bluuebunny/crossref_metadata_2025 huggingface dataset:
Noradrenergic Depletion Potentiates β-Amyloid-Induced Cortical Inflammation: Implications for Alzheimer's Disease
Authors: Heneka Michael T. , Galea Elena , Gavriluyk Vitaliy , Dumitrescu-Ozimek Lucia , Daeschner JoAnna , O'Banion M. Kerry , Weinberg Guy , Klockgether Thomas , Feinstein Douglas L.
Published: April 2018

Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid β (Aβ). Adult rats were injected with the selective neurotoxinN-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Aβ (aggregated 1–42 peptide). DSP4 treatment potentiated the Aβ-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1β, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Aβ induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Aβ increased IL-1β expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1β expression were attenuated by coinjection with NE or the β-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Aβ and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.
Synaptically Released Acetylcholine Evokes Ca2+Elevations in Astrocytes in Hippocampal Slices
Authors: Araque Alfonso , Martı́n Eduardo D. , Perea Gertrudis , Arellano Jon I. , Buño Washington
Published: April 2018

Recent results have demonstrated the existence of bidirectional communication between glial cells and neurons. We investigated in brain slices whether rat hippocampal astrocytes respond to acetylcholine synaptically released by an extrinsic pathway. We stimulated the stratum oriens/alveus, which contains cholinergic afferents from the septum and diagonal band of Broca, and recorded whole-cell membrane currents and intracellular Ca2+levels of astrocytes located in the hippocampal stratum oriens. Nerve-fiber stimulation evoked a long-lasting inward current and increased the Ca2+levels in astrocytes. Both astrocytic responses were abolished by tetrodotoxin or Cd2+and were increased by 4-aminopyridine, indicating that the responses were attributable to synaptically released neurotransmitter. The inward current was inhibited by glutamate transporter antagonists, indicating that it was attributable to the electrogenic glutamate transporter activity. The synaptically evoked intracellular Ca2+elevations were not affected by glutamate receptor antagonists but were abolished by atropine, indicating that they were mediated by muscarinic cholinergic receptors. Thapsigargin prevented the Ca2+elevation but did not modify the inward current, indicating that the Ca2+signal was attributable to intracellular Ca2+mobilization. These results indicate that hippocampal astrocytes respond to acetylcholine released by synaptic terminals. The synaptically released acetylcholine acts on muscarinic receptors, mobilizing Ca2+from the intracellular stores. Different regions in the recorded astrocytes showed independent stimulus-induced Ca2+variations, suggesting the existence of subcellular domains in the astrocytic responses evoked by the synaptic cholinergic activity. Therefore, our results show the existence of cholinergic neuron–astrocyte signaling and suggest that astrocytes are a target of axonal inputs from different brain areas.
Rapid, Experience-Dependent Changes in Levels of Synaptic Zinc in Primary Somatosensory Cortex of the Adult Mouse
Authors: Brown Craig E. , Dyck Richard H.
Published: April 2018

Electrophysiological studies have established that the adult cerebral cortex undergoes immediate functional reorganizations after perturbations of the sensory periphery. These activity-dependent modifications are thought to be mediated via the rapid regulation of the synaptic strength of existing connections. Recent studies have implicated synaptic zinc as contributing to activity-dependent mechanisms of cortical plasticity, such as long-term potentiation and long-term depression, by virtue of its potent ability to modulate glutamatergic neurotransmission. To investigate the role of synaptic zinc in cortical plasticity, we examined changes in the barrel-specific distribution of zinc in axon terminals innervating the primary somatosensory cortex of adult mice at different time points after whisker plucking. In layer IV of normal adult mice, zinc staining in the barrel field was characterized by intense staining in inter-barrel septae and low levels of staining in barrel hollows. Within 3 hr, and up to 1 week after the removal of a row of whiskers, zinc staining increased significantly in barrel hollows corresponding to the plucked whiskers. With longer survival times, levels of zinc staining gradually declined in deprived barrel hollows, returning to normal levels by 2–3 weeks after whisker removal. Increased levels of zinc staining in deprived barrel hollows were highly, negatively correlated with the length of whiskers as they regrew. These results indicate that levels of synaptic zinc in the neocortex are rapidly regulated by changes in sensory experience and suggest that zinc may participate in the plastic changes that normally occur in the cortex on a moment-to-moment basis.
Functional Asymmetries in ON and OFF Ganglion Cells of Primate Retina
Authors: Chichilnisky E. J. , Kalmar Rachel S.
Published: April 2018

Functional asymmetries in the ON and OFF pathways of the primate visual system were examined using simultaneous multi-electrode recordings from dozens of retinal ganglion cells (RGCs)in vitro. Light responses of RGCs were characterized using white noise stimulation. Two distinct functional types of cells frequently encountered, one ON and one OFF, had non-opponent spectral sensitivity, relatively high response gain, transient light responses, and large receptive fields (RFs) that tiled the region of retina recorded, suggesting that they belonged to the same morphological cell class, most likely parasol. Three principal functional asymmetries were observed. (1) Receptive fields of ON cells were 20% larger in diameter than those of OFF cells, resulting in higher full-field sensitivity. (2) ON cells had faster response kinetics than OFF cells, with a 10–20% shorter time to peak, trough and zero crossing in the biphasic temporal impulse response. (3) ON cells had more nearly linear light responses and were capable of signaling decrements, whereas OFF cells had more strongly rectifying responses that provided little information about increments. These findings suggest specific mechanistic asymmetries in retinal ON and OFF circuits and differences in visual performance on the basis of the activity of ON and OFF parasol cells.
Direct and Indirect Excitation of Laterodorsal Tegmental Neurons by Hypocretin/Orexin Peptides: Implications for Wakefulness and Narcolepsy
Authors: Burlet Sophie , Tyler Christopher J. , Leonard Christopher S.
Published: April 2018

Compelling evidence links the recently discovered hypothalamic peptides Hypocretin/Orexin (Hcrt/Orx) to rapid eye movement sleep (REM) control and the sleep disorder narcolepsy, yet how they influence sleep-related systems is not well understood. We investigated the action of Hcrt/Orx on mesopontine cholinergic (MPCh) neurons of the laterodorsal tegmental nucleus (LDT), a target group whose function is altered in canine narcolepsy and appears pivotal for normal REM and wakefulness. Extracellular recordings from mouse brainstem slices revealed that Hcrt/Orx evoked prolonged firing of LDT neurons. Whole-cell recordings revealed that Hcrt/Orx had actions on both presynaptic neurons and at postsynaptic sites. Hcrt/Orx produced an increase in frequency and amplitude of spontaneous EPSCs without equivalent effect on IPSCs, by triggering action potentials and enhancing spike-evoked synaptic transmission in glutamatergic afferents. Postsynaptically, Hcrt/Orx produced an inward current and an increase in membrane current noise, which were accompanied by a conductance increase. These persisted in TTX, ionotropic glutamate receptor antagonists, and low extracellular calcium. Both presynaptic and postsynaptic actions were specific because they were not mimicked by an Hcrt/Orx fragment, and both actions were observed for cholinergic and noncholinergic LDT neurons. Finally, extracellular recordings during postsynaptic potential blockade demonstrated that postsynaptic actions of Hcrt/Orx alone could evoke prolonged firing. In the context of other recent work, our findings suggest that Hcrt/Orx neurons may coordinate the activity of the entire reticular activating system during waking. Moreover, these findings address specific hypotheses regarding the cellular mechanisms underlying REM disregulation in narcolepsy.
Conservation of Spatial Memory Function in the Pallial Forebrain of Reptiles and Ray-Finned Fishes
Authors: Rodrı́guez Fernando , López J. Carlos , Vargas J. Pedro , Gómez Yolanda , Broglio Cristina , Salas Cosme
Published: April 2018

The hippocampus of mammals and birds is critical for spatial memory. Neuroanatomical evidence indicates that the medial cortex (MC) of reptiles and the lateral pallium (LP) of ray-finned fishes could be homologous to the hippocampus of mammals and birds. In this work, we studied the effects of lesions to the MC of turtles and to the LP of goldfish in spatial memory. Lesioned animals were trained in place, and cue maze tasks and crucial probe and transfer tests were performed. In experiment 1, MC-lesioned turtles in the place task failed to locate the goal during trials in which new start positions were used, whereas sham animals navigated directly to the goal independently of start location. In contrast, no deficit was observed in cue learning. In experiment 2, LP lesion produced a dramatic impairment in goldfish trained in the place task, whereas medial and dorsal pallium lesions did not decrease accuracy. In addition, none of these pallial lesions produced deficits in cue learning. These results indicate that lesions to the MC of turtles and to the LP of goldfish, like hippocampal lesions in mammals and birds, selectively impair map-like memory representations of the environmental space. Thus, the forebrain structures of reptiles and teleost fish neuroanatomically equivalent to the mammalian and avian hippocampus also share a central role in spatial cognition. Present results suggest that the presence of a hippocampus-dependent spatial memory system is a primitive feature of the vertebrate forebrain that has been conserved through evolution.
Cocaine Administered into the Medial Prefrontal Cortex Reinstates Cocaine-Seeking Behavior by Increasing AMPA Receptor-Mediated Glutamate Transmission in the Nucleus Accumbens
Authors: Park W.-K. , Bari A. A. , Jey A. R. , Anderson S. M. , Spealman R. D. , Rowlett J. K. , Pierce R. C.
Published: April 2018

One of the major determinants of reinstatement to cocaine use among human addicts is acute reexposure to the drug, which often precipitates cocaine craving and relapse. We used an animal model of cocaine relapse to determine the role of the glutamatergic pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens in the reinstatement of cocaine-seeking behavior after a cocaine priming injection. Rats were trained to self-administer cocaine intravenously on a second order schedule. Responding was extinguished subsequently by substituting saline for cocaine. During subsequent reinstatement sessions, drug-seeking behavior was assessed after noncontingent priming injections. Results indicated that reinstatement induced by a systemic cocaine injection was blocked by intra-mPFC administration of the dopamine antagonist flupenthixol. Consistent with this finding, administration of cocaine directly into the mPFC reinstated cocaine-seeking behavior. Administration of cocaine into the nucleus accumbens also reinstated drug seeking, whereas microinjection of cocaine into the neostriatum or lateral septum did not. Reinstatement of cocaine seeking induced by intra-mPFC cocaine was blocked by administration of the AMPA receptor antagonist CNQX into the nucleus accumbens. Administration of the NMDA receptor antagonist AP-5 into the nucleus accumbens had variable effects on reinstatement induced by intra-mPFC cocaine in that AP-5 had no effect in some animals but augmented reinstatement in others. Subsequent experiments showed that intra-accumbal microinjection of AP-5 alone dose-dependently reinstated cocaine seeking. These data indicate that the glutamatergic pathway from the mPFC to the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drug seeking. Moreover, the present results demonstrate that AMPA and NMDA receptors in the nucleus accumbens have opposing roles in the reinstatement of cocaine-seeking behavior.
Role of Dopamine D2-like Receptors in Cocaine Self-Administration: Studies with D2 Receptor Mutant Mice and Novel D2 Receptor Antagonists
Authors: Caine S. Barak , Negus S. Stevens , Mello Nancy K. , Patel Smita , Bristow Linda , Kulagowski Janusz , Vallone Daniela , Saiardi Adolfo , Borrelli Emiliana
Published: April 2018

Dopamine receptor subtypes have been classified generally as D1-like (e.g., D1, D5) or D2-like (D2, D3, D4), and converging evidence suggests that D2-like receptors may be especially important in mediating the abuse-related effects of cocaine. However, it has been difficult to differentiate the roles of the D2-like receptor subtypes in the behavioral effects of cocaine because of the relatively low selectivity of drugs for D2, D3, and D4 receptorsin vivo. The goal of the present series of studies was to investigate the contributions of D2-like receptor subtypes in the reinforcing effects of cocaine using new genetic and pharmacological tools. First, we evaluated cocaine self-administration behavior, and related effects of nonselective D2-like drugs, in mutant mice that lack the D2 receptor but express D3 and D4 receptors. When high doses of cocaine on the descending limb of the cocaine dose–effect function were available, D2 mutant mice self-administered at higher rates than their heterozygous or wild-type littermates, but the ascending limb of the cocaine dose–effect function did not differ between genotypes. Elevated rates of drug intake were not attributable to nonspecific increases in response rate, because response rates maintained by presentation of a range of food concentrations were significantly lower in D2 mutant mice than in wild-type mice. In wild-type mice, pretreatment with the D2-like antagonist eticlopride increased rates of self-administration of high doses of cocaine, and the D2-like agonist quinelorane served as a positive reinforcer when substituted for cocaine. However, these effects of eticlopride and quinelorane were not observed in mice that lacked the D2 receptor. Next, we compared the effects of novel antagonists selective for different D2 receptor subtypes on cocaine self-administration behavior in outbred rats. In rats, a D2 selective antagonist increased rates of self-administration of high doses of cocaine and also combinations of cocaine and the D2-like agonist quinelorane, whereas D3/D4 antagonists were ineffective. Collectively, these findings suggest that the D2 receptor is not necessary for cocaine self-administration, but this receptor subtype is involved in mechanisms that limit rates of high-dose cocaine self-administration. Our results also suggest that D3 and D4 receptors do not play major roles in the modulation of cocaine self-administration by D2-like drugs.
Inhibition of mRNA and Protein Synthesis in the CA1 Region of the Dorsal Hippocampus Blocks Reinstallment of an Extinguished Conditioned Fear Response
Authors: Cammarota Martı́n , Bevilaqua Lia R. M. , Kerr Daniel , Medina Jorge H. , Izquierdo Iván
Published: April 2018

Memories are extinguished by the repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus to which it has been associated. It is believed that extinction establishes a new hierarchy of responses rather than an actual forgetting of the original response, which can usually reappear spontaneously after interruption of the extinction process. In this study, our aim was to analyze how profound extinction can be. Rats were trained in a one-trial, step-down inhibitory avoidance paradigm and then were exposed to several extinction sessions in which they were allowed to freely explore the apparatus for 30 sec after having stepped down. Extinction was complete enough so that there was no spontaneous recovery, and test session performance could not be enhanced by pharmacological agents with well known facilitative actions on retrieval. After being submitted to a new training session, control animals reacquired the avoidance response; however, animals failed to do so after receiving bilateral intra-CA1 infusions of either the protein synthesis inhibitor anisomycin or the mRNA synthesis blocker 5,6-dichloro-1-β-d-ribofuranosyl benzimidazole 15 min before the retraining session. Our results indicate that extinction can be carried to a point at which reinstallment of the conditioned response requires, like the original learning,de novogene expression and protein synthesis in the CA1 region of the dorsal hippocampus.
Oxytocin Regulates Neurosteroid Modulation of GABAAReceptors in Supraoptic Nucleus around Parturition
Authors: Koksma Jan-Jurjen , van Kesteren Ronald E. , Rosahl Thomas W. , Zwart Ruud , Smit August B. , Lüddens Hartmut , Brussaard Arjen B.
Published: April 2018

In this study, we investigate how neurosteroid sensitivity of GABAAreceptors (GABAARs) is regulated. We examined this issue in neurons of the supraoptic nucleus (SON) of the rat and found that, during parturition, the GABAARs become insensitive to the neurosteroid allopregnanolone attributable to a shift in the balance between the activities of endogenous Ser/Thr phosphatase and PKC. In particular, a constitutive endogenous tone of oxytocin within the SON after parturition suppressed neurosteroid sensitivity of GABAARs via activation of PKC. Vice versa before parturition, during late pregnancy, application of exogenous oxytocin brings the GABAARs from a neurosteroid-sensitive mode toward a condition in which the receptors are not sensitive. This indicates that there may be an inverse causal relationship between the extent to which the GABAAR or one of its interacting proteins is phosphorylated and the neurosteroid sensitivity of the GABAAR. Neurosteroid sensitivity was not affected by changes in subunit composition of GABAARs known to occur concurrently in these cells.
Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease
Authors: Cepeda Carlos , Hurst Raymond S. , Calvert Christopher R. , Hernández-Echeagaray Elizabeth , Nguyen Oanh K. , Jocoy Emily , Christian Lindsey J. , Ariano Marjorie A. , Levine Michael S.
Published: April 2018

Alterations in the corticostriatal pathway may precede symptomatology and striatal cell death in Huntington's disease (HD) patients. Here we examined spontaneous EPSCs in striatal medium-sized spiny neurons in slices from a mouse model of HD (R6/2). Spontaneous EPSC frequency was similar in young (3–4 weeks) transgenics and controls but decreased significantly in transgenics when overt behavioral symptoms began (5–7 weeks) and was most pronounced in severely impaired transgenics (11–15 weeks). These differences were maintained after bicuculline or tetrodotoxin, indicating they were specific to glutamatergic input and likely presynaptic in origin. Decreases in presynaptic and postsynaptic protein markers, synaptophysin and postsynaptic density-95, occurred in 11–15 week R6/2 mice, supporting the electrophysiological results. Furthermore, isolated, large-amplitude synaptic events (>100 pA) occurred more frequently in transgenic animals, particularly at 5–7 weeks, suggesting additional dysregulation of cortical inputs. Large events were blocked by tetrodotoxin, indicating a possible cortical origin. Addition of bicuculline and 4-aminopyridine facilitated the occurrence of large events. Riluzole, a compound that decreases glutamate release, reduced these events. Together, these observations indicate that both progressive and transient alterations occur along the corticostriatal pathway in experimental HD. These alterations are likely to contribute to the selective vulnerability of striatal medium-sized spiny neurons.
Adaptive Plasticity in the Auditory Thalamus of Juvenile Barn Owls
Authors: Miller Greg L. , Knudsen Eric I.
Published: April 2018

Little is known about the capacity of the thalamus for experience-dependent plasticity. Here, we demonstrate adaptive changes in the tuning of auditory thalamic neurons to a major category of sound localization cue, interaural time differences (ITDs), in juvenile barn owls that experience chronic abnormal hearing. Abnormal hearing was caused by a passive acoustic filtering device implanted in one ear that altered the timing and level of sound differently at different frequencies. Experience with this device resulted in adaptive, frequency-dependent shifts in the tuning of thalamic neurons to ITD that mimicked the acoustic effects of the device. Abnormal hearing did not alter ITD tuning in the central nucleus of the inferior colliculus, the primary source of input to the auditory thalamus. Therefore, the thalamus is the earliest stage in the forebrain pathway in which this plasticity is expressed. A visual manipulation, chronic prismatic displacement of the visual field, which causes adaptive changes in ITD tuning at higher levels in the forebrain, had no effect on thalamic ITD tuning. The results demonstrate that, during the juvenile period, auditory experience shapes neuronal response properties in the thalamus in a frequency-specific manner and suggest that this thalamic plasticity is driven by self-organizational forces and not by visual instruction.
Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis
Authors: Arévalo-Martı́n Ángel , Vela José Miguel , Molina-Holgado Eduardo , Borrell José , Guaza Carmen
Published: April 2018

Theiler's virus infection of the CNS induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis (MS). Cannabinoids may act as immunosuppressive compounds that have shown therapeutic potential in chronic inflammatory disorders. Using the Theiler's murine encephalomyelitis virus model, we report here that treatment with the synthetic cannabinoids WIN 55,212–2, ACEA, and JWH-015 during established disease significantly improved the neurological deficits in a long-lasting way. At a histological level, cannabinoids reduced microglial activation, abrogated major histocompatibility complex class II antigen expression, and decreased the number of CD4+ infiltrating T cells in the spinal cord. Both recovery of motor function and diminution of inflammation paralleled extensive remyelination. Overall, the data presented may have potential therapeutic implications in demyelinating pathologies such as MS; in particular, the possible involvement of cannabinoid receptor CB2 would enable nonpsychoactive therapy suitable for long-term use.
Increased Sensitivity to Agonist-Induced Seizures, Straub Tail, and Hippocampal Theta Rhythm in Knock-In Mice Carrying Hypersensitive α4 Nicotinic Receptors
Authors: Fonck Carlos , Nashmi Raad , Deshpande Purnima , Damaj M. Imad , Marks Michael J. , Riedel Anett , Schwarz Johannes , Collins Allan C. , Labarca Cesar , Lester Henry A.
Published: April 2018

We studied a strain of exon replacement mice (“L9′S knock-in”) whose α4 nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9′ position (Labarca et al., 2001); this mutation renders α4-containing receptors hypersensitive to agonists. Nicotine induced seizures at concentrations (1 mg/kg) approximately eight times lower in L9′S than in wild-type (WT) littermates. At these concentrations, L9′S but not WT showed increases in EEG amplitude and theta rhythm. L9′S mice also showed higher seizure sensitivity to the nicotinic agonist epibatidine, but not to the GABAAreceptor blocker and proconvulsant bicuculline. Dorsiflexion of the tail (Straub tail) was the most sensitive nicotine effect found in L9′S mice (0.1 mg/kg). The L9′S mice were hypersensitive to galanthamine- and tacrine-induced seizures and Straub tails. There were no apparent neuroanatomical differences between L9′S and WT mice in several brain regions. [125I]Epibatidine binding to brain membranes showed that the mutant allele was expressed at ∼25% of WT levels, presumably because of the presence of a neomycin selection cassette in a nearby intron.86Rb efflux experiments on brain synaptosomes showed an increased fraction of function at low agonist concentrations in L9′S mice. These data support the possible involvement of gain-of-function α4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy.
A Cell Surface Receptor Complex for Fibrillar β-Amyloid Mediates Microglial Activation
Authors: Bamberger Maria E. , Harris Meera E. , McDonald Douglas R. , Husemann Jens , Landreth Gary E.
Published: April 2018

Senile plaques found in the Alzheimer's disease brain are foci of local inflammatory reactions mediated by plaque-associated microglia. The interaction of microglia with compacted deposits of β-amyloid (Aβ) fibrils results in the stimulation of intracellular Tyr kinase-based signaling cascades and cellular activation, leading to the secretion of proinflammatory molecules. This study identifies a cell surface receptor complex that mediates the binding of microglia to Aβ fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response. The receptor complex includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the α6β1-integrin. Antagonists of scavenger receptors, CD36, CD47, and α6β1inhibited the adhesion of THP-1 monocytes to Aβ fibrils. In addition, peptide competitors of Aβ fibril interactions with CD36, scavenger receptors, CD47, and the α6β1-integrin inhibited Aβ stimulation of Tyr kinase-based signaling cascades in both THP-1 monocytes and murine microglia as well as interleukin 1β production. A scavenger receptor antagonist and antibodies specific for CD36 and the β1-integrin subunit also inhibited the Aβ-stimulated generation of reactive oxygen species. Importantly, the principal components of this receptor complex are shared with those for other fibrillar proteins and thus represent general elements through which myeloid lineage cells recognize complex fibrillar proteins. Identification of the cell surface molecules that interact with Aβ fibrils and mediate their activation of intracellular signaling cascades represents a potential intervention point in the treatment of Alzheimer's disease.
Exocytosis at the Ribbon Synapse of Retinal Bipolar Cells Studied in Patches of Presynaptic Membrane
Authors: Llobet Artur , Cooke Anne , Lagnado Leon
Published: April 2018

The distribution of exocytic sites and ion channels in the synaptic terminal of retinal bipolar cells was investigated by measuring capacitance and conductance changes in cell-attached patches of presynaptic membrane. Patch depolarization evoked capacitance and conductance increases that were inhibited by blocking Ca2+influx or loading the terminal with EGTA. The increase in capacitance declined as the depolarization approached the reversal potential for Ca2+, indicating that it was a result of Ca2+-dependent exocytosis. The conductance increase was caused by KCachannels that were also activated by Ca2+influx. Two observations indicated that sites of exocytosis and endocytosis colocalized with clusters of Ca2+channels and KCachannels; the initial rate of exocytosis was correlated with the activation of KCachannels, and exocytosis did not occur in the 41% of patches lacking this conductance. Electron microscopy demonstrated that there were ∼16 vesicles docked to the plasma membrane at each active zone marked by a ribbon, but vesicles were also attached to the rest of the membrane at a density of 1.5/μm2. The density of ribbons was 0.10 ± 0.02/μm2, predicting that ∼43% of cell-attached patches would lack an active zone. The density of Ca2+channel clusters assayed by capacitance and conductance responses was therefore similar to the density of ribbons. These results are consistent with the idea that Ca2+channel clusters were colocalized with ribbons but do not exclude the possibility that calcium channels also occurred at other sites. The wide distribution of vesicles docked to the plasma membrane suggests that exocytosis might also be triggered by the spread of Ca2+from Ca2+channel clusters.
Glutamate-Dependent Inhibition of Dopamine Release in Striatum Is Mediated by a New Diffusible Messenger, H2O2
Authors: Avshalumov Marat V. , Chen Billy T. , Marshall Sarah P. , Peña Dianna M. , Rice Margaret E.
Published: April 2018

How glutamate regulates dopamine (DA) release in striatum has been a controversial issue. Here, we resolve this by showing that glutamate, acting at AMPA receptors, inhibits DA release by a nonclassic mechanism mediated by hydrogen peroxide (H2O2). Moreover, we show that GABAA-receptor activation opposes this process, thereby enhancing DA release. The influence of glutamate and GABA on DA release was assessed in striatal slices using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Modulation by both transmitters was prevented by H2O2-metabolizing enzymes. In addition, the influence of GABAA-receptor activation was lost when AMPA receptors were blocked with GYKI-52466. Together, these data show that modulation of DA release by glutamate and GABA depends on H2O2generated downstream from AMPA receptors. This is the first evidence that endogenous glutamate can lead to the generation of reactive oxygen species under physiological conditions. We also show that inhibition of DA release by H2O2is mediated by sulfonylurea-sensitive K+channels: tolbutamide blocked DA modulation by glutamate and by GABA. The absence of ionotropic glutamate or GABA receptors on DA terminals indicates that modulatory H2O2is generated in non-DA cells. Thus, in addition to its known excitatory actions in striatum, glutamate mediates inhibition by generating H2O2that must diffuse from postsynaptic sites to inhibit presynaptic DA release via K+-channel opening. These findings have significant implications not only for normal striatal function but also for understanding disease states that involve DA and oxidative stress, including disorders as diverse as Parkinson's disease and schizophrenia.
Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide Activate Hyperpolarization-Activated Cationic Current and Depolarize Thalamocortical NeuronsIn Vitro
Authors: Sun Qian-Quan , Prince David A. , Huguenard John R.
Published: April 2018

Ascending pathways mediated by monoamine neurotransmitters regulate the firing mode of thalamocortical neurons and modulate the state of brain activity. We hypothesized that specific neuropeptides might have similar actions. The effects of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) were tested on thalamocortical neurons using whole-cell patch-clamp techniques applied to visualized neurons in rat brain slices. VIP (2 μm) and PACAP (100 nm) reversibly depolarized thalamocortical neurons (7.8 ± 0.6 mV;n= 16), reduced the membrane resistance by 33 ± 3%, and could convert the firing mode from bursting to tonic. These effects on resting membrane potential and membrane resistance persisted in the presence of TTX. Morphologically diverse thalamocortical neurons located in widespread regions of thalamus were all depolarized by VIP and PACAP38. In voltage-clamp mode, we found that VIP and PACAP38 reversibly activated a hyperpolarization-activated cationic current (IH) in thalamocortical neurons and altered voltage- and time-dependent activation properties of the current. The effects of VIP on membrane conductance were abolished by the hyperpolarization-activated cyclic-nucleotide-gated channel (HCN)-specific antagonist ZD7288, showing that HCN channels are the major target of VIP modulation. The effects of VIP and PACAP38 on HCN channels were mediated by PAC1receptors and cAMP. The actions of PACAP-related peptides on thalamocortical neurons suggest an additional and novel endogenous neurophysiological pathway that may influence both normal and pathophysiological thalamocortical rhythm generation and have important behavioral effects on sensory processing and sleep–wake cycles.
Spinal Cats on the Treadmill: Changes in Load Pathways
Authors: Côté Marie-Pascale , Ménard Ariane , Gossard Jean-Pierre
Published: April 2018

Treadmill training and clonidine, an α-2 noradrenergic agonist, have been shown to improve locomotion after spinal cord injury. We speculate that transmission in load pathways, which are involved in body support during stance, is specifically modified by training. This was evaluated by comparing two groups of spinal cats; one group (n= 11) was trained to walk until full-weight-bearing (3–4 weeks), and the other (shams;n= 7) was not. During an acute experiment, changes in group I pathways, monosynaptic excitation, disynaptic inhibition, and polysynaptic excitation were investigated by measuring the response amplitude in extensor motoneurons before and after clonidine injection. Monosynaptic excitation was not modified by clonidine but was decreased significantly by training. Disynaptic inhibition was significantly decreased by clonidine in both groups, but more significantly in trained cats, and significantly reduced by training after clonidine. Also, clonidine could reverse group IB inhibition into polysynaptic excitation in both groups but more frequently in trained cats. We also investigated whether fictive stepping revealed additional changes. In trained cats, the phase-dependent modulation of all three responses was similar to patterns reported previously, but in shams, modulation of monosynaptic and polysynaptic responses was not. Overall, training appears to decrease monosynaptic excitation and enhance the effects of clonidine in the reduction of disynaptic inhibition and reversal to polysynaptic excitation. Because it is believed that polysynaptic excitatory group I pathways transmit locomotor drive to extensor motoneurons, we suggest that the latter changes would facilitate the recruitment of extensor muscles for recovering weight-bearing during stepping.
Dopamine Modulates Cell Cycle in the Lateral Ganglionic Eminence
Authors: Ohtani Nobuyo , Goto Tomohide , Waeber Christian , Bhide Pradeep G.
Published: April 2018

Dopamine is a neuromodulator the functions of which in the regulation of complex behaviors such as mood, motivation, and attention are well known. Dopamine appears in the brain early in the embryonic period when none of those behaviors is robust, raising the possibility that dopamine may influence brain development. The effects of dopamine on specific developmental processes such as neurogenesis are not fully characterized. The neostriatum is a dopamine-rich region of the developing and mature brain. If dopamine influenced neurogenesis, the effects would likely be pronounced in the neostriatum. Therefore, we examined whether dopamine influenced neostriatal neurogenesis by influencing the cell cycle of progenitor cells in the lateral ganglionic eminence (LGE), the neuroepithelial precursor of the neostriatum. We show that dopamine arrives in the LGE via the nigrostriatal pathway early in the embryonic period and that neostriatal neurogenesis progresses in a dopamine-rich milieu. Dopamine D1-like receptor activation reduces entry of progenitor cells from the G1- to S-phase of the cell cycle, whereas D2-like receptor activation produces the opposite effects by promoting G1- to S-phase entry. D1-like effects are prominent in the ventricular zone, and D2-like effects are prominent in the subventricular zone. The overall effects of dopamine on the cell cycle are D1-like effects, most likely because of the preponderance of D1-like binding sites in the embryonic neostriatum. These data reveal a novel developmental role for dopamine and underscore the relevance of dopaminergic signaling in brain development.
Nucleus Accumbens μ-Opioids Regulate Intake of a High-Fat Diet via Activation of a Distributed Brain Network
Authors: Will M. J. , Franzblau E. B. , Kelley A. E.
Published: April 2018

Endogenous opioid peptides within the nucleus accumbens, a forebrain site critical for the regulation of reward-related behavior, are believed to play an important role in the control of appetite. In particular, this system is thought to mediate the hedonic aspects of food intake, governing the positive emotional response to highly palatable food such as fat and sugar. Previous work has shown that intra-accumbens administration of the μ-opioid agonistd-Ala2,Nme-Phe4,Glyol5-enkephalin (DAMGO) markedly increases food intake and preferentially enhances the intake of palatable foods such as fat, sucrose, and salt. Using information from recently performed c-fosmapping experiments, we sought to explore the involvement of structures efferent to the nucleus accumbens in this feeding response. Free-feeding rats with dual sets of bilateral cannulas aimed at the nucleus accumbens and one of several output structures were infused with DAMGO (0, 0.25 μg/0.5 μl) in the accumbens, and fat intake was measured over a 2 hr period. Concurrent temporary inactivation with the GABAAagonist muscimol (5–20 ng/0.25 μl) of the dorsomedial hypothalamic nucleus, lateral hypothalamus, ventral tegmental area, or the intermediate region of the nucleus of the solitary tract blocked the robust increase in fat intake induced by intra-accumbens DAMGO at doses of muscimol that did not affect general motor activity. Muscimol alone also inhibited and augmented baseline fat intake in the lateral and dorsomedial hypothalamic nuclei, respectively. These results suggest that intake of energy-dense palatable food is controlled by activity in a neural network linking ventral striatal opioids with diencephalic and brainstem structures.
On the Transmission of Rate Code in Long Feedforward Networks with Excitatory–Inhibitory Balance
Authors: Litvak Vladimir , Sompolinsky Haim , Segev Idan , Abeles Moshe
Published: April 2018

The capability of feedforward networks composed of multiple layers of integrate-and-fire neurons to transmit rate code was examined. Synaptic connections were made only from one layer to the next, and excitation was balanced by inhibition. When time is discrete and the synaptic potentials rise instantaneously, we show that, for random uncorrelated input to layer one, the mean rate of activity in deep layers is essentially independent of input firing rate. This implies that the input rate cannot be transmitted reliably in such feedforward networks because neurons in a given layer tend to synchronize partially with each other because of shared inputs. As a result of this synchronization, the average firing rate in deep layers will either decay to zero or reach a stable fixed point, depending on model parameters. When time is treated continuously and the synaptic potentials rise instantaneously, these effects develop slowly, and rate transmission over a limited number of layers is possible. However, the correlations among neurons at the same layer hamper reliable assessment of firing rate by averaging over 100 msec (or less). When the synaptic potentials develop gradually, as is the realistic case, transmission of rate code fails. In a network in which inhibition only balances the mean excitation but is not timed precisely with it, neurons in each layer fire together, and this volley successively propagates from layer to layer. We conclude that the transmission of rate code in feedforward networks is highly unlikely.
Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation
Authors: Schäfers Maria , Lee Doo H. , Brors Dominik , Yaksh Tony L. , Sorkin Linda S.
Published: April 2018

Tumor necrosis factor-α (TNF) is upregulated after nerve injury, causes pain on injection, and its blockade reduces pain behavior resulting from nerve injury; thus it is strongly implicated in neuropathic pain. We investigated responses of intact and nerve-injured dorsal root ganglia (DRG) neurons to locally applied TNF using parallelin vivoandin vitroparadigms.In vivo, TNF (0.1–10 pg/ml) or vehicle was injected into L5 DRG in naive rats and in rats that had received L5 and L6 spinal nerve ligation (SNL) immediately before injection. In naive rats, TNF, but not vehicle, elicited long-lasting allodynia. In SNL rats, subthreshold doses of TNF synergized with nerve injury to elicit faster onset of allodynia and spontaneous pain behavior. Tactile allodynia was present in both injured and adjacent uninjured (L4) dermatomes. Preemptive treatment with the TNF antagonist etanercept reduced SNL-induced allodynia by almost 50%.In vitro, the electrophysiological responses of naive, SNL-injured, or adjacent uninjured DRG to TNF (0.1–1000 pg/ml) were assessed by single-fiber recordings of teased dorsal root microfilaments.In vitroperfusion of TNF (100–1000 pg/ml) to naive DRG evoked short-lasting neuronal discharges. In injured DRG, TNF, at much lower concentrations, elicited earlier onset, markedly higher, and longer-lasting discharges. TNF concentrations that were subthreshold in naive DRG also elicited high-frequency discharges when applied to uninjured, adjacent DRG. We conclude that injured and adjacent uninjured DRG neurons are sensitized to TNF after SNL. Sensitization to endogenous TNF may be essential for the development and maintenance of neuropathic pain.
Temporal Masking Reveals Properties of Sound-Evoked Inhibition in Duration-Tuned Neurons of the Inferior Colliculus
Authors: Faure Paul A. , Fremouw Thane , Casseday John H. , Covey Ellen
Published: April 2018

The inferior colliculus (IC) is the first place in the central auditory pathway where duration-selective neurons are found. Previous neuropharmacological and electrophysiological studies have shown that they are created there and have led to a conceptual model in which excitatory and inhibitory inputs are offset in time so that the cell fires only when sound duration is such that onset- and offset-evoked excitation coincide; the response is suppressed by inhibition at other durations. We tested predictions from the model using paired tone stimulation and extracellular recording in the IC of the big brown bat,Eptesicus fuscus. Responses to a best duration (BD) tone were used as a probe to examine the strength and time course of inhibition activated by a nonexcitatory (NE) tone of the same frequency but differing in duration. As the relative time between the BD and NE tones was varied, the activity evoked by the BD tone was affected in ways comparable with backward, simultaneous, and forward masking. Responses to the BD tone were completely suppressed at short interstimulus intervals when the BD tone preceded the NE tone. Suppression was also seen when the stimuli temporally overlapped and summed and at intervals when the BD tone followed the NE tone. The results show that duration-selective neurons receive an onset-evoked, inhibitory input that precedes their excitatory input. The period of leading inhibition was correlated with BD and first spike latency. The results suggest how inhibition in the CNS could explain temporal masking phenomena, including backward masking.
System Identification Applied to a Visuomotor Task: Near-Optimal Human Performance in a Noisy Changing Task
Authors: Baddeley R. J. , Ingram H. A. , Miall R. C.
Published: April 2018

Sensory-motor integration has frequently been studied using a single-step change in a control variable such as prismatic lens angle and has revealed human visuomotor adaptation to often be partial and inefficient. We propose that the changes occurring in everyday life are better represented as the accumulation of many smaller perturbations contaminated by measurement noise. We have therefore tested human performance to random walk variations in the visual feedback of hand movements during a pointing task. Subjects made discrete targeted pointing movements to a visual target and received terminal feedback via a cursor the position of which was offset from the actual movement endpoint by a random walk element and a random observation element. By applying ideal observer analysis, which for this task compares human performance against that of a Kalman filter, we show that the subjects' performance was highly efficient with Fisher efficiencies reaching 73%. We then used system identification techniques to characterize the control strategy used. A “modified” delta-rule algorithm best modeled the human data, which suggests that they estimated the random walk perturbation of feedback in this task using an exponential weighting of recent errors. The time constant of the exponential weighting of the best-fitting model varied with the rate of random walk drift. Because human efficiency levels were high and did not vary greatly across three levels of observation noise, these results suggest that the algorithm the subjects used exponentially weighted recent errors with a weighting that varied with the level of drift in the task to maintain efficient performance.
Convergent Mechanisms Mediate Preparatory States and Repetition Priming in the Feeding Network ofAplysia
Authors: Proekt Alex , Weiss Klaudiusz R.
Published: April 2018

Improvement of behavioral responses to expected stimuli has been attributed to a change in the preparatory state. In this study, we take advantage of the accessibility of the nervous system ofAplysiaand develop anin vitroanalog of the preparatory state for feeding behaviors. We provide evidence that the change in the preparatory state may be elicited initially by activity of identified serotonergic metacerebral cells (MCCs). We demonstrate, however, that the preparatory state is maintained through MCC-independent repetition priming that is embedded in the properties of the behavior-generating network. Both MCC-dependent and MCC-independent processes converge on the same site in the behavior-generating network to mediate the change in the preparatory state. Thus, we propose a model of how multiple neuronal structures interact to elicit and maintain changes in the preparatory states in the CNS.