey Bee,Apis mellifera(L.)
Authors: Sigg Dominique , Thompson Caryn M. , Mercer Alison R.
Published: April 2018

To explore the origins and possible behavioral consequences of structural plasticity in an insect brain, we have taken advantage of the following: (1) the highly compartmentalized nature of the primary antenno-sensory centers (antennal lobes) of the brain, (2) the ease with which individual compartments, or glomeruli, within the antennal-lobe neuropil can be identified, and (3) the predictability of changes to readily identifiable glomeruli in the antennal lobes of the adult worker honey bee. Treatment with the juvenile hormone analog methoprene and hive manipulation techniques are used to induce precocious foraging behavior in young worker honey bees. The impact of these treatments on the ontogeny of olfactory learning performance and on the volumes of readily identifiable glomeruli in the antennal lobes of the bee brain are examined in parallel. The study reveals that (1) significant changes in glomerular volume are activity dependent and (2) associative learning of floral odors improves with experience. Improvements in associative learning performance coincide temporally with increases in glomerular volume. This raises an important question: are changes in glomerular volume that result from shifts in behavior simply a consequence of changes in the use of peripheral sensory pathways, or are they associated with events that underlie learning and the formation of long-term memories?
Evidence for an Intramedullary Prostaglandin-Dependent Mechanism in the Activation of Stress-Related Neuroendocrine Circuitry by Intravenous Interleukin-1
Authors: Ericsson A. , Arias C. , Sawchenko P. E.
Published: April 2018

We have provided evidence that the stimulatory effects of intravenous interleukin-1 (IL-1) on neurosecretory neurons in the paraventricular nucleus (PVH) that express corticotropin-releasing factor (CRF) depend specifically on the integrity of catecholaminergic projections originating in caudal medulla. Here we report on experiments designed to test alternative means by which circulating IL-1 might access medullary aminergic neurons, including mechanisms involving sensory components of the vagus, the area postrema, or perivascular cells bearing IL-1 receptors. Neither abdominal vagotomy nor area postrema lesions reliably altered Fos expression induced in the medulla or PVH in response to a moderately suprathreshold dose of IL-1β. Cytokine-stimulated increases in CRF mRNA in the PVH were also unaffected by either ablation. By contrast, systemic administration of the cyclooxygenase inhibitor indomethacin resulted in parallel dose-related attenuations of IL-1 effects in hypothalamus and medulla. Microinjections of prostaglandin E2 (PGE2; ≥10 ng) in rostral ventrolateral medulla, the principal seat of IL-1-sensitive neurons that project to the PVH, provoked discrete patterns of cellular activation in hypothalamus and medulla that mimicked those seen in response to intravenous IL-1. We interpret these findings as supporting the hypothesis that paracrine effects of PGE2 released from perivascular cells in the medulla as a consequence of IL-1 stimulation and, acting through prostanoid receptors on or near local aminergic neurons that project to the PVH, contribute to the stimulatory effects of increased circulating IL-1 on neurons constituting the central limb of the hypothalamo–pituitary–adrenal axis.
Synchronization of Neuronal Activity during Stimulus Expectation in a Direction Discrimination Task
Authors: de Oliveira Simone Cardoso , Thiele Alexander , Hoffmann Klaus-Peter
Published: April 2018

The dorsal pathway of the primate brain, especially the middle temporal area (MT or V5) and the superior middle temporal area (MST or V5a), is strongly involved in motion detection. The relation between neural firing rates and psychophysical performance has led to the assumption that the neural code used by these areas consists of the relative discharge rates of neuronal populations. As an additional neural code, temporal correlation of neural activity has been suggested. Our study addresses the involvement of such a code in awake monkeys performing a motion discrimination task.

We found significant temporal correlations between simultaneously recorded pairs of units in areas MT and MST and other extrastriate cortical areas. Units recorded from the same electrode were more frequently synchronized than units recorded from different electrodes placed within the same or different cortical areas. Activity synchronization was present in the expectation period before stimulus presentation and could not be inducedde novoby the stimulus. Rather, we found a contrast-dependent reduction of correlation strength on stimulus onset. Correlation strength did not vary systematically with stimulus directions. We conclude that under the conditions of this study, temporal decorrelation of MT and MST neurons could be used to detect the stimulus, but synchronization does not convey specific information about its direction of motion and therefore is unlikely to contribute to performance in our direction discrimination task. Activity synchronization in the period before stimulus onset could be related to attentive expectation.
Dissociable Forms of Inhibitory Control within Prefrontal Cortex with an Analog of the Wisconsin Card Sort Test: Restriction to Novel Situations and Independence from “On-Line” Processing
Authors: Dias R. , Robbins T. W. , Roberts A. C.
Published: April 2018

Attentional set-shifting and discrimination reversal are sensitive to prefrontal damage in the marmoset in a manner qualitatively similar to that seen in man and Old World monkeys, respectively (Dias et al., 1996b). Preliminary findings have demonstrated that although lateral but not orbital prefrontal cortex is the critical locus inshiftingan attentional setbetweenperceptual dimensions, orbital but not lateral prefrontal cortex is the critical locus inreversinga stimulus–reward associationwithina particular perceptual dimension (Dias et al., 1996a). The present study presents this analysis in full and extends the results in three main ways by demonstrating that (1) mechanisms of inhibitory control and “on-line” processing are independent within the prefrontal cortex, (2) impairments in inhibitory control induced by prefrontal damage are restricted to novel situations, and (3) those prefrontal areas involved in the suppression of previously established response sets are not involved in the acquisition of such response sets.

These findings suggest that inhibitory control is a general process that operates across functionally distinct regions within the prefrontal cortex. Although damage to lateral prefrontal cortex causes a loss of inhibitory control in attentional selection, damage to orbitofrontal cortex causes a loss of inhibitory control in affective processing. These findings provide an explanation for the apparent discrepancy between human and nonhuman primate studies in which disinhibition as measured on the Wisconsin Card Sort Test is associated with dorsolateral prefrontal damage, whereas disinhibition as measured on discrimination reversal is associated with orbitofrontal damage.
Cortical Networks Underlying Mechanisms of Time Perception
Authors: Harrington Deborah L. , Haaland Kathleen Y. , Knight Robert T.
Published: April 2018

Precise timing of sensory information from multiple sensory streams is essential for many aspects of human perception and action. Animal and human research implicates the basal ganglia and cerebellar systems in timekeeping operations, but investigations into the role of the cerebral cortex have been limited. Individuals with focal left (LHD) or right hemisphere (RHD) lesions and control subjects performed two time perception tasks (duration perception, wherein the standard tone pair interval was 300 or 600 msec) and a frequency perception task, which controlled for deficits in time-independent processes shared by both tasks. When frequency perception deficits were controlled, only patients with RHD showed time perception deficits. Time perception competency was correlated with an independent test of switching nonspatial attention in the RHD but not the LHD patients, despite attention deficits in both groups. Lesion overlays of patients with RHD and impaired timing showed that 100% of the patients with anterior damage had lesions in premotor and prefrontal cortex (Brodmann areas 6, 8, 9, and 46), and 100% with posterior damage had lesions in the inferior parietal cortex. All LHD patients with normal timing had damage in these same regions, whereas few, if any, RHD patients with normal timing had similar lesion distributions. These results implicate a right hemisphere prefrontal–inferior parietal network in timing. Time-dependent attention and working memory functions may contribute to temporal perception deficits observed after damage to this network.
Effects of Glucose Deprivation, Chemical Hypoxia, and Simulated Ischemia on Na+Homeostasis in Rat Spinal Cord Astrocytes
Authors: Rose Christine R. , Waxman Stephen G. , Ransom Bruce R.
Published: April 2018

A steep inwardly directed Na+gradient is essential for glial functions such as glutamate reuptake and regulation of intracellular ion concentrations. We investigated the effects of glucose deprivation, chemical hypoxia, and simulated ischemia on intracellular Na+concentration ([Na+]i) in cultured spinal cord astrocytes using fluorescence ratio imaging with sodium-binding benzofuran isophthalate (SBFI) AM. Glucose removal or chemical hypoxia (induced by 10 mmNaN3) for 60 min increased [Na+]ifrom a baseline of 8.3 to 11 mm. Combined glycolytic and respiratory blockage by NaN3and 0 glucose saline caused [Na+]ito increase by 20 mm, similar to the [Na+]iincreases elicited by blocking the Na+/K+-ATPase with ouabain. Recovery from large [Na+]iincreases (>15 mm) induced by the glutamatergic agonist kainate was attenuated during glucose deprivation or NaN3application and was blocked in NaN3and 0 glucose. To mimicin vivoischemia, we exposed astrocytes to NaN3and 0 glucose saline containingl-lactate and glutamate with increased [K+] and decreased [Na+], [Ca2+], and pH. This induced an [Na+]idecrease followed by an [Na+]irise and a further [Na+]iincrease after reperfusion with standard saline. Similar multiphasic [Na+]ichanges were observed after NaN3and 0 glucose saline with only reduced [Na+]e. Our results suggest that the ability to maintain a low [Na+]ienables spinal cord astrocytes to continue uptake of K+and/or glutamate at the onset of energy failure. With prolonged energy failure, however, astrocytic [Na+]irises; with loss of their steep transmembrane Na+gradient, astrocytes may aggravate metabolic insults by carrier reversal and release of acid, K+, and/or glutamate into the extracellular space.
Involvement of Stretch-Activated Cl−Channels in Ramification of Murine Microglia
Authors: Eder Claudia , Klee Rolf , Heinemann Uwe
Published: April 2018

A stretch-activated Cl−current (ICl) was investigated in cultured murine microglia using the whole-cell configuration of the patch-clamp technique. After application of membrane stretch, a Cl−current appeared within seconds, and its amplitude increased further within 3–8 min.IClunderwent rundown, which was prevented by addition of 4 mmATP to the intracellular perfusing solution. The stretch-activated Cl−current exhibited outward rectification and did not show any voltage-dependent gating. Lowering the concentration of extracellular Cl−from 142 to 12 mmby equimolar substitution of Cl−with gluconate shifted the reversal potential ofIClby 41.6 ± 1.8 mV in the depolarizing direction. 4,4′-Diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) and 4-acetamido-4′-isothiocyanatostilbene-2,2′-disulfonic acid (SITS) blockedIClin a voltage- and time-dependent manner. At a test potential of +40 mV, a half-maximal blockade at 16.1 μmDIDS and at 71.0 μmSITS was determined forICl. At a concentration of 200 μm, 5-nitro-2-(3-phenylpropylamino)benzoic acid or flufenamic acid blockedIClby 88% and 75%, respectively. Each of these four Cl−channel blockers reversibly inhibited the ramification process of microglia, whereas blockers of voltage-gated Na+and K+channels did not affect the transformation of microglia from their ameboid into the ramified phenotype. It is suggested that in microglia functional stretch-activated Cl−channels are required for the induction of ramification but not for maintaining the ramified shape.
The Neuronal Growth-Associated Protein GAP-43 Interacts with Rabaptin-5 and Participates in Endocytosis
Authors: Neve Rachael L. , Coopersmith Robert , McPhie Donna L. , Santeufemio Christopher , Pratt Kara G. , Murphy Curran J. , Lynn Stephanie D.
Published: April 2018

Structural plasticity of nerve cells is a requirement for activity-dependent changes in the brain. The growth-associated protein GAP-43 is thought to be one determinant of such plasticity, although the molecular mechanism by which it mediates dynamic structural alterations at the synapse is not known. GAP-43 is bound by calmodulin when Ca2+levels are low, and releases the calmodulin when Ca2+levels rise, suggesting that calmodulin may act as a negative regulator of GAP-43 during periods of low activity in the neurons. To identify the function of GAP-43 during activity-dependent increases in Ca2+levels, when it is not bound to calmodulin, we sought proteins with which GAP-43 interacts in the presence of Ca2+. We show here that rabaptin-5, an effector of the small GTPase Rab5 that mediates membrane fusion in endocytosis, is one such protein. We demonstrate that GAP-43 regulates endocytosis and synaptic vesicle recycling. Modulation of endocytosis by GAP-43, in association with rabaptin-5, may constitute a common molecular mechanism by which GAP-43 regulates membrane dynamics during its known roles in activity-dependent neurotransmitter release and neurite outgrowth.
Retrograde Regulation of Growth-Associated Gene Expression in Adult Rat Purkinje Cells by Myelin-Associated Neurite Growth Inhibitory Proteins
Authors: Zagrebelsky Marta , Buffo Annalisa , Skerra Arne , Schwab Martin E. , Strata Piergiorgio , Rossi Ferdinando
Published: April 2018

Axon regeneration requires that injured neurons reinitiate long-distance growth and upregulate specific genes. To address the question of whether inhibitory environmental cues along the axon could exert a negative, tonic downregulation of growth-associated genes, we have examined adult rat Purkinje cells, which are endowed with poor regenerative capabilities. First we have compared their response to axotomy with that of neurons of the inferior olive, lateral reticular nucleus, and deep cerebellar nuclei, all of which vigorously regenerate into growth-permissive transplants. These injured neurons upregulate the transcription factors c-Jun and JunD, GAP-43, and NADPH diaphorase. In contrast, most axotomized Purkinje cells fail to express any of these markers, showing that the strength of this response parallels the regenerative potential of the examined neuron populations. However, strong upregulation of the same genes can be induced in Purkinje cells after colchicine injection into the uninjured adult cerebellum, indicating that their expression could be controlled by retrograde signals. To assess whether myelin-associated neurite growth inhibitory proteins contribute to this regulation, we applied the neutralizing antibodies IN-1 against one of the main inhibitory components of central myelin (NI-250) eitherin vivoorin vitroto organotypic cerebellar cultures. Application of IN-1 antibodies induces the upregulation of c-Jun, JunD, and NADPH diaphorase in Purkinje cells, showing that their expression is suppressed constitutively by myelin-associated neurite growth inhibitors. Thus, the inhibitory activity of the IN-1 antigen on axon growth is not restricted to the control of growth cone motility but also involves a retrograde regulation of gene expression in adult central neurons.
Dopamine Decreases the Excitability of Layer V Pyramidal Cells in the Rat Prefrontal Cortex
Authors: Gulledge Allan T. , Jaffe David B.
Published: April 2018

In both primates and rodents, the prefrontal cortex (PFC) is highly innervated by dopaminergic fibers originating from the ventral tegmental area, and activation of this mesocortical dopaminergic system decreases spontaneous and evoked activity in the PFCin vivo. We have examined the effects of dopamine (DA), over a range of concentrations, on the passive and active membrane properties of layer V pyramidal cells from the rat medial PFC (mPFC). Whole-cell and perforated-patch recordings were made from neurons in rat mPFC. As a measure of cell excitability, trains of action potentials were evoked with 1-sec-long depolarizing current steps. Bath application of DA (0.05–30 μm) produced a reversible decrease in the number of action potentials evoked by a given current step. In addition, DA reversibly decreased the input resistance (RN) of these cells. In a subset of experiments, a transient increase in excitability was observed after the washout of DA. Control experiments suggest that these results are not attributable to changes in spontaneous synaptic activity, age-dependent processes, or strain-specific differences in dopaminergic innervation and physiology. Pharmacological analyses, using D1 agonists (SKF 38393 and SKF 81297), a D1 antagonist (SCH 23390), a D2 receptor agonist (quinpirole), and a D2 antagonist (sulpiride) suggest that decreases in spiking andRNare mediated by D2 receptor activation. Together, these results demonstrate that DA, over a range of concentrations, has an inhibitory effect on layer V pyramidal neurons in the rat mPFC, possibly through D2 receptor activation.
Induction of Progestin Receptors by Estradiol in the Forebrain of Estrogen Receptor-α Gene-Disrupted Mice
Authors: Moffatt C. A. , Rissman E. F. , Shupnik M. A. , Blaustein J. D.
Published: April 2018

Mice, rats, and humans have two types of estrogen receptors, estrogen receptor-α (ERα) and estrogen receptor-β (ERβ). Estrogen receptor-α gene-disrupted (ERα-disrupted) mice bear two nonfunctional copies of the ERα gene. This mutation blocks the synthesis of full-length ERα, renders the animals infertile, and inhibits the induction of female sexual behaviors by estradiol and progesterone. It is likely that many of the processes contributing to the regulation of sexual receptivity by estradiol and progesterone are compromised in ERα-disrupted mice. However, given the importance of progesterone in the regulation of sexual receptivity and given the importance of progestin receptors (PRs) in mediating the responses of females to progesterone, we investigated the effects of ERα disruption on the induction of PRs by estradiol in the forebrain.

We hypothesized that estradiol would induce PRs in wild-type mice but not in ERα-disrupted mice. Ovariectomized wild-type and ERα-disrupted mice were implanted with either estradiol-filled capsules or empty capsules for 5 d, after which their brains were processed for the immunocytochemical detection of PR. Estradiol increased the number of PR-immunoreactive cells in both wild-type and ERα-disrupted mice. The residual responsiveness of ERα-disrupted mice to estradiol could be accounted for by an ERβ-dependent mechanism or another as yet unidentified estrogen receptor; however, because ERα-immunoreactivity and PCR product representing the 3′ end of ERα mRNA were found in at least one PR-containing region of the ERα-disrupted mice, an ERα splice variant may also mediate the induction of PR-immunoreactivity in ERα-disrupted mice.
Requirement for the NINAC Kinase/Myosin for Stable Termination of the Visual Cascade
Authors: Li Hong-Sheng , Porter Jeffery A. , Montell Craig
Published: April 2018

Activation of theDrosophilaphotoresponse is a rapid process that results in plasma membrane Ca2+and Na+conductances. Ca2+functions in negative feedback regulation ofDrosophilavision including deactivation. Protein kinase C (PKC) binds directly to Ca2+and is required for deactivation. However, the consequences of disrupting phosphorylation of any individual PKC substrate in theDrosophilaretina have not been addressed. In the current work, we show that NINAC p174, which consists of a protein kinase domain joined to the head region of myosin heavy chain, is a phosphoprotein and is phosphorylatedin vitroby PKC. Mutation of either of two PKC sites in the p174 tail resulted in an unusual defect in deactivation that had not been detected previously for otherninaCalleles or other loci. After cessation of the light stimulus, there appeared to be a transient reactivation of the visual cascade. This phenotype suggests that a mechanism exists to prevent reactivation of the visual cascade and that p174 participates in this process.
G-Proteins Are Involved in 5-HT Receptor-Mediated Modulation of N- and P/Q- But Not T-Type Ca2+Channels
Authors: Sun Qian-Quan , Dale Nicholas
Published: April 2018

5-HT produces voltage-independent inhibition of the N-, P/Q-, and T-type Ca2+currents in sensory neurons ofXenopuslarvae by acting on 5-HT1Aand 5-HT1Dreceptors. We have explored the underlying mechanisms further and found that the inhibition of high voltage-activated (HVA) currents by 5-HT is mediated by a pertussis toxin-sensitive G-protein that activates a diffusible second messenger. Although modulation of T-type currents is membrane-delimited, it was not affected by GDP-β-S (2 mm), GTP-γ-S (200 μm), 5′-guanylyl-imidodiphosphate tetralithium (200 μm), aluminum fluoride (AlF4−, 100 μm), or pertussis toxin, suggesting that a GTP-insensitive pathway was involved. To investigate the modulation of the T currents further, we synthesized peptides that were derived from conserved cytoplasmic regions of the rat 5-HT1Aand 5-HT1Dreceptors. Although two peptides derived from the third cytoplasmic loop inhibited the HVA currents by activating G-proteins and occluded the modulation of HVA currents by 5-HT, two peptides from the second cytoplasmic loop and the C tail had no effect. None of the four receptor-derived peptides had any effect on the T-type currents. We conclude that 5-HT modulates T-type channels by a membrane-delimited pathway that does not involve G-proteins and is mediated by a functional domain of the receptor that is distinct from that which couples to G-proteins.
Cellular Mechanisms Contributing to Response Variability of Cortical NeuronsIn Vivo
Authors: Azouz Rony , Gray Charles M.
Published: April 2018

Cortical neurons recordedin vivoexhibit highly variable responses to the repeated presentation of the same stimulus. To further understand the cellular mechanisms underlying this phenomenon, we performed intracellular recordings from neurons in cat striate cortexin vivoand examined the relationships between spontaneous activity and visually evoked responses. Activity was assessed on a trial-by-trial basis by measuring the membrane potential (Vm) fluctuations and spike activity during brief epochs immediately before and after the onset of an evoked response. We found that the response magnitude, expressed as a change inVmrelative to baseline, was linearly correlated with the preceding spontaneousVm. This correlation was enhanced when the cells were hyperpolarized to reduce the activation of voltage-gated conductances. The output of the cells, expressed as spike counts and latencies, was only moderately correlated with fluctuations in the preceding spontaneousVm. Spike-triggered averaging ofVmrevealed that visually evoked action potentials arise from transient depolarizations having a rise time of ∼10 msec. Consistent with this, evoked spike count was found to be linearly correlated with the magnitude ofVmfluctuations in the γ (20–70 Hz) frequency band. We also found that the threshold of visually evoked action potentials varied over a range of ∼10 mV. Examination of simultaneously recorded intracellular and extracellular activity revealed a correlation betweenVmdepolarization and spike discharges in adjacent cells. Together these results demonstrate that response variability is attributable largely to coherent fluctuations in cortical activity preceding the onset of a stimulus, but also to variations in action potential threshold and the magnitude of high-frequency fluctuations evoked by the stimulus.