bluuebunny/crossref_metadata_2025 huggingface dataset:
GABA Receptors Containing Rdl Subunits Mediate Fast Inhibitory Synaptic Transmission inDrosophilaNeurons
Authors: Lee Daewoo , Su Hailing , O'Dowd Diane K.
Published: April 2018

GABAergic inhibition inDrosophila, as in other insects and mammals, is important for regulation of activity in the CNS. However, the functional properties of synaptic GABA receptors inDrosophilahave not been described. Here, we report that spontaneous GABAergic postsynaptic currents (sPSCs) in cultured embryonicDrosophilaneurons are mediated by picrotoxin-sensitive chloride-conducting receptors. A rapid increase in spontaneous firing in response to bath application of picrotoxin demonstrates that these GABA receptors mediate inhibition in the neuronal networks formed in culture. Many of the spontaneous GABAergic synaptic currents are sodium action potential independent [miniature IPSCs (mIPSCs)] but are regulated by external calcium levels. The large variation in mIPSC frequency, amplitude, and kinetics properties between neurons suggests heterogeneity in GABA receptor number, location, and/or subtype. A decrease in the mean mIPSC decay time constant between 2 and 5 d, in the absence of a correlated change in rise time, demonstrates that the functional properties of the synaptic GABA receptors are regulated during maturationin vitro. Finally, neurons from the GABA receptor subunit mutantRdlexhibit reduced sensitivity to picrotoxin blockade of the mIPSCs and resistance to picrotoxin-induced increases in spontaneous firing frequency. This demonstrates that Rdl containing GABA receptors play a direct role in mediating synaptic inhibition inDrosophilaneural circuits formed in culture.
Evidence for Enhanced Neurobehavioral Vulnerability to Nicotine during Periadolescence in Rats
Authors: Adriani Walter , Spijker Sabine , Deroche-Gamonet Véronique , Laviola Giovanni , Le Moal Michel , Smit August B. , Piazza Pier Vincenzo
Published: April 2018

Epidemiological studies indicate that there is an increased likelihood for the development of nicotine addiction when cigarette smoking starts early during adolescence. These observations suggest that adolescence could be a “critical” ontogenetic period, during which drugs of abuse have distinct effects responsible for the development of dependence later in life. We compared the long-term behavioral and molecular effects of repeated nicotine treatment during either periadolescence or postadolescence in rats. It was found that exposure to nicotine during periadolescence, but not a similar exposure in the postadolescent period, increased the intravenous self-administration of nicotine and the expression of distinct subunits of the ligand-gated acetylcholine receptor in adult animals. Both these changes indicated an increased sensitivity to the addictive properties of nicotine. In conclusion, adolescence seems to be a critical developmental period, characterized by enhanced neurobehavioral vulnerability to nicotine.
Transient Receptor Potential Channel Activation Causes a Novel Form of [Ca2+]iOscillations and Is Not Involved in Capacitative Ca2+Entry in Glial Cells
Authors: Grimaldi Maurizio , Maratos Marina , Verma Ajay
Published: April 2018

Astrocytes express transient receptor potential channels (TRPCs), which have been implicated in Ca2+influx triggered by intracellular Ca2+stores depletion, a phenomenon known as capacitative Ca2+entry. We studied the properties of capacitative Ca2+entry in astrocytes by means of single-cell Ca2+imaging with the aim of understanding the involvement of TRPCs in this function. We found that, in astrocytes, capacitative Ca2+entry is not attributable to TRPC opening because the TRPC-permeable ions Sr2+and Ba2+do not enter astrocytes during capacitative Ca2+entry. Instead, natively expressed oleyl-acetyl-glycerol (OAG) (a structural analog of DAG) -sensitive TRPCs, when activated, initiate oscillations of cytosolic Ca2+concentration ([Ca2+]i) pharmacologically and molecularly consistent with TRPC3 activation. OAG-induced [Ca2+]ioscillations are not affected by inhibition of inositol trisphosphate (InsP3) production or blockade of the InsP3receptor, therefore representing a novel form of [Ca2+]isignaling. Instead, high [Ca2+]iinhibited oscillations, by closing the OAG-sensitive channel. Also, treatment of astrocytes with antisense against TRPC3 caused a consistent decrease of the cells responding to OAG. Exogenous OAG but not endogenous DAG seems to activate TRPC3. In conclusion, in glial cells, natively expressed TRPC3s mediates a novel form of Ca2+signaling, distinct from capacitative Ca2+entry, which suggests a specific signaling function for this channel in glial cells.
The Receptive-Field Organization of Simple Cells in Primary Visual Cortex of Ferrets under Natural Scene Stimulation
Authors: Smyth Darragh , Willmore Ben , Baker Gary E. , Thompson Ian D. , Tolhurst David J.
Published: April 2018

The responses of simple cells in primary visual cortex to sinusoidal gratings can primarily be predicted from their spatial receptive fields, as mapped using spots or bars. Although this quasilinearity is well documented, it is not clear whether it holds for complex natural stimuli. We recorded from simple cells in the primary visual cortex of anesthetized ferrets while stimulating with flashed digitized photographs of natural scenes. We applied standard reverse-correlation methods to quantify the average natural stimulus that invokes a neuronal response. Although these maps cannot be the receptive fields, we find that they still predict the preferred orientation of grating for each cell very well (r= 0.91); they do not predict the spatial-frequency tuning. Using a novel application of the linear reconstruction method called regularized pseudoinverse, we were able to recover high-resolution receptive-field maps from the responses to a relatively small number of natural scenes. These receptive-field maps not only predict the optimum orientation of each cell (r= 0.96) but also the spatial-frequency optimum (r= 0.89); the maps also predict the tuning bandwidths of many cells. Therefore, our first conclusion is that the tuning preferences of the cells are primarily linear and constant across stimulus type. However, when we used these maps to predict the actual responses of the cells to natural scenes, we did find evidence of expansive output nonlinearity and nonlinear influences from outside the classical receptive fields, orientation tuning, and spatial-frequency tuning.
Morphine Withdrawal Increases Glutamate Uptake and Surface Expression of Glutamate Transporter GLT1 at Hippocampal Synapses
Authors: Xu Nan-Jie , Bao Lan , Fan Hua-Ping , Bao Guo-Bin , Pu Lu , Lu Ying-Jin , Wu Chun-Fu , Zhang Xu , Pei Gang
Published: April 2018

Opiate abuse causes adaptive changes in several processes of synaptic transmission in which the glutamatergic system appears a critical element involved in opiate tolerance and dependence, but the underlying mechanisms remain unclear. In the present study, we found that glutamate uptake in hippocampal synaptosomes was significantly increased (by 70% in chronic morphine-treated rats) during the morphine withdrawal period, likely attributable to an increase in the number of functional glutamate transporters. Immunoblot analysis showed that expression of GLT1 (glutamate transporter subtype 1) was identified to be upregulated in synaptosomes but not in total tissues, suggesting a redistribution of glutamate transporter expression. Moreover, the increase in glutamate uptake was reproduced in cultured neurons during morphine withdrawal, and the increase of uptake in neurons could be blocked by dihydrokainate, a specific inhibitor of GLT1. Cell surface biotinylation and immunoblot analysis showed that morphine withdrawal produced an increase in GLT1 expression rather than EAAC1 (excitatory amino acids carrier 1), a neuronal subtype, at the cultured neuronal cell surface, whereas no significant change was observed in that of cultured astrocytes. Electron microscopy also revealed that GLT1 expression was markedly increased in the nerve terminals of hippocampus and associated with the plasma membranein vivo. These results suggest that GLT1 in hippocampal neurons can be induced to translocate to the nerve terminals and express on the cell surface during morphine withdrawal. The translocation of GLT1 at synapses during morphine withdrawal provides a neuronal mechanism for modulation of excitatory neurotransmission during opiate abuse.
The Glucocorticoid Receptor as a Potential Target to Reduce Cocaine Abuse
Authors: Deroche-Gamonet Véronique , Sillaber Inge , Aouizerate Bruno , Izawa Ryozuke , Jaber Mohamed , Ghozland Sandy , Kellendonk Christoph , Le Moal Michel , Spanagel Rainer , Schütz Günther , Tronche François , Piazza Pier Vincenzo
Published: April 2018

Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose–response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose-dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment.
The Identification and Characterization of Oxidized RNAs in Alzheimer's Disease
Authors: Shan Xiu , Tashiro Hirofumi , Lin Chien-liang Glenn
Published: April 2018

It has been shown that cytoplasmic RNA oxidation occurs to a great extent in the brains of Alzheimer's disease (AD) patients. The goal of this study was to isolate and identify oxidized RNA species in AD. We show that significant amounts of poly(A)+mRNAs are oxidized in AD brains. RNA oxidation is not random but highly selective. Importantly, many identified oxidized mRNA species have been implicated in the pathogenesis of AD. Quantitative analysis revealed that some mRNA species are more susceptible to oxidative damage. We also investigated the biological consequence of oxidatively damaged mRNAs by expressing them in cell lines. Our data indicated that abnormal processing of proteins occurred to the oxidized mRNAs. This may implicate the potential contribution of RNA oxidation in the pathogenesis of AD.
Chloride Influx Aggravates Ca2+-Dependent AMPA Receptor-Mediated Motoneuron Death
Authors: Van Damme P. , Callewaert G. , Eggermont J. , Robberecht W. , Van Den Bosch L.
Published: April 2018

AMPA receptor-mediated excitotoxicity has been implicated in the pathogenesis of stroke, neurotrauma, epilepsy, and many neurodegenerative diseases such as motoneuron disease. We studied the role of Cl-in AMPA receptor-mediated Ca2+-dependent excitotoxicity in cultured rat spinal motoneurons. Using the gramicidin perforated patch-clamp technique, the intracellular Cl-concentration could be calculated from the reversal potential of the GABA-induced current. The membrane depolarization caused by AMPA receptor stimulation resulted in Cl-influx through 5-nitro-2(3-phenylpropyl-amino) benzoic acid- and niflumic acid-sensitive Cl-channels. Cl-influx during AMPA receptor stimulation aggravated excitotoxic motoneuron death by two mechanisms: an increase of AMPA receptor conductance and an elevation of the Ca2+driving force through a partial repolarization. The Cl-influx during AMPA receptor stimulation was enhanced by coadministration of GABA. This resulted in an increased Ca2+influx and an enhanced cell death, suggesting that concomitant GABAergic stimulation may aggravate excitotoxic motoneuron death.
Differential Effects of Neurotrophins and Schwann Cell-Derived Signals on Neuronal Survival/Growth and Synaptogenesis
Authors: Peng H. Benjamin , Yang Jie-Fei , Dai Zhengshan , Lee Chi Wai , Hung Hiu Wai , Feng Zhi Hua , Ko Chien-Ping
Published: April 2018

Recent studies have shown that the survival of mammalian motoneuronsin vitrois promoted by neurotrophins (NTs) and cAMP. There is also evidence that neurotrophins enhance transmitter release. We thus investigated whether these agents also promote synaptogenesis. CulturedXenopusspinal cord neurons were treated with a mixture of BDNF, glia-derived neurotrophic factor, NT-3, and NT-4, in addition to forskolin and IBMX or the cell-permeant form of cAMP, to elevate the cAMP level. The outgrowth and survival of neurons were dramatically increased by this trophic stimulation. However, when these neurons were cocultured with muscle cells, the trophic agents resulted in a failure of synaptogenesis. Specifically, the induction of ACh receptor (AChR) clustering in cultured muscle cells was inhibited at nerve—muscle contacts, in sharp contrast to control, untreated cocultures. Because AChR clustering induced by agrin or growth factor-coated beads in muscle cells was unaffected by trophic stimulation, its effect on synaptogenesis is presynaptic in origin. In the control, agrin was deposited along the neurite and at nerve—muscle contacts. This was significantly downregulated in cultures treated with trophic stimuli. Reverse transcriptase-PCR analyses showed that this decrease in agrin deposition was caused by an inhibition of agrin synthesis by trophic stimuli. Both agrin synthesis and induction of AChR clustering were restored under trophic stimulation when Schwann cell-conditioned medium was introduced. These results suggest that trophic stimulation maintains spinal neurons in the growth state, and Schwann cell-derived factors allow them to switch to the synaptogenic state.
Distinguishing between Directional Guidance and Motility Regulation in Neuronal Migration
Authors: Ward Michael , McCann Corey , DeWulf Michael , Wu Jane Y. , Rao Yi
Published: April 2018

Although neuronal migration is an essential process in development, how neural precursors reach their final destination in the nervous system is not well understood. Secreted molecules that are known to be involved in axon guidance are likely to play important roles in regulating neuronal migration, but an important issue that remains unclear is whether such molecules act as directional guidance cues or as motility regulators in neuronal migration. The secreted protein Slit was initially suggested to be a repellent for migrating neurons (Wu et al., 1999). However, it was concluded recently that Slit plays an inhibitory rather than a repulsive role in neuronal migration (Mason et al., 2001). We have developed a series of assays that allow us to differentiate between repulsive and inhibitory effects of secreted molecules, and we demonstrate that Slit is a repellent capable of reversing the direction of neurons migrating either in culture or in their native pathways. We also show that although Slit reduces migratory speed under certain conditions, it can function as a repellent without concurrent inhibition of neuronal migration. This is the first study to clearly demonstrate that migrating neurons can be directionally guided by secreted molecules. These findings provide a basis to understand the physiological roles of secreted molecules in the developing nervous system and have implications on how they could be applied therapeutically. Our results also indicate that it should be possible to determine the specific action of other molecules as directional guidance cues or as motility regulators of cell migration.
Lateral Asymmetry in the Hippocampal Response to the Remoteness of Autobiographical Memories
Authors: Maguire Eleanor A. , Frith Christopher D.
Published: April 2018

The time scale of hippocampal involvement in retrieving memories, particularly those more remote, is still a matter of debate. Some propose that the hippocampus is not involved in the retrieval of remote memories, whereas others assert that it is necessary for memory retrieval in perpetuity. Functional magnetic resonance imaging was used to examine the effect of remoteness on the neural basis of memory. We used a parametric event-related random-effects design in a large group of subjects to overcome some of the limitations of previous neuroimaging studies. We found that the hippocampi were significantly active during the retrieval of autobiographical memories. Notably, the two hippocampi diverged in their responses to remoteness. The right hippocampus showed a temporal gradient, decreasing in activity the more remote the autobiographical memories. No such effect was apparent in the left hippocampus, suggesting its invariant involvement in remembering autobiographical events throughout the lifespan. The dorsal amygdalas showed a temporal gradient similar to the right hippocampus, but emotional valence and intensity were not directly associated with changes in activity. The current results indicate that consideration of lateral asymmetry may help to broaden the scope of theoretical interpretations concerning hippocampal involvement in remote memory.
Activation of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase in Hippocampal Circuitry Is Required for Consolidation and Reconsolidation of Recognition Memory
Authors: Kelly Áine , Laroche Serge , Davis Sabrina
Published: April 2018

Consolidation and reconsolidation of long-term memory have been shown to be dependent on the synthesis of new proteins, but the specific molecular mechanisms underlying these events remain to be elucidated. The mitogen-activated protein kinase (MAPK) pathway can trigger genomic responses in neurons, leading to changes in protein synthesis, and several studies have identified its pivotal role in synaptic plasticity and long-term memory formation. In this study, we analyze the involvement of this pathway in the consolidation and reconsolidation of long-term recognition memory, using an object recognition task. We show that inhibition of the MAPK pathway by intracerebroventricular injection of the MEK [MAPK/extracellular signal-regulated kinase (ERK)] inhibitor UO126 blocks consolidation of object recognition memory but does not affect short-term memory. Brain regions of the entorhinal cortex—hippocampal circuitry were analyzed for ERK activation, and it was shown that consolidation of recognition memory was associated with increased phosphorylation of ERK in the dentate gyrus and entorhinal cortex, although total expression of ERK was unchanged. We also report that inhibition of the MAPK pathway blocks reconsolidation of recognition memory, and this was shown to be dependent on reactivation of the memory trace by brief reexposure to the objects. In addition, reconsolidation of memory was associated with an increase in the phosphorylation of ERK in entorhinal cortex and CA1. In summary, our data show that the MAPK kinase pathway is required for both consolidation and reconsolidation of long-term recognition memory, and that this is associated with hyperphosphorylation of ERK in different subregions of the entorhinal cortex—hippocampal circuitry.
A Dual Role of Adenosine A2AReceptors in 3-Nitropropionic Acid-Induced Striatal Lesions: Implications for the Neuroprotective Potential of A2AAntagonists
Authors: Blum David , Galas Marie-Christine , Pintor Annita , Brouillet Emmanuel , Ledent Catherine , Muller Christa E. , Bantubungi Kadiombo , Galluzzo Mariangela , Gall David , Cuvelier Laetitia , Rolland Anne-Sophie , Popoli Patrizia , Schiffmann Serge N.
Published: April 2018

Reduction of A2Areceptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A2Areceptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A2Areceptors in the pathogenesis of HD remains obscure. In the present study, using A2A-/-mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A2Areceptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A2Areceptors and the protective activity of postsynaptic A2Areceptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A2Apresynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A2Areceptors has differential effects on striatal cell deathin vivodepending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A2Aantagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective—neurotoxic effects.
Modulation of Early Olfactory Processing by an Octopaminergic Reinforcement Pathway in the Honeybee
Authors: Farooqui Tahira , Robinson Kellie , Vaessin Harald , Smith Brian H.
Published: April 2018

Processing of olfactory information in the antennal lobes of insects and olfactory bulbs of vertebrates is modulated by centrifugal inputs that represent reinforcing events. Octopamine release by one such pathway in the honeybee antennal lobe modulates olfactory processing in relation to nectar (sucrose) reinforcement. To test more specifically what role octopamine plays in the antennal lobe, we used two treatments to disrupt an octopamine receptor fromApis melliferabrain (AmOAR) function: (1) an OAR antagonist, mianserin, was used to block receptor function, and (2) AmOAR double-stranded RNA was used to silence receptor expression. Both treatments inhibited olfactory acquisition and recall, but they did not disrupt odor discrimination. These results suggest that octopamine mediates consolidation of a component of olfactory memory at this early processing stage in the antennal lobe. Furthermore, after consolidation, octopamine release becomes essential for recall, which suggests that the modulatory circuits become incorporated as essential components of neural representations that activate odor memory.
The Amyloid Precursor Protein and Its Regulatory Protein, FE65, in Growth Cones and SynapsesIn VitroandIn Vivo
Authors: Sabo Shasta L. , Ikin Annat F. , Buxbaum Joseph D. , Greengard Paul
Published: April 2018

Although the Alzheimer amyloid protein precursor (APP) has been studied intensely for more than a decade, its function in neurons is unresolved. Much less is known about its binding partner FE65. We have shown recently that APP and FE65 synergistically regulate the movement of transfected cells. It remained to be shown whether endogenous APP and FE65 could play a similar rolein vivo. Here, we show that FE65, like APP, is expressed at high levels in neurons. Using a combination of immunofluorescence, live imaging, and subcellular fractionation, we find that FE65 and APP localizein vitroandin vivoto the most motile regions of neurons, the growth cones. Within growth cones, APP and FE65 concentrate in actin-rich lamellipodia. Finally, APP and FE65 interact in nerve terminals, where they associate with Rab5-containing synaptic organelles but not with synaptic vesicles. Our data are consistent with a role for the APP/FE65 complex in regulation of actin-based membrane motility in neurons, which could be important for highly dynamic processes such as neurite growth and synapse modification.
Blockade of NMDA Receptors in Prelimbic Cortex Induces an Enduring Amnesia for Odor–Reward Associative Learning
Authors: Tronel Sophie , Sara Susan J.
Published: April 2018

The competitive antagonist 2-amino-5-phosphonoeptanoic acid (APV) was injected intracerebroventricularly to determine the involvement of NMDA receptors in different stages of memory consolidation. Subsequent experiments used local injections to determine possible sites of drug action. Rats were trained in a rapidly learned olfactory task to find palatable food in a hole in a sponge impregnated with the target odor in the presence of two other sponges with nonrewarded odors. APV injections were made intracerebroventricularly 5 min or 2 hr after the end of the training, and a retention test was given 48 hr later. The results showed that blockade of NMDA receptors immediately after training induces a profound and enduring amnesia with no effect when the treatment is delayed at 2 hr after training. To address the question of the effective sites of action of the intracerebroventricular treatment, APV injections into the hippocampus and into the prelimblic region of the frontal cortex (PLC) were made. Blockade of NMDA receptors into the PLC but not into the hippocampus impaired memory formation of the odor–reward association. The amnesia is not transient, because the retention tests were made 48 hr after training. These results underlie the role of NMDA receptors in the early stage of consolidation of a simple odor–reward associative memory and confirm the role of the PLC in the consolidation of long-term memory.
Acid-Sensing Ion Channel 1 Is Localized in Brain Regions with High Synaptic Density and Contributes to Fear Conditioning
Authors: Wemmie John A. , Askwith Candice C. , Lamani Ejvis , Cassell Martin D. , Freeman John H. , Welsh Michael J.
Published: April 2018

The acid-sensing ion channel, ASIC1, contributes to synaptic plasticity in the hippocampus and to hippocampus-dependent spatial memory. To explore the role of ASIC1 in brain, we examined the distribution of ASIC1 protein. Surprisingly, although ASIC1 was present in the hippocampal circuit, it was much more abundant in several areas outside the hippocampus. ASIC1 was enriched in areas with strong excitatory synaptic input such as the glomerulus of the olfactory bulb, whisker barrel cortex, cingulate cortex, striatum, nucleus accumbens, amygdala, and cerebellar cortex. Because ASIC1 levels were particularly high in the amygdala, we focused further on this area. We found that extracellular acidosis elicited a greater current density in amygdala neurons than hippocampal neurons and that disrupting the ASIC1 gene eliminated H+-evoked currents in the amygdala. We also tested the effect of ASIC1 on amygdala-dependent behavior; ASIC1-null mice displayed deficits in cue and context fear conditioning, yet baseline fear on the elevated plus maze was intact. These studies suggest that ASIC1 is distributed to regions supporting high levels of synaptic plasticity and contributes to the neural mechanisms of fear conditioning.
Enhancement of Neuroplastic P2 and N1c Auditory Evoked Potentials in Musicians
Authors: Shahin Antoine , Bosnyak Daniel J. , Trainor Laurel J. , Roberts Larry E.
Published: April 2018

P2 and N1c components of the auditory evoked potential (AEP) have been shown to be sensitive to remodeling of the auditory cortex by training at pitch discrimination in nonmusician subjects. Here, we investigated whether these neuroplastic components of the AEP are enhanced in musicians in accordance with their musical training histories. Highly skilled violinists and pianists and nonmusician controls listened under conditions of passive attention to violin tones, piano tones, and pure tones matched in fundamental frequency to the musical tones. Compared with nonmusician controls, both musician groups evidenced larger N1c (latency, 138 msec) and P2 (latency, 185 msec) responses to the three types of tonal stimuli. As in training studies with nonmusicians, N1c enhancement was expressed preferentially in the right hemisphere, where auditory neurons may be specialized for processing of spectral pitch. Equivalent current dipoles fitted to the N1c and P2 field patterns localized to spatially differentiable regions of the secondary auditory cortex, in agreement with previous findings. These results suggest that the tuning properties of neurons are modified in distributed regions of the auditory cortex in accordance with the acoustic training history (musical- or laboratory-based) of the subject. Enhanced P2 and N1c responses in musicians need not be considered genetic or prenatal markers for musical skill.
Phorbol Myristate Acetate-Dependent Interaction of Protein Kinase Cα and the Neuronal Glutamate Transporter EAAC1
Authors: González Marco I. , Bannerman Peter G. , Robinson Michael B.
Published: April 2018

Sodium-dependent transporters clear extracellular glutamate in the mammalian CNS. Activation of protein kinase C (PKC) rapidly increases the activity of the neuronal glutamate transporter EAAC1 (excitatory amino acid carrier-1). This effect is associated with redistribution of EAAC1 to the cell membrane and appears to be dependent on a particular PKC subtype, PKCα. In the present study, we sought to determine whether this specificity for regulation of EAAC1 is associated with the formation of EAAC1–PKCα complexes. In C6 glioma cells, activation of PKC with phorbol 12-myristate 13-acetate (PMA) induced formation of EAAC1–PKCα complexes but did not induce formation of complexes with PKCδ, a PKC not thought to regulate EAAC1. Formation of these complexes was blocked by inhibitors of PKC. Confocal microscopy revealed that PMA caused EAAC1 and PKCα to colocalize in clusters at or near the cell surface. The EAAC1–PKCα complexes were also observed in rat brain synaptosomes, demonstrating that this interaction is not restricted to C6 cells. These data demonstrate that EAAC1 and PKCα interact in a PKC-dependent manner that is associated with EAAC1 redistribution. Although PKC activation has been implicated in the regulation of many different neurotransmitter transporters, this study provides the first example of an interaction between a neurotransmitter transporter and PKC. PKCα also forms complexes with GluR2 (glutamate receptor subunit 2) and causes a reduction in the levels of GluR2-containing AMPA receptors at the plasma membrane. Together, these data suggest that PKCα may simultaneously trigger the redistribution of EAAC1 and glutamate receptors.
Activation of Metabotropic Glutamate 5 and NMDA Receptors Underlies the Induction of Persistent Bursting and Associated Long-Lasting Changes in CA3 Recurrent Connections
Authors: Stoop Ron , Conquet François , Zuber Benoit , Voronin Leon L. , Pralong Etienne
Published: April 2018

The aim of this study was to describe the induction and expression mechanisms of a persistent bursting activity in a horizontal slice preparation of the rat limbic system that includes the ventral part of the hippocampus and the entorhinal cortex. Disinhibition of this preparation by bicuculline led to interictal-like bursts in the CA3 region that triggered synchronous activity in the entorhinal cortex. Washout of bicuculline aftera1hr application resulted in a maintained production of hippocampal bursts that continued to spread to the entorhinal cortex. Separation of CA3 from the entorhinal cortex caused the activity in the latter to become asynchronous with CA3 activity in the presence of bicuculline and disappear after washout; however, in CA3, neither the induction of bursting nor its persistence were affected. Associated with the CA3 persistent bursting, a strengthening of recurrent collateral excitatory input to CA3 pyramidal cells and a decreased input to CA3 interneurons was found. Both the induction of the persistent bursting and the changes in synaptic strength were prevented by antagonists of metabotropic glutamate 5 (mGlu5) or NMDA receptors or protein synthesis inhibitors and did not occur in slices from mGlu5 receptor knock-out mice. The above findings suggest potential synaptic mechanisms by which the hippocampus switches to a persistent interictal bursting mode that may support a spread of interictal-like bursting to surrounding temporal lobe regions.
Within- and Across-Channel Processing in Auditory Masking: A Physiological Study in the Songbird Forebrain
Authors: Hofer Sonja B. , Klump Georg M.
Published: April 2018

Synchronous envelope fluctuations in different frequency ranges of an acoustic background enhance the detection of signals in background noise. This effect, termed comodulation masking release (CMR), is attributed to both processing within one frequency channel of the auditory system and comparisons across separate frequency channels. Here we present data on CMR from a study in field L2 of the auditory forebrain of the European starling (Sturnus vulgaris) using two 25-Hz-wide bands of masking noise that provide the opportunity to distinguish between within-channel and across-channel effects. Acoustically evoked responses were recorded from unrestrained birds via radio telemetry. The signal was a 800 msec pure tone presented at the most sensitive frequency of the units in a previously determined frequency-tuning curve (FTC). One band of masking noise was centered on the signal frequency while the flanking band of noise was presented either within the limits of the excitatory FTC (i.e., within the same frequency channel as the on-frequency masker) or in the suppression area of the FTC (i.e., in a separate channel). For flanking bands inside the excitatory FTC, signal detection thresholds based on the rate code were lower in noise maskers with identical envelope fluctuations (comodulated) than in maskers with uncorrelated envelopes resulting in a neural CMR of ∼4–7 dB. For flanking bands inside the suppression areas, the neural CMR was reduced. Although the average neural CMR was below the behaviorally determined CMR, a subsample of between 11 and 26% of the recording sites resembled the behavioral performance.
Novel Role of Vitamin K in Preventing Oxidative Injury to Developing Oligodendrocytes and Neurons
Authors: Li Jianrong , Lin Judith C. , Wang Hong , Peterson James W. , Furie Barbara C. , Furie Bruce , Booth Sara L. , Volpe Joseph J. , Rosenberg Paul A.
Published: April 2018

Oxidative stress is believed to be the cause of cell death in multiple disorders of the brain, including perinatal hypoxia/ischemia. Glutamate, cystine deprivation, homocysteic acid, and the glutathione synthesis inhibitor buthionine sulfoximine all cause oxidative injury to immature neurons and oligodendrocytes by depleting intracellular glutathione. Although vitamin K is not a classical antioxidant, we report here the novel finding that vitamin K1and K2(menaquinone-4) potently inhibit glutathione depletion-mediated oxidative cell death in primary cultures of oligodendrocyte precursors and immature fetal cortical neurons with EC50values of 30 nmand 2 nm, respectively. The mechanism by which vitamin K blocks oxidative injury is independent of its only known biological function as a cofactor for γ-glutamylcarboxylase, an enzyme responsible for posttranslational modification of specific proteins. Neither oligodendrocytes nor neurons possess significant vitamin K-dependent carboxylase or epoxidase activity. Furthermore, the vitamin K antagonists warfarin and dicoumarol and the direct carboxylase inhibitor 2-chloro-vitamin K1have no effect on the protective function of vitamin K against oxidative injury. Vitamin K does not prevent the depletion of intracellular glutathione caused by cystine deprivation but completely blocks free radical accumulation and cell death. The protective and potent efficacy of this naturally occurring vitamin, with no established clinical side effects, suggests a potential therapeutic application in preventing oxidative damage to undifferentiated oligodendrocytes in perinatal hypoxic/ischemic brain injury.
Local Excitatory Network and NMDA Receptor Activation Generate a Synchronous and Bursting Command from the Superior Colliculus
Authors: Saito Yasuhiko , Isa Tadashi
Published: April 2018

The generation of bursting spike activity in the deeper layers of the superior colliculus (SC) is a critical determinant of decision making in the initiation of orienting behaviors, such as saccades. The bursting activity exhibits a typical threshold effect that may arise from a nonlinear signal amplification process in the deeper layers of the SC. We used whole-cell patch-clamp recordings in rat SC slices to investigate the neuronal mechanism underlying the generation of such bursting activity. We found that (1) neurons in the intermediate gray layer [stratum griseum intermediale (SGI)] produce a prolonged bursting response when released from GABAAreceptor-mediated inhibition, (2) this GABAAinhibition may partially arise from inhibitory interneurons within the SGI that are driven synaptically by glutamatergic excitatory inputs to the SC, (3) the bursting is not the result of the intrinsic membrane properties of individual SC neurons but is instead produced by local circuits within the SGI, (4) the bursting is mediated by activation of NMDA receptors, and (5) the bursting can be synchronous among SGI neurons. These results suggest that activation of a local excitatory network within the deeper layers of the SC and NMDA receptor-dependent synaptic transmission after release from GABAAinhibition are fundamental mechanisms that may explain the nonlinear signal amplification process in the deeper layers of the SC.
Cognitive Strategies Dependent on the Hippocampus and Caudate Nucleus in Human Navigation: Variability and Change with Practice
Authors: Iaria Giuseppe , Petrides Michael , Dagher Alain , Pike Bruce , Bohbot Véronique D.
Published: April 2018

The human brain activity related to strategies for navigating in space and how it changes with practice was investigated with functional magnetic resonance imaging. Subjects used two different strategies to solve a place-learning task in a computer-generated virtual environment. One-half of the subjects used spatial landmarks to navigate in the early phase of training, and these subjects showed increased activation of the right hippocampus. The other half used a nonspatial strategy and showed, with practice, sustained increased activity within the caudate nucleus during navigation. Activation common to both groups was observed in the posterior parietal and frontal cortex. These results provide the first evidence for spontaneous variability and shift in neural mechanisms during navigation in humans.
CNS Glucagon-Like Peptide-1 Receptors Mediate Endocrine and Anxiety Responses to Interoceptive and Psychogenic Stressors
Authors: Kinzig Kimberly P. , D'Alessio David A. , Herman James P. , Sakai Randall R. , Vahl Torsten P. , Figueiredo Helmer F. , Murphy Erin K. , Seeley Randy J.
Published: April 2018

Responses to stressors serve to adjust physiology and behavior to increase short-term survival at the potential expense of increasing susceptibility to disease over the long term. We show that glucagon-like peptide-1 (7–36) amide (GLP-1) increases levels of the stress-activated hormones ACTH and corticosterone when administered directly into the rat brain and increases levels of anxiety as measured by the elevated plus maze. The endocrine response is preferentially activated by GLP-1 administration in the paraventricular nucleus of the hypothalamus, whereas the anxiety response is preferentially activated by administration in the central nucleus of the amygdala. Furthermore, GLP-1 antagonists block increases in stress hormones associated with the toxin LiCl and both the endocrine and anxiety responses to vertical heights. Although diverse neural circuits must necessarily process disparate stressors, the current data implicate a role for the GLP-1 system as a critical mediator of multiple stress responses.
Gaze-Centered Updating of Visual Space in Human Parietal Cortex
Authors: Medendorp W. Pieter , Goltz Herbert C. , Vilis Tutis , Crawford J. Douglas
Published: April 2018

Single-unit recordings have identified a region in the posterior parietal cortex (PPC) of the monkey that represents and updates visual space in a gaze-centered frame. Here, using event-related functional magnetic resonance imaging, we identified an analogous bilateral region in the human PPC that shows contralateral topography for memory-guided eye movements and arm movements. Furthermore, when eye movements reversed the remembered horizontal target location relative to the gaze fixation point, this PPC region exchanged activity across the two cortical lobules. This shows that the human PPC dynamically updates the spatial goals for action in a gaze-centered frame.
Differential Regulation of Transmitter Release by Alternatively Spliced Forms of Synaptotagmin I
Authors: Nakhost Arash , Houeland Gry , Castellucci Vincent F. , Sossin Wayne S.
Published: April 2018

We discovered a novel alternatively spliced form of synaptotagmin I (Syt I). This splicing event is conserved over evolution and, inAplysia, results in a two amino acid insert in the juxtamembrane domain of Syt I (Syt IVQ). Both Syt I and Syt IVQare localized to synaptic vesicles; however, we also observed punctae that contained one or the other spliced products. Both Syt I and Syt IVQare phosphorylated at the adjacent PKC site. Overexpression of Syt IVQ,but not of Syt I, inAplysianeurons blocked the ability of serotonin to reverse synaptic depression. This effect is upstream of PKC activation, because neither Syt IVQnor Syt I blocked the effects of phorbol esters on reversing synaptic depression or the effects of serotonin on facilitating nondepressed synapses. Our results demonstrate a physiological role for splicing in the juxtamembrane domain of Syt I.
Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia
Authors: Hashimoto Takanori , Volk David W. , Eggan Stephen M. , Mirnics Karoly , Pierri Joseph N. , Sun Zhuoxin , Sampson Allan R. , Lewis David A.
Published: April 2018

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-labelin situhybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominately in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r= 0.84) with the decrease in the density of neurons containing detectable levels of GAD67mRNA. Furthermore, simultaneous detection of PV and GAD67mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.
Purkinje Cell Synapses Target Physiologically Unique Brainstem Neurons
Authors: Sekirnjak Chris , Vissel Bryce , Bollinger Jacob , Faulstich Michael , du Lac Sascha
Published: April 2018

The cerebellum controls motor learning via Purkinje cell synapses onto discrete populations of neurons in the deep cerebellar nuclei and brainstem vestibular nuclei. In the circuitry that subserves the vestibulo-ocular reflex, the postsynaptic targets of Purkinje cells, termed flocculus target neurons (FTNs), are thought to be a critical site of learning. Little is known, however, about the intrinsic cellular properties of FTNs, which are sparsely distributed in the medial vestibular nucleus. To identify these neurons, we used the L7 promoter to express a tau-green fluorescent protein fusion protein selectively in Purkinje cells. Fluorescent Purkinje cell axons and terminal boutons surrounded the somata and proximal dendrites of a small subset of neurons, presumed FTNs, in the medial vestibular nucleus. Targeted intracellular recordings revealed that FTNs fired spontaneously at high rates in brain slices (mean, 47 spikes/sec) and exhibited dramatic postinhibitory rebound firing after the offset of membrane hyperpolarization. These intrinsic firing properties were exceptional among brainstem vestibular nucleus neurons but strikingly similar to neurons in the deep cerebellar nuclei, indicating a common role for intrinsic firing mechanisms in cerebellar control of diverse behaviors.
Individual Differences in the Expression of a “General” Learning Ability in Mice
Authors: Matzel Louis D. , Han Yu Ray , Grossman Henya , Karnik Meghana S. , Patel Dave , Scott Nicholas , Specht Steven M. , Gandhi Chetan C.
Published: April 2018

Human performance on diverse tests of intellect are impacted by a “general” regulatory factor that accounts for up to 50% of the variance between individuals on intelligence tests. Neurobiological determinants of general cognitive abilities are essentially unknown, owing in part to the paucity of animal research wherein neurobiological analyses are possible. We report a methodology with which we have assessed individual differences in the general learning abilities of laboratory mice. Abilities of mice on tests of associative fear conditioning, operant avoidance, path integration, discrimination, and spatial navigation were assessed. Tasks were designed so that each made unique sensory, motor, motivational, and information processing demands on the animals. A sample of 56 genetically diverse outbred mice (CD-1) was used to assess individuals' acquisition on each task. Indicative of a common source of variance, positive correlations were found between individuals' performance on all tasks. When tested on multiple test batteries, the overall performance ranks of individuals were found to be highly reliable and were “normally” distributed. Factor analysis of learning performance variables determined that a single factor accounted for 38% of the total variance across animals. Animals' levels of native activity and body weights accounted for little of the variability in learning, although animals' propensity for exploration loaded strongly (and was positively correlated) with learning abilities. These results indicate that diverse learning abilities of laboratory mice are influenced by a common source of variance and, moreover, that the general learning abilities of individual mice can be specified relative to a sample of peers.