bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Neuroanatomy of Human Slow Wave Sleep
Authors: Maquet Pierre , Degueldre Christian , Delfiore Guy , Aerts Joël , Péters Jean-Marie , Luxen André , Franck Georges
Published: April 2018

The distribution of regional cerebral blood flow (rCBF) was estimated during sleep and wakefulness by using H215O positron emission tomography (PET) and statistical parametric mapping. A group analysis on 11 good sleepers (8 with steady slow wave sleep, SWS) showed a significant negative correlation between the occurrence of SWS and rCBF in dorsal pons and mesencephalon, thalami, basal ganglia, basal forebrain/hypothalamus, orbitofrontal cortex, anterior cingulate cortex, precuneus, and, on the right side, in a region that follows the medial aspect of the temporal lobe. Given the known decrease in global cerebral blood flow levels during SWS, these negative correlations suggest that rCBF is decreased significantly more in these cerebral areas than in the rest of the brain.

The marked rCBF decreases in the pons, mesencephalon, thalamic nuclei, and basal forebrain reflect their close implication in the generation of SWS rhythms. The influence of these rhythms on the telencephalon usually are thought to be global and homogeneous. In contrast, our results show that rCBF is decreased more in some cortical areas (especially in orbitofrontal cortex) than in the rest of the cortex. We hypothesize that cellular processes taking place during SWS might be modulated differently in these regions.

Given the functions of the ventromedial frontal areas, we surmise that SWS might be particularly critical for the adaptation of behavior to environmental pressures. This hypothesis is supported indirectly by results of sleep deprivation experiments.
Differential Roles of Apamin- and Charybdotoxin-Sensitive K+Conductances in the Generation of Inferior Olive RhythmicityIn Vivo
Authors: Lang E. J. , Sugihara I. , Llinás R.
Published: April 2018

The basic electrical rhythmicity of the olivocerebellar system was investigatedin vivousing multiple electrode recordings of Purkinje cell (PC) complex spike (CS) activity. CSs demonstrate a 10 Hz rhythmicity, thought to result from the interaction of Ca2+and Ca2+-dependent K+conductances present in inferior olivary (IO) neurons. To assess the roles of different K+channels in generating this rhythmicity, intraolivary microinjections of charybdotoxin (CTX) and apamin were used. Both K+channel blockers increased average CS spike-firing rates. However, apamin produced a tonic increase in firing with a decrement in the CS rhythmicity. In contrast, after CTX administration, highly rhythmic CS discharges were interleaved with silent periods, suggesting that apamin- and CTX-sensitive K+channels have distinct rhythmogenic roles in IO neurons. CTX-sensitive channels seem to be functionally coupled to low threshold Ca2+channels, whereas the apamin-sensitive channels relate to high threshold Ca2+channels.

Blocking intraolivary GABAAreceptors increases IO excitability and the spatial distribution of synchronized CS activity while disrupting its rostrocaudal banding pattern (Lang et al., 1996). The present experiments show that K+channel blockers increase IO excitability without causing widespread synchronization of CS activity. Thus, changes in the IO excitability have relatively little effect in determining the spatial organization of CS synchrony. In contrast, the degree of CS rhythmicity seemed to influence the patterns of CS synchrony. Thus, after CTX, increased CS rhythmicity was associated with increased intraband synchrony and decreased interband synchrony, whereas apamin had the opposite effects on intra- and interband synchronization.
Correlated Size Variations in Human Visual Cortex, Lateral Geniculate Nucleus, and Optic Tract
Authors: Andrews Timothy J. , Halpern Scott D. , Purves Dale
Published: April 2018

We have examined several components of the human visual system to determine how the dimensions of the optic tract, lateral geniculate nucleus (LGN), and primary visual cortex (V1) vary within the same brain. Measurements were made of the cross-sectional area of the optic tract, the volumes of the magnocellular and parvocellular layers of the LGN, and the surface area and volume of V1 in one or both cerebral hemispheres of 15 neurologically normal human brains obtained at autopsy. Consistent with previous observations, there was a two- to threefold variation in the size of each of these visual components among the individuals studied. Importantly, this variation was coordinated within the visual system of any one individual. That is, a relatively large V1 was associated with a commensurately large LGN and optic tract, whereas a relatively small V1 was associated with a commensurately smaller LGN and optic tract. This relationship among the components of the human visual system indicates that the development of its different parts is interdependent. Such coordinated variation should generate substantial differences in visual ability among humans.
A Simplified Preparation for Relating Cellular Events to Behavior: Contribution of LE and Unidentified Siphon Sensory Neurons to Mediation and Habituation of theAplysiaGill- and Siphon-Withdrawal Reflex
Authors: Frost Lina , Kaplan Saul W. , Cohen Tracey E. , Henzi Victor , Kandel Eric R. , Hawkins Robert D.
Published: April 2018

We have begun to analyze several elementary forms of learning in a simple preparation consisting of the isolated mantle organs and abdominal ganglion ofAplysia. Previous studies suggested that plasticity at siphon sensory neuron synapses contributes to habituation and dishabituation of the gill- and siphon-withdrawal reflex in this preparation. We next wished to identify the sensory neurons that participate in the reflex and examine their plasticity more directly. To investigate the contribution of the LE siphon mechanosensory cells, we recorded from them and gill or siphon motor neurons during the same siphon stimulation that has been used in behavioral experiments in this preparation. Our results indicate that the LE cells make a substantial contribution to the evoked response in the motor neurons under these conditions, but they suggest that other as yet unidentified siphon sensory neurons with lower thresholds and shorter latencies also contribute. In addition, we find that homosynaptic depression of monosynaptic postsynaptic potentials (PSPs) from LE sensory cells makes an important contribution to habituation of the response in the motor neurons. To investigate plasticity of PSPs from the unidentified sensory neurons, we recorded the PSP that was produced in a motor neuron by water-movement stimulation of the siphon, which does not cause firing of LE cells. Our results suggest that PSPs from the unidentified sensory neurons and the LE neurons undergo similar plasticity during habituation and dishabituation training. These results support the idea that plasticity at synapses of both LE and unidentified sensory neurons contributes to habituation and dishabituation of the reflex response in this preparation.
Response Variability of Neurons in Primary Visual Cortex (V1) of Alert Monkeys
Authors: Gur Moshe , Beylin Alexander , Snodderly D. Max
Published: April 2018

Response variability of neurons limits the reliability and resolution of sensory systems. It is generally thought that response variability in the visual system increases at cortical levels, but the causes of the variability have not been identified. We have measured the response variability of neurons in primary visual cortex (V1) of alert monkeys. We recorded from 80 single cells distributed over all V1 layers and from 8 parvocellular cells of the lateral geniculate nucleus. All cells were stimulated with a bar of near-optimal orientation, color, and dimensions while continuously monitoring the eye movements of fixation. To minimize the effects of eye movements, responses that occurred while the eye was relatively steady were selected for analysis. The impulses elicited by each stimulus presentation were counted, and the variance and coefficient of variation were computed. Both measures of response variability were much lower than reported previously for V1 cells of both alert and anesthetized monkeys. Our data show that fixational eye movements cause a large component of response variance in alert monkeys. Moreover, the reliability of V1 neurons is not obviously degraded compared with lateral geniculate nucleus cells. The high reliability of neurons in alert monkeys is consistent with expectations from conventional biophysical models, and it suggests that activity in a modest number of neurons may suffice to form a perceptual decision.
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex
Authors: Moghaddam Bita , Adams Barbara , Verma Anita , Daly Darron
Published: April 2018

Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests. Several lines of evidence suggest that ketamine may impair PFC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ketamine may disrupt dopaminergic neurotransmission in, and cognitive functions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggesting that at these doses ketamine may increase glutamatergic neurotransmission in the PFC at non-NMDA glutamate receptors. An anesthetic dose of ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increased the release of dopamine in the PFC. This increase was blocked by intra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activation of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by systemic pretreatment with AMPA/kainate receptor antagonist LY293558. These findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, therebystimulatingpostsynaptic non-NMDA glutamate receptors.
Activity-Dependent Expression of NT-3 in Muscle Cells in Culture: Implications in the Development of Neuromuscular Junctions
Authors: Xie Kewei , Wang Ti , Olafsson Petur , Mizuno Keiko , Lu Bai
Published: April 2018

Although activity-dependent expression of neurotrophins has been studied extensively in the CNS, its physiological role during synapse development is not well established. At the developing neuromuscular junction in culture, exogenous application of the neurotrophin BDNF or NT-3 has been shown to acutely potentiate synaptic transmission and chronically promote synapse maturation. Using the same cell culture model, we have investigated activity-dependent neurotrophin expression in muscle cells and its role in developing neuromuscular synapses. Membrane depolarization, elicited by either depolarizing agents or repetitive electric stimulation, rapidly and specifically increased the levels of NT-3 mRNA in developingXenopus laevismuscle cells in culture. NT-3 gene expression also was enhanced by acetylcholine (ACh), the neurotransmitter that causes muscle membrane depolarization. The effects of depolarization were mediated by increasing intracellular calcium concentration. Moreover, factor(s) induced by membrane depolarization appeared to enhance synaptic transmission at the developing neuromuscular junction. The frequency of spontaneous synaptic currents (SSCs) recorded from neuromuscular synapses was increased significantly after treatment with conditioned medium from depolarized muscle cultures. The amplitude, rise time, and decay time of SSCs were not affected, indicating a presynaptic action of the conditioned medium. The effects of the conditioned medium were blocked, partially, by the NT-3 scavenger TrkC-IgG, suggesting that the potentiation of synaptic efficacy was attributable, at least in part, to elevated NT-3 as a consequence of muscle depolarization. Thus, activity-dependent expression of muscle NT-3 may contribute to the development of the neuromuscular synapse.
Second Messengers, Trafficking-Related Proteins, and Amino Acid Residues that Contribute to the Functional Regulation of the Rat Brain GABA Transporter GAT1
Authors: Quick Michael W. , Corey Janis L. , Davidson Norman , Lester Henry A. i
Published: April 2018

Recent evidence indicates that several members of the Na+-coupled transporter family are regulated, and this regulation in part occurs by redistribution of transporters between intracellular locations and the plasma membrane. We elucidate components of this process for both wild-type and mutant GABA transporters (GAT1) expressed inXenopusoocytes using a combination of uptake assays, immunoblots, and electrophysiological measurements of membrane capacitance, transport-associated currents, and GAT1-specific charge movements. At low GAT1 expression levels, activators of protein kinase C (PKC) induce redistribution of GAT1 from intracellular vesicles to the plasma membrane; at higher GAT1 expression levels, activators of PKC fail to induce this redistribution. However, coinjection of total rat brain mRNA with GAT1 permits PKC-mediated modulation at high transporter expression levels. This effect of brain mRNA on modulation is mimicked by coinjection of syntaxin 1a mRNA and is eliminated by injecting synaptophysin or syntaxin antisense oligonucleotides. Additionally, botulinum toxins, which inactivate proteins involved in vesicle release and recycling, reduce basal GAT1 expression and prevent PKC-induced translocation. Mutant GAT1 proteins, in which most or all of a leucine heptad repeat sequence was removed, display altered basal distribution and lack susceptibility to modulation by PKC, delineating one region of GAT1 necessary for its targeting. Thus, functional regulation of GAT1 in oocytes occurs via components common to transporters and to trafficking in both neural and non-neural cells, and suggests a relationship between factors that control neurotransmitter secretion and the components necessary for neurotransmitter uptake.
Regulation of Neurotransmission in the Arcuate Nucleus of the Rat by Different Neuropeptide Y Receptors
Authors: Rhim Hyewhon , Kinney Gregory A. , Emmerson Paul J. , Miller Richard J.
Published: April 2018

We examined the effects of peptides of the neuropeptide Y (NPY)/pancreatic polypeptide (PP) family on synaptic transmission in the arcuate nucleus in rat hypothalamic slices. Application of NPY produced two effects. In some cells NPY produced an outward current that had the properties of a K+current. NPY also inhibited the evoked glutamatergic EPSC recorded in these arcuate neurons by a presynaptic mechanism. Although the effects of NPY on the K+current reversed within a few minutes of washout of the peptide, its effects on the EPSC frequently were longer lasting (>30 min). Similar effects were observed using peptide YY or the NPY analog [Leu31, Pro34]NPY. Although K+current activation by [Leu31,Pro34]NPY was blocked by the selective Y1 antagonist BIBP 3226, inhibition of the EPSC was blocked only partially. Other NPY-related peptides such as NPY(13–36), PP, and [d-Trp32]NPY also inhibited the EPSC. However, none of these peptides produced activation of the K+current. Thus, activation of more than one NPY receptor produces synaptic inhibition in the arcuate nucleus. A Y1 receptor activates a K+current postsynaptically, and several receptor types appear to inhibit the EPSC by a presynaptic mechanism.
The mGluR6 5′ Upstream Transgene Sequence Directs a Cell-Specific and Developmentally Regulated Expression in Retinal Rod and ON-Type Cone Bipolar Cells
Authors: Ueda Yoshiki , Iwakabe Hideki , Masu Masayuki , Suzuki Misao , Nakanishi Shigetada
Published: April 2018

We generated transgenic mice, using 9.5 kilobase pairs of the 5′ upstream sequence from the mouse metabotropic glutamate receptor subtype 6 (mGluR6) gene fused to the β-galactosidase (lacZ) reporter gene, and investigated the promoter function of the cell-specific and developmentally regulated expression of mGluR6. Most of the independent transgenic lines commonly showed thelacZexpression in the defined cell layers of the retina, and four transgenic lines were characterized in detail for cell-specificlacZexpression patterns by X-gal staining andlacZimmunostaining. ThelacZ-expressing retinal cells were classified into two cell types. One cell type was identified as rod bipolar cells on the basis of colocalization of protein kinase C (PKC) immunoreactivity and morphological criteria. The other cell type was PKC-immunonegative and resided at the cell layers corresponding precisely to ON-type cone bipolar cells. The latter bipolar cells were found to exist as a large cell population comparable to rod bipolar cells. This observation was confirmed by coimmunostaining of dissociated retinal cells with thelacZand PKC antibodies. The ontogeny analysis indicated that thelacZexpression completely agrees with a temporal expression pattern of mGluR6 during retinal development. This study demonstrates that the mGluR6 5′ upstream genomic sequence is capable of directing a cell-specific and developmentally regulated expression of mGluR6 in ON-type bipolar cells and supports the view that mGluR6 is responsible for ON responses in both the rod and cone systems.
Formation of Specific Monosynaptic Connections between Muscle Spindle Afferents and Motoneurons in the Mouse
Authors: Mears Simon C. , Frank Eric
Published: April 2018

In adult vertebrates, sensory neurons innervating stretch-sensitive muscle spindles make monosynaptic excitatory connections with specific subsets of motoneurons in the spinal cord. Spindle afferents (Ia fibers) make the strongest connections with motoneurons supplying the same (homonymous) muscle but make few or no connections with motoneurons supplying antagonistic or functionally unrelated muscles. In lower vertebrates these connections are specific from the time they first are formed, but there is comparatively little information about how these reflex connections form in mammals. We therefore studied the pattern of these synaptic connections during postnatal development in mice. Intracellular recordings were made from identified hindlimb motoneurons in an isolated spinal cord preparation, and monosynaptic inputs from Ia fibers in identified hindlimb muscle nerves were measured at different times during the first postnatal week. The pattern of connections was specific throughout this period. Ia fibers made strong connections with homonymous motoneurons but only weak connections with antagonistic motoneurons at every time point examined, from P0 through P7. Even when muscle nerves were stimulated at only 0.1 Hz, the pattern of connections was still highly specific, arguing against a special subpopulation of labile inappropriate connections. The absence of appreciable rearrangements in the pattern of these connections during the first postnatal week is, therefore, analogous to the situation in lower vertebrates, suggesting that mechanisms responsible for establishing this specificity have been conserved during evolution.
Differential Expression of K4-APCurrents and Kv3.1 Potassium Channel Transcripts in Cortical Neurons that Develop Distinct Firing Phenotypes
Authors: Massengill Jennifer L. , Smith Martin A. , Son Dong Ik , O’Dowd Diane K.
Published: April 2018

Maturation of electrical excitability during early postnatal development is critical to formation of functional neural circuitry in the mammalian neocortex. Little is known, however, about the changes in gene expression underlying the development of firing properties that characterize different classes of cortical neurons. Here we describe the development of cortical neurons with two distinct firing phenotypes, regular-spiking (RS) and fast-spiking (FS), that appear to emerge from a population of immature multiple-spiking (IMS) neurons during the first two postnatal weeks, bothin vivo(within layer IV) andin vitro. We report the expression of a slowly inactivating, 4-AP-sensitive potassium current (K4-AP) at significantly higher density in FS compared with RS neurons. The same current is expressed at intermediate levels in IMS neurons. The kinetic, voltage-dependent, and pharmacological properties of the K4-APcurrent are similar to those observed by heterologous expression of Kv3.1 potassium channel mRNA. Single-cell RT-PCR analysis demonstrates that PCR products representing Kv3.1 transcripts are amplified more frequently from FS than RS neurons, with an intermediate frequency of Kv3.1 detection in neurons with immature firing properties. Taken together, these data suggest that the Kv3.1 gene encodes the K4-APcurrent and that expression of this gene is regulated in a cell-specific manner during development. Analysis of the effects of 4-AP on firing properties suggests that the K4-APcurrent is important for rapid action potential repolarization, fast after-hyperpolarization, brief refractory period, and high firing frequency characteristic of FS GABAergic interneurons.
Spatial Attention Effects in Macaque Area V4
Authors: Connor Charles E. , Preddie Dean C. , Gallant Jack L. , Van Essen David C.
Published: April 2018

Focal visual attention typically produces enhanced perceptual processing at the psychological level and relatively stronger neural responses at the physiological level. A longstanding mechanistic question is whether these attentional effects pertain specifically to the attended (target) object or to the region of space it occupies. We show here that attentional response enhancement in macaque area V4 extends to behaviorally irrelevant objects in the vicinity of the target object, indicating that focal attention has a strong spatial component at the physiological level. In addition, we find that spatial attention effects typically show a striking directional asymmetry. The direction of the asymmetry varies between cells, so that some cells respond best when attention is directed to the left of the stimulus, some when attention is directed to the right, etc. Thus, attention involves not only enhanced responses to behavioral targets but also a complex modulation of responses to other stimuli in the surrounding visual space.
Repeated Cocaine Modifies the Mechanism by which Amphetamine Releases Dopamine
Authors: Pierce R. Christopher , Kalivas Peter W.
Published: April 2018

This study determined whether daily cocaine administration initiates a calcium requirement for the increase in extracellular dopamine produced by psychostimulants. The increase in extracellular dopamine induced by perfusion of amphetamine through a microdialysis probe in the nucleus accumbens shell was enhanced in cocaine- relative to saline-pretreated rats. The augmented portion of the amphetamine-induced increase in nucleus accumbens dopamine was abolished by the coperfusion of L- or N-type calcium channel blockers. Inhibition of calcium/calmodulin-dependent protein kinase II (CaM-KII) also prevented the augmented increase in dopamine by amphetamine, whereas inhibition of vesicular exocytosis by botulinum toxin B was ineffective. When the concentration of extracellular dopamine in the nucleus accumbens was elevated by blocking the plasmallemal dopamine transporter with GBR-12909, the augmented increase in extracellular dopamine in rats sensitized to repeated cocaine was blocked by a CaM-KII inhibitor. Pretreatment with botulinum toxin B prevented the increase in extracellular dopamine by GBR-12909 in both cocaine-pretreated and control rats. Taken together, these results demonstrate that the psychostimulant-induced enhanced increase in extracellular dopamine in the nucleus accumbens shell of cocaine-pretreated rats arises from the induction of calcium- and CaM-KII-dependent mechanisms.
Inhibition of Tumor Necrosis Factor-α Action within the CNS Markedly Reduces the Plasma Adrenocorticotropin Response to Peripheral Local Inflammation in Rats
Authors: Turnbull Andrew V. , Pitossi Fernando J. , Lebrun Jean-Jacques , Lee Soon , Meltzer Jon C. , Nance Dwight M. , del Rey Adriana , Besedovsky Hugo O. , Rivier Catherine
Published: April 2018

The present study tested the hypothesis that the cytokine tumor necrosis factor-α (TNF-α) is an important CNS mediator of the hypothalamo-pituitary-adrenal (HPA) axis response to local inflammation in the rat. Recombinant murine TNF-α administered directly into the cerebroventricles of normal rats produced a dose-dependent increase in plasma adrenocorticotropin (ACTH) concentration. Local inflammation induced by the intramuscular injection of turpentine (50 μl/100 gm body weight) also produced an increase in plasma ACTH, peaking at 160–200 pg/ml at 7.5 hr after injection (compared with 10–30 pg/ml in controls). Intracerebroventricular pretreatment with either 5 μl of anti-TNF-α antiserum or 1–50 μg of soluble TNF receptor construct (rhTNFR:Fc) reduced the peak of the ACTH response to local inflammation by 62–72%. In contrast, intravenous treatment with the same doses of anti-TNF-α or rhTNFR:Fc had no significant effect on the ACTH response to local inflammation. Although these data indicated an action of TNF-α specifically within the brain, no increase in brain TNF-α protein (measured by bioassay) or mRNA (assessed using eitherin situhybridization histochemical or semi-quantitative RT-PCR procedures) was demonstrable during the onset or peak of HPA activation produced by local inflammation. Furthermore, increased passage of TNF-α from blood to brain seems unlikely, because inflammation did not affect plasma TNF-α biological activity. Collectively these data demonstrate that TNF-α action within the brain is critical to the elaboration of the HPA axis response to local inflammation in the rat, but they indicate that increases in cerebral TNF-α synthesis are not a necessary accompaniment.
Morphology and Distribution of Spinothalamic Lamina I Neurons in the Monkey
Authors: Zhang En-Tan , Craig A. D.
Published: April 2018

Lamina I spinothalamic tract (STT) neurons were identified by retrograde labeling with cholera toxin subunit b (CTb) in monkeys. On the basis of the criteria of somatal shape and dendritic orientation in horizontal sections used in prior work in the cat, three distinct morphological types were recognized: fusiform (F) cells with spindle-shaped somata and two main longitudinal dendritic arbors; pyramidal (P) cells with triangular somata and three main dendrites oriented primarily longitudinally; and multipolar (M) cells with polygonal somata and four or more dendrites directed longitudinally and mediolaterally. Some cells had transitional shapes, but cells with indeterminate shapes and a few with small round, unipolar, or eccentric somata were grouped as unclassified (U). Greater variation appeared in the monkey than had been seen in the cat, and more subtypes were noted. The overall proportions of these cell types were: 47% F, 27% P, 22% M, and 5% U. Differential longitudinal distributions were found over the length of the spinal cord (from the second cervical through the first coccygeal segments). Pyramidal and multipolar cells together predominated in the enlargements, whereas fusiform cells predominated in thoracic segments. We conclude that three distinct morphological types of lamina I STT cells are present in the monkey as in the cat. Considered with other recent findings, the present results support the possibility that these three cell types may correspond to distinct physiological classes of nociceptive and thermoreceptive lamina I STT cells.
Involvement of cGMP in Nociceptive Processing by and Sensitization of Spinothalamic Neurons in Primates
Authors: Lin Qing , Peng Yuan Bo , Wu Jing , Willis William D.
Published: April 2018

Central sensitization of spinothalamic tract (STT) neurons in anesthetized monkeys after intradermal injection of capsaicin depends in part on disinhibition. Protein kinase C is suggested to participate in this process. The present study shows that the nitric oxide-cGMP (NO-cGMP) signal transduction system also contributes to sensitization of wide dynamic range (WDR) STT neurons located in the deep dorsal horn. The NO-cGMP system was activated by microdialysis administration into the dorsal horn of 8-bromo-cGMP, an analog of cGMP. Sensitization of STT cells by 8-bromo-cGMP increased the responses of deep WDR STT cells to both weak and strong mechanical stimulation of the skin and simultaneously attenuated the inhibition of the same neurons produced by stimulation in the periaqueductal gray (PAG). In contrast, WDR STT cells in the superficial dorsal horn and high-threshold (HT) STT cells in superficial or deep layers showed reduced responses to mechanical stimulation of the skin after infusion of 8-bromo-cGMP, and PAG inhibition of these neurons was unaffected. Sensitization of STT cells and the attenuation of PAG inhibition induced by intradermal injection of capsaicin were prevented by preteatment of the dorsal horn with a guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1–one. The results support the hypothesis that activation of the NO-cGMP signal transduction system contributes to the sensitization of WDR STT neurons in the deep dorsal horn and helps explain why intradermal capsaicin injections often fail to sensitize superficial and HT STT cells. The results also support the idea that sensitization of STT cells is produced in part by disinhibition.
D1Receptor Activation Enhances Evoked Discharge in Neostriatal Medium Spiny Neurons by Modulating an L-Type Ca2+Conductance
Authors: Hernández-López Salvador , Bargas José , Surmeier D. James , Reyes Arturo , Galarraga Elvira
Published: April 2018

Mostin vitrostudies of D1dopaminergic modulation of excitability in neostriatal medium spiny neurons have revealed inhibitory effects. Yet studies made in more intact preparations have shown that D1receptors can enhance or inhibit the responses to excitatory stimuli. One explanation for these differences is that the effects of D1receptors on excitability are dependent on changes in the membrane potential occurring in response to cortical inputs that are seen only in intact preparations. To test this hypothesis, we obtained voltage recordings from medium spiny neurons in slices and examined the impact of D1receptor stimulation at depolarized and hyperpolarized membrane potentials. As previously reported, evoked discharge was inhibited by D1agonists when holding at negative membrane potentials (approximately −80 mV). However, at more depolarized potentials (approximately −55 mV), D1agonists enhanced evoked activity. At these potentials, D1agonists or cAMP analogs prolonged or induced slow subthreshold depolarizations and increased the duration of barium- or TEA-induced Ca2+-dependent action potentials. Both effects were blocked by L-type Ca2+channel antagonists (nicardipine, calciseptine) and were occluded by the L-type channel agonist BayK 8644—arguing that the D1receptor-mediated effects on evoked activity at depolarized membrane potential were mediated by enhancement of L-type Ca2+currents. These results reconcile previousin vitroandin vivostudies by showing that D1dopamine receptor activation can either inhibit or enhance evoked activity, depending on the level of membrane depolarization.
Immunocytochemical Characterization of AMPA-Selective Glutamate Receptor Subunits: Laminar and Compartmental Distribution in Macaque Striate Cortex
Authors: Carder Renee K.
Published: April 2018

Subunit proteins that comprise functional AMPA receptors were localized by immunocytochemical methods in the adult macaque primary visual cortex (V1). GluR1, GluR2/3/4c, and GluR4 immunoreactivity consisted of rich plexuses of punctate profiles scattered throughout the neuropil, in radial arrays, and outlining the membrane of somata and proximal dendrites. Cytoplasmic immunoreactivity was limited. GluR2/3/4c immunostaining was more prominent along the somata surface and exhibited greater levels of cytoplasmic immunoreactivity than GluR1 and GluR4 immunostaining. The density of AMPA subunit immunoreactive elements also varied across layers and compartments of macaque V1. Immunoreactivity for GluR1, GluR2/3/4c, and GluR4 was densest in three bands that corresponded to layers IVA, IVC, and VI. Immunostaining for each subunit was also unevenly distributed within many of the layers. In layers II–III, patches of intense immunostaining coincided with cytochrome oxidase (CO)-rich blobs. In layer IVA, intense subunit staining formed a conspicuous honeycomb pattern. In layer IVC, subunit staining formed a radial lattice. GluR2/3/4c subunit immunostaining was also preferentially distributed within the CO-rich blobs of layers V–VI. These findings demonstrate that AMPA subunit immunoreactivity is densely concentrated in layers and compartments receiving direct geniculocortical innervation. This distribution, which differs from that of excitatory synapses, suggests that the density of AMPA receptors is unevenly distributed at synaptic and possibly extrasynaptic sites within macaque visual circuits.
Endogenous Adenosine Mediates the Presynaptic Inhibition Induced by Aglycemia at Corticostriatal Synapses
Authors: Calabresi Paolo , Centonze Diego , Pisani Antonio , Bernardi Giorgio
Published: April 2018

Energy deprivation, as a result of aglycemia, leads to depression of the central synaptic transmission. Endogenous adenosine has been implicated in this depressant effect. We have studied the possible involvement of endogenous adenosine in the depression of corticostriatal excitatory transmission induced by glucose deprivation by using intracellular recordings in brain slices. After stimulation of corticostriatal fibers, EPSPs were recorded from striatal spiny neurons. Adenosine (3–300 μm) or brief periods (5–10 min) of aglycemia reduced the EPSP amplitude but did not alter the membrane potential and the resistance of the recorded cells. These inhibitory effects were not associated with an alteration of the postsynaptic sensitivity to exogenous glutamate but were coupled with an increased paired-pulse facilitation, suggesting the involvement of presynaptic mechanisms. A delayed postsynaptic membrane depolarization/inward current was detected after 15–20 min of glucose deprivation. The presynaptic inhibitory effects induced by adenosine and aglycemia were both antagonized either by the nonselective adenosine receptor antagonist caffeine (2.5 mm) or by the A1 receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine (CPT, 1 μm) and 1,3-dipropyl-8-cyclopentylxanthine (CPX, 300 nm). Conversely, these antagonists affected neither the delayed membrane depolarization/inward current nor the underlying conductance increase produced by glucose deprivation. The ATP-sensitive potassium channel blockers tolbutamide (1 mm) and glipizide (100 nm) had no effect on the aglycemia-induced decrease of EPSP amplitude. Our data demonstrate that endogenous adenosine acting on A1 receptors mediates the presynaptic inhibition induced by aglycemia at corticostriatal synapses, whereas ATP-dependent potassium channels do not play a significant role in this presynaptic inhibition.
Resurgent Sodium Current and Action Potential Formation in Dissociated Cerebellar Purkinje Neurons
Authors: Raman Indira M. , Bean Bruce P.
Published: April 2018

Voltage-dependent sodium channels were studied in dissociated cerebellar Purkinje neurons from rats. In whole-cell recordings, a tetrodotoxin (TTX)-sensitive inward current was elicited when the membrane was repolarized to voltages between −60 and −20 mV after depolarizations to +30 mV long enough to produce maximal inactivation. At −40 mV, this “resurgent” current peaked in 8 msec and decayed with a time constant of 30 msec. With 50 mmsodium as a charge carrier, the resurgent current was on average ∼120 pA. CA3 pyramidal neurons had no such current. The current may reflect recovery of inactivated channels through open states, because in Purkinje neurons (but not CA3 neurons) there was partial recovery from inactivation at −40 mV, coinciding with the rise of resurgent current. In single-channel recordings, individual channels gave openings corresponding to resurgent and conventional transient current. Action potentials were recorded from dissociated neurons under current clamp to investigate the role of the resurgent current in action potential formation. Purkinje neurons fired spontaneously at ∼30 Hz. Hyperpolarization to −85 mV prevented spontaneous firing, and brief depolarization then induced all-or-none firing of conglomerate action potentials comprising three to four spikes. When conglomerate action potentials were used as command voltages in voltage-clamp experiments, TTX-sensitive sodium current was elicited between spikes. The falling phase of an action potential is similar to voltage patterns that activate resurgent sodium current, and thus, resurgent sodium current likely contributes to the formation of conglomerate action potentials in Purkinje neurons.
Abnormal Synaptic Plasticity in the Striatum of Mice Lacking Dopamine D2 Receptors
Authors: Calabresi Paolo , Saiardi Adolfo , Pisani Antonio , Baik Ja-Hyun , Centonze Diego , Mercuri Nicola B. , Bernardi Giorgio , Borrelli Emiliana
Published: April 2018

Dopamine D2 receptors (D2Rs) are of crucial importance in the striatal processing of motor information received from the cortex. Disruption of the D2R gene function in mice results in a severe locomotor impairment. This phenotype has analogies with Parkinson’s disease symptoms. D2R-null mice were used to investigate the role of this receptor in the generation of striatal synaptic plasticity. Tetanic stimulation of corticostriatal fibers produced long-term depression (LTD) of EPSPs in slices from wild-type (WT) mice. Strikingly, recordings from D2R-null mice showed the converse: long-term potentiation (LTP). This LTP, unlike LTD, was blocked by an NMDA receptor antagonist. In magnesium-free medium, LTP was also revealed in WT mice and found to be enhanced byl-sulpiride, a D2R antagonist, whereas it was reversed into LTD by LY 17555, a D2R agonist. In D2R-null mice this modulation was lost. Thus, our study indicates that D2Rs play a key role in mechanisms underlying the direction of long-term changes in synaptic efficacy in the striatum. It also shows that an imbalance between D2R and NMDA receptor activity induces altered synaptic plasticity at corticostriatal synapses. This abnormal synaptic plasticity might cause the movement disorders observed in Parkinson’s disease.
Comparison of N- and P/Q-Type Voltage-Gated Calcium Channel Current Inhibition
Authors: Currie Kevin P. M. , Fox Aaron P.
Published: April 2018

Activation of N- and P/Q-type voltage-gated calcium channels triggers neurotransmitter release at central and peripheral synapses. These channels are targets for regulatory mechanisms, including inhibition by G-protein-linked receptors. Inhibition of P/Q-type channels has been less well studied than the extensively characterized inhibition of N-type channels, but it is thought that they are inhibited by similar mechanisms although possibly to a lesser extent than N-type channels. The aim of this study was to compare the inhibition of the two channel types.

Calcium currents were recorded from adrenal chromaffin cells and isolated by the selective blockers ω-conotoxin GVIA (1 μm) and ω-agatoxin IVA (400 nm). The inhibition was elicited by ATP (100 μm) or intracellular application of GTP-γ-S. It was classified as voltage-sensitive (relieved by a conditioning prepulse) or voltage-insensitive (present after a conditioning prepulse). The voltage-insensitive inhibition accounted for a 20% reduction of both currents, whereas the voltage-sensitive inhibition reduced the N-type current by 45% but the P/Q-type current by 18%. However, the voltage dependence of the inhibition, the time course of relief from inhibition during a conditioning prepulse, and the time course of reinhibition after such a prepulse showed few differences between the N- and P/Q-type channels. Assuming a simple bimolecular reaction, our data suggest that changes in the kinetics of the G-protein/channel interaction alone cannot explain the differences in the inhibition of the N- and P/Q-type calcium channels. The subtle differences in inhibition may facilitate the selective regulation of neurotransmitter release.
RNA Transport in Dendrites: Acis-Acting Targeting Element Is Contained within Neuronal BC1 RNA
Authors: Muslimov Ilham A. , Santi Elisabetta , Homel Peter , Perini Sean , Higgins Dennis , Tiedge Henri
Published: April 2018

In nerve cells, a select group of RNAs has been localized to dendritic domains. Here we have examined dendritic RNA transport in sympathetic neurons in primary culture, using a microinjection protocol with neuronal BC1 RNA and with BC1-derived sequence segments. After cytoplasmic microinjection, full-length BC1 RNA was selectively transported to dendrites; in contrast, control RNAs such as nuclear RNAs and random-sequence irrelevant RNAs remained restricted to cytoplasmic areas proximal to the injection sites. Chimeric RNAs were constructed that contained the full-length BC1 sequence inserted upstream or downstream of the coding regions of nondendritic mRNAs. After microinjection, such chimeric RNAs were specifically targeted to dendrites; microinjected corresponding nonchimeric mRNAs were not. Dendritic transport of BC1 RNA was rapid: the average dendritic delivery rate within the first hour after microinjection was 242 ± 25 μm/hr. Whereas a 5′-BC1 segment of 62 nucleotides was transported to dendrites to extents and at levels similar to full-length BC1 RNA, a 3′-BC1 segment of 60 nucleotides did not exit injected somata to any significant degree. Acis-acting dendritic targeting element is thus contained in the 5′ part of neuronal BC1 RNA. These results demonstrate that mechanisms exist in neurons for fast and specific transport of selected RNAs to dendrites.
Prevention of Normally Occurring and Deafferentation-Induced Neuronal Death in Chick Brainstem Auditory Neurons by Periodic Blockade of AMPA/Kainate Receptors
Authors: Solum Derek , Hughes David , Major M. Scott , Parks Thomas N.
Published: April 2018

The role of glutamate receptors in regulating programmed neuronal death and deafferentation-induced neuronal death in the brainstem auditory nuclei was studied byin ovodrug administration to chick embryos. The nucleus laminaris (NL) undergoes programmed developmental cell death of 19% between embryonic day 9 (E9) and E17. The AMPA/kainate receptor antagonist CNQX, when administered at doses of 200–300 μg/d from E8 to E15, prevented programmed neuronal death in NL through at least posthatching day 8, without producing anatomical or behavioral abnormalities. 3-((RS)−2-Carboxypiperazin-4-yl)-propyl-1-phos-phonic acid, an antagonist of NMDA receptors, had no effect on normal cell death in the NL. CNQX, given from E8 to E15 or only from E8 to E10, also blocked the 33% neuronal loss in the nucleus magnocellularis (NM) that follows surgical destruction of the otocyst on E3, a procedure that deafferents NM neurons by preventing formation of the cochlear nerve. Treatment either with CNQX or the more highly selective NBQX from E8 to E10, before the onset of synaptic transmission in NM and NL, was also effective in preventing normal neuronal death in NL. Analysis of the effects of CNQX or NBQX on spontaneous embryonic motility at E10 showed that the doses effective in preventing neuronal death suppressed motility for <8 hr. We conclude that periodic blockade of AMPA/kainate receptors can protect CNS neurons against subsequent programmed cell death or deafferentation-induced death.
Glutamatergic Enteric Neurons
Authors: Liu Min-Tsai , Rothstein Jeffrey D. , Gershon Michael D. , Kirchgessner Annette L.
Published: April 2018

We tested the hypothesis that glutamate, the major excitatory neurotransmitter of the CNS, is also an excitatory neurotransmitter in the enteric nervous system (ENS). Glutamate immunoreactivity was found in cholinergic enteric neurons, many of which were identified as sensory by their co-storage of substance P and/or calbindin. Glutamate immunoreactivity was concentrated in terminal varicosities with a majority of small clear synaptic vesicles. The immunoreactivities of both AMPA and NMDA receptor subunits were also detected on neurons in both submucosal and myenteric plexuses. The immunoreactivity of the EAAC1 neuronal glutamate transporter was widespread in both plexuses. Glutamate evoked depolarizing responses in myenteric neurons that had fast and slow components. The fast component was mimicked by AMPA, and the slow component was mimicked by NMDA. The fast component and the response to AMPA mimicked fast EPSPs evoked in 2/AH neurons; moreover, fast EPSPs as well as fast glutamate and AMPA responses were blocked by selective AMPA antagonists and potentiated by the glutamate uptake inhibitorl-(−)-threo-3-hydroxyaspartic acid. These observations demonstrate, for the first time, the presence of glutamatergic neurons and glutamate-mediated neurotransmission in the ENS.
GABA Activity Mediating Cytosolic Ca2+Rises in Developing Neurons Is Modulated by cAMP-Dependent Signal Transduction
Authors: Obrietan Karl , van den Pol Anthony N.
Published: April 2018

In the majority of developing neurons, GABA can exert depolarizing actions, thereby raising neuronal Ca2+. Ca2+elevations can have broad consequences during development, inducing gene expression, altering neurite outgrowth and growth cone turning, activating enzyme pathways, and influencing neuronal survival. We used fura-2 and fluo-3 Ca2+digital imaging to assess the effects of inhibiting or activating the cAMP signal transduction pathway on GABA activity mediating Ca2+rises during the early stages ofin vitrohypothalamic neural development. Our experiments stemmed from the finding that stimulation of transmitter receptors shown to either activate or inhibit adenylyl cyclase activity caused a rapid decrease in Ca2+rises mediated by synaptically released GABA.

Both the adenylyl cyclase activator forskolin and the inhibitor SQ-22,536 reduced the Ca2+rise elicited by the synaptic release of GABA. Bath application of the membrane-permeable cAMP analogs 8-bromo-cAMP (8-Br-cAMP) or 8-(4-chlorophenylthio)-cAMP (0.2–5 mm) produced a rapid, reversible, dose-dependent inhibition of Ca2+rises triggered by synaptic GABA release. Potentiation of GABAergic activity mediating Ca2+rises was observed in some neurons at relatively low concentrations of the membrane-permeable cAMP analogs (20–50 μm). In the presence of tetrodotoxin (TTX), postsynaptic Ca2+rises triggered by the bath application of GABA were only moderately depressed (13%) by 8-Br-cAMP (1 mm), suggesting that the inhibitory effects of 8-Br-cAMP were largely the result of a presynaptic mechanism.

The protein kinase A (PKA) inhibitors H89 and Rp-3′,5′-cyclic monophosphothioate triethylamine also caused a large reduction (>70%) in Ca2+rises triggered by synaptic GABA release. Unlike the short-term depression elicited by activation of the cAMP signal transduction pathway, Ca2+depression elicited by PKA inhibition persisted for an extended period (>30 min) after PKA inhibitor washout. Postsynaptic depression of GABA-evoked Ca2+rises triggered by H89 (in the presence of TTX) recovered rapidly, suggesting that the extended depression observed during synaptic GABA release was largely through a presynaptic mechanism. Long-term Ca2+modulation by cAMP-regulating hypothalamic peptides may be mediated through a parallel mechanism.

Together, these results suggest that GABAergic activity mediating Ca2+rises is dependent on ongoing PKA activity that is maintained within a narrow zone for GABA to elicit a maximal Ca2+elevation. Thus, neuromodulator-mediated changes in the cAMP-dependent signal transduction pathway (activation or inhibition) could lead to a substantial decrease in GABA-mediated Ca2+rises during early development.