bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relay of High-Frequency Sensory Signals in the Whisker-to-Barreloid Pathway
Authors: Deschênes Martin , Timofeeva Elena , Lavallée Philippe
Published: April 2018

The present study investigated the operational features of whisker-evoked EPSPs in barreloid cells and the ability of the whisker-to-barreloid pathway to relay high rates of whisker deflection in lightly anesthetized rats. Results show that lemniscal EPSPs are single-fiber events with fast rise times (<500 μsec) that strongly depress at short inter-EPSP intervals. They occur at short latencies (3.84 ± 0.96 msec) with little jitters (<300 μsec) after electrical stimulation of the whisker follicle. Waveform analysis indicates that one to three lemniscal axons converge on individual barreloid cells to produce EPSPs of similar rise times but different amplitudes. When challenged by high rates of whisker deflection, cells in the whisker-to-barreloid pathway demonstrate a remarkable frequency-following ability. Primary vibrissa afferents could follow in a phase-locked manner trains of sinusoidal deflections at up to 1 kHz. Although trigeminothalamic cells could still faithfully follow deflection rates of 200-300 Hz, the actual frequency-following ability of individual cells depends on the amplitude, velocity, and direction of displacements. The discharges of trigeminothalamic cells induce corresponding phase-locked EPSPs in barreloid cells, which trigger burst discharges at stimulus onset. During the following cycles of the stimulus train, few action potentials ensue because of the strong synaptic depression at lemniscal synapses. It is concluded that the whisker-to-barreloid pathway can relay vibratory inputs with a high degree of temporal precision, but that the relay of this information to the cerebral cortex requires the action of modulators, and possibly phase-locked discharges among an ensemble of relay cells.
Response Suppression in V1 Agrees with Psychophysics of Surround Masking
Authors: Zenger-Landolt Barbara , Heeger David J.
Published: April 2018

When a target stimulus is embedded in a high contrast surround, the target appears reduced in contrast and is harder to detect, and neural responses in visual cortex are suppressed. We used functional magnetic resonance imaging (fMRI) and psychophysics to quantitatively compare these physiological and perceptual effects. Observers performed a contrast discrimination task on a contrast-reversing sinusoidal target grating. The target was either presented in isolation or embedded in a high-contrast surround. While observers performed the task, we also measured fMRI responses as a function of target contrast, both with and without a surround. We found that the surround substantially increased the psychophysical thresholds while reducing fMRI responses. The two data sets were compared, on the basis of the assumption that a fixed response difference is required for correct discrimination, and we found that the psychophysics accounted for 96.5% of the variance in the measured V1 responses. The suppression in visual areas V2 and V3 was stronger, too strong to agree with psychophysics. The good quantitative agreement between psychophysical thresholds and V1 responses suggests V1 as a plausible candidate for mediating surround masking.
Presynaptic Calcium Stores Modulate Afferent Release in Vestibular Hair Cells
Authors: Lelli Andrea , Perin Paola , Martini Marta , Ciubotaru Catalin D. , Prigioni Ivo , Valli Paolo , Rossi Maria L. , Mammano Fabio
Published: April 2018

Hair cells, the mechanoreceptors of the acoustic and vestibular system, are presynaptic to primary afferent neurons of the eighth nerve and excite neural activity by the release of glutamate. In the present work, the role played by intracellular Ca2+stores in afferent transmission was investigated, at the presynaptic level, by monitoring changes in the intracellular Ca2+concentration ([Ca2+]i) in vestibular hair cells, and, at the postsynaptic level, by recording from single posterior canal afferent fibers. Application of 1-10 mmcaffeine to hair cells potentiated Ca2+responses evoked by depolarization at selected Ca2+hot spots, and also induced a graded increase in cell membrane capacitance (ΔCm), signaling exocytosis of the transmitter. Ca2+signals evoked by caffeine peaked in a region located ∼10 μm from the base of the hair cell. [Ca2+]iincreases, similarly localized, were observed after 500 msec depolarizations, but not with 50 msec depolarizations, suggesting the occurrence of calcium-induced calcium release (CICR) from the same stores. Both Ca2+and ΔCmresponses were inhibited after incubation with ryanodine (40 μm) for 8-10 min. Consistent with these results, afferent transmission was potentiated by caffeine and inhibited by ryanodine both at the level of action potentials and of miniature EPSPs (mEPSPs). Neither caffeine nor ryanodine affected the shape and amplitude of mEPSPs, indicating that both drugs acted at the presynaptic level. These results strongly suggest that endogenous modulators of the CICR process will affect afferent activity elicited by mechanical stimuli in the physiological frequency range.
DNA Synthesis and Neuronal Apoptosis Caused by Familial Alzheimer Disease Mutants of the Amyloid Precursor Protein Are Mediated by the p21 Activated Kinase PAK3
Authors: McPhie Donna L. , Coopersmith Robert , Hines-Peralta Andrew , Chen Yuzhi , Ivins Kathryn J. , Manly Susan P. , Kozlowski Michael R. , Neve Kim A. , Neve Rachael L.
Published: April 2018

Apoptotic pathways and DNA synthesis are activated in neurons in the brains of individuals with Alzheimer disease (AD). However, the signaling mechanisms that mediate these events have not been defined. We show that expression of familial AD (FAD) mutants of the amyloid precursor protein (APP) in primary neurons in culture causes apoptosis and DNA synthesis. Both the apoptosis and the DNA synthesis are mediated by the p21 activated kinase PAK3, a serine-threonine kinase that interacts with APP. A dominant-negative kinase mutant of PAK3 inhibits the neuronal apoptosis and DNA synthesis; this effect is abolished by deletion of the PAK3 APP-binding domain or by coexpression of a peptide representing this binding domain. The involvement of PAK3 specifically in FAD APP-mediated apoptosis rather than in general apoptotic pathways is suggested by the facts that a dominant-positive mutant of PAK3 does not alone cause neuronal apoptosis and that the dominant-negative mutant of PAK3 does not inhibit chemically induced apoptosis. Pertussis toxin, which inactivates the heterotrimeric G-proteins Goand Gi, inhibits the apoptosis and DNA synthesis caused by FAD APP mutants; the apoptosis and DNA synthesis are rescued by coexpression of a pertussis toxin-insensitive Go. FAD APP-mediated DNA synthesis precedes FAD APP-mediated apoptosis in neurons, and inhibition of neuronal entry into the cell cycle inhibits the apoptosis. These data suggest that a normal signaling pathway mediated by the interaction of APP, PAK3, and Gois constitutively activated in neurons by FAD mutations in APP and that this activation causes cell cycle entry and consequent apoptosis.
Formation of Whisker-Related Principal Sensory Nucleus-Based Lemniscal Pathway Requires a Paired Homeodomain Transcription Factor,Drg11
Authors: Ding Yu-Qiang , Yin Jun , Xu Hai-Ming , Jacquin Mark F. , Chen Zhou-Feng
Published: April 2018

Little is known about the molecular mechanisms underlying the formation of the principal sensory nucleus (PrV) of the trigeminal nerve, a major relay station for somatotopic pattern formation in the trigeminal system. Here, we show that mice lackingDrg11, a homeodomain transcription factor, exhibit defects within the PrV, which include an aberrant distribution ofDrg11-/-cells, altered expression of a molecular marker, unusual projections of primary afferents from trigeminal ganglion cells, and, subsequently, increased cell death. In addition, surviving PrV cells exhibit delayed and more spatially restricted ascending projections to the ventral posterior medial nucleus of the thalamus (VPm). These early embryonic abnormalities in the PrV lead to the failure to develop whisker-related patterns in the PrV, VPm, and somatosensory cortex. By contrast, somatotopic patterns exist in the spinal trigeminal subnuclei interpolaris (SpVi) and subnuclei caudalis (SpVc) and the dorsal column nucleus-based lemniscal and cortical pathway. Thus, the deficits in the trigeminal system ofDrg11-/-mice are specific to the PrV. Our results demonstrate thatDrg11is essential for proper cellular differentiation and, subsequently, for the formation of the whisker-related lemniscal and cortical structures.
Stress-Related Modulation of Hippocampal Long-Term Potentiation in Rats: Involvement of Adrenal Steroid Receptors
Authors: Korz Volker , Frey Julietta U.
Published: April 2018

Stress is usually correlated with an increased release of glucocorticoids from the adrenal glands. Within the hippocampus, a structure long known to be involved in spatial learning, two corticosterone-binding receptors are identified: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Activation of these receptors impairs or facilitates hippocampal long-term potentiation (LTP), respectively. Stress elicited by behavioral manipulations may interfere with cognitive modulations of LTP during learning experiments. Here, we explore the influence of two stress-inducing procedures, handling and swimming, on the maintenance of dentate gyrus LTP in the rat induced by a weak tetanization of the perforant path. Manipulations started 15 min after tetanization. Handling alone resulted in a complete reversal of LTP. Handling followed by a 2 min swim in a water tank elicited prolonged protein synthesis but not β-adrenergic-dependent LTP compared with either control or handled animals. Blockade of the GRs but not of the MRs prevented the reversal of LTP by handling. Inactivation of the MRs but not of the GRs hindered LTP prolongation by swimming. Because the activated receptor complexes act as transcription factors, MR- and GR-related proteins may play a role in the maintenance of LTP. The data suggest a complex interplay of corticosterone-binding receptors on modulations of hippocampal LTP and thus, of stress on learning and functional plasticity in general.
The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation
Authors: Einat Haim , Yuan Peixiong , Gould Todd D. , Li Jianling , Du JianHua , Zhang Lei , Manji Husseini K. , Chen Guang
Published: April 2018

The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.
p38 MAP Kinase Mediates Both Short-Term and Long-Term Synaptic Depression inAplysia
Authors: Guan Zhonghui , Kim Joung-Hun , Lomvardas Stavros , Holick Kerri , Xu Shiqin , Kandel Eric R. , Schwartz James H.
Published: April 2018

AtAplysiasensory-to-motor neuron synapses, the inhibitory neuropeptide Phe-Met-Arg-Phe-NH2(FMRFa) produces depression, and serotonin (5-HT) produces facilitation. Short-term depression has been found to result from the activation of a phospholipase A2. The released arachidonate is metabolized by 12-lipoxygenase to active second messengers. We find that FMRFa leads to the phosphorylation and activation of p38 mitogen-activated protein (MAP) kinase. Short-term depression and the release of arachidonate are blocked by the specific p38 kinase inhibitor SB 203580. Both the inhibitor and an affinity-purified antibody raised against recombinantAplysiap38 kinase injected into sensory neurons prevented long-term depression, which depends on the phosphorylation of translation factors cAMP response element-binding protein 2 (CREB2) and activating transcription factor 2. Facilitation produced by 5-HT, on the other hand, inactivates p38 kinase. Chromatin immunoprecipitation assays indicate that p38 kinase activates CREB2. p38 kinase also is pivotal in the bidirectional regulation of synaptic plasticity: when the kinase is inhibited, brief treatment with 5-HT that normally produces only short-term facilitation now results in long-term facilitation. Conversely, in sensory neurons injected with the activated kinase, long-term facilitation is blocked, and brief exposure to FMRFa, which normally results in short-term depression, results in long-term depression. We conclude that p38 kinase, which itself is bidirectionally regulated by FMRFa and 5-HT, acts as a modulator of synaptic plasticity by positively regulating depression and serving as an inhibitory constraint for facilitation.
p75 Neurotrophin Receptor Protects Primary Cultures of Human Neurons against Extracellular Amyloid β Peptide Cytotoxicity
Authors: Zhang Yan , Hong Yanguo , Bounhar Younes , Blacker Megan , Roucou Xavier , Tounekti Omar , Vereker Emily , Bowers William J. , Federoff Howard J. , Goodyer Cynthia G. , LeBlanc Andréa
Published: April 2018

The cytotoxicity of extracellular amyloid β peptide (Aβ) has been clearly demonstrated in many cell types. In contrast, primary human neurons in culture are resistant to extracellular Aβ-mediated toxicity. Here, we investigate the involvement of p75 neurotrophin receptor (p75NTR) in Aβ-treated human neurons. We find that Aβ1-40and Aβ1-42, but not the reverse control peptide, Aβ40-1, rapidly increase the levels of p75NTRin a specific and dose-dependent manner. In contrast to observations in cell lines, enhanced expression of p75NTRin human neurons via a herpes simplex virus amplicon vector does not increase the susceptibility of neurons to Aβ. Unexpectedly, inhibition of p75NTRexpression with an antisense expression construct or incubation of the cells with an antibody to the extracellular domain of p75NTRsensitizes human neurons to extracellular nonfibrillar or fibrillar Aβ1-42cytotoxicity. Unlike intracellular Aβ, extracellular Aβ toxicity is independent of p53 and Bax activity. However, Aβ toxicity is inhibited by caspase inhibitors and the glycogen synthase kinase 3β inhibitor lithium. Neuroprotection against Aβ is phosphatidylinositide 3-kinase dependent but Akt independent. These results are consistent with a neuroprotective role for p75NTRagainst extracellular Aβ toxicity in human neurons.
Altered Aβ Formation and Long-Term Potentiation in a Calsenilin Knock-Out
Authors: Lilliehook Christina , Bozdagi Ozlem , Yao Jun , Gomez-Ramirez Manuel , Zaidi Nikhat F. , Wasco Wilma , Gandy Sam , Santucci Anthony C. , Haroutunian Vahram , Huntley George W. , Buxbaum Joseph D.
Published: April 2018

Calsenilin has been identified as a presenilin-binding protein, a transcription factor regulating dynorphin expression, and a β-subunit of Kv4 channels and could, thus, be a multifunctional protein. To study these functions of calsenilinin vivoand to determine the neuroanatomical expression pattern of calsenilin, we generated mice with a disruption of the calsenilin gene by the targeted insertion of the β-galactosidase gene. We found that calsenilin expression (as represented by β-galactosidase activity) is very restricted but overlaps better with that of presenilins and Kv4 channels than with dynorphin, suggesting that calsenilin may regulate presenilin and Kv4 channels in brain. Aβ peptide levels are reduced in calsenilin knock-out mice, demonstrating that calsenilin affects presenilin-dependent γ-cleavagein vivo. Furthermore, long-term potentiation (LTP) in dentate gyrus of hippocampus, in which calsenilin is strongly and selectively expressed, is enhanced in calsenilin knock-out mice. This enhancement of LTP coincides with a downregulation of the Kv4 channel-dependent A-type current and can be mimicked in wild-type animals by a Kv4 channel blocker. The data presented here show that lack of calsenilin affects both Aβ formation and the A-type current. We suggest that these effects are separate events, caused by a common mechanism possibly involving protein transport.
sup-9, sup-10, andunc-93May Encode Components of a Two-Pore K+Channel that Coordinates Muscle Contraction inCaenorhabditis elegans
Authors: de la Cruz Ignacio Perez , Levin Joshua Z. , Cummins Claudia , Anderson Philip , Horvitz H. Robert
Published: April 2018

Genetic studies ofsup-9, unc-93, andsup-10strongly suggest that these genes encode components of a multi-subunit protein complex that coordinates muscle contraction inCaenorhabditis elegans. We clonedsup-9andsup-10and found that they encode a two-pore K+channel and a novel transmembrane protein, respectively. We also found that UNC-93 and SUP-10 colocalize with SUP-9 within muscle cells, and that UNC-93 is a member of a novel multigene family that is conserved amongC. elegans, Drosophila, and humans. Our results indicate that SUP-9 and perhaps other two-pore K+channels function as multiprotein complexes, and that UNC-93 and SUP-10 likely define new classes of ion channel regulatory proteins.
Encoding of Whisker Vibration by Rat Barrel Cortex Neurons: Implications for Texture Discrimination
Authors: Arabzadeh Ehsan , Petersen Rasmus S. , Diamond Mathew E.
Published: April 2018

Rats, using their whiskers, have excellent capabilities in texture discrimination. What is the representation of texture in rat somatosensory cortex? We hypothesize that as rats “whisk” over a surface, the spatial frequency of a grooved or pebbled texture is converted to a temporal frequency of whisker vibration. Surface features such as groove depth or grain size modulate the amplitude of this vibration. Validation of the hypothesis depends on showing that vibration parameters have distinct neuronal representations in cortex. To test this, we delivered sinusoidal vibrations to the whisker shaft and analyzed cortical neuronal activity. Seven amplitudes and seven frequencies were combined to construct 49 stimuli while recording activity through a 10 × 10 microelectrode array inserted into the middle layers of barrel cortex. We find that cortical neurons do not explicitly encode vibration frequency (f) or amplitude (A) by any coding measure (average spike counts over different time windows, spike timing patterns in the peristimulus time histograms or in autocorrelograms). Instead, neurons explicitly encode the product of frequency and amplitude, which is proportional to the mean speed of the vibration. The quantityAfis an invariant because neuronal response encodes this feature independently of the values of the individual termsAandf. This was true across a wide time scale of firing rate measurements, from 5 to 500 msec. We conclude that vibration kinetics are rapidly and reliably encoded in the firing rate of cortical ensembles. Therefore, the cortical representation of vibration speed could underlie texture discrimination.
Involvement of AMPA Receptor GluR2 Subunits in Stimulus-Reward Learning: Evidence from Glutamate Receptorgria2Knock-Out Mice
Authors: Mead Andy N. , Stephens David N.
Published: April 2018

Presence of the glutamate receptor 2 (GluR2) subunit prevents calcium influx through AMPA-receptor complexes; deletion of this subunit results in enhanced hippocampal long-term potentiation. We investigated whether mice lacking the GluR2 subunit [gria2knock-out (KO) mice] displayed impairments in learning stimulus-reward associations, and the subsequent ability of reward-paired cues to control motivated behavior. Bothgria2KO and wild-type (WT) mice learned to associate a light/tone stimulus with food delivery, as evidenced by approach toward the food magazine after the presentation of the cues (pavlovian conditioning). Subsequently, the cues also served to reinforce an operant response in both KO and WT mice (conditioned reinforcement), although response rates were greater ingria2KOs. Responding for conditioned reinforcement was enhanced after 0.5 mg/kg amphetamine administration in WT mice, but not in KO mice. The ability of the cues to elicit approach behavior (conditioned approach) and to enhance responding for the reward (pavlovian-to-instrumental transfer; PIT) were also impaired ingria2KO mice. This pattern of behavior resembles that seen after lesions of the central nucleus of the amygdala (CeA), an area rich in GluR2-containing AMPA receptors. Immunostaining revealed reduced GluR1 expression within both the basolateral amygdala and the CeA, suggesting that the behavioral deficits observed were unlikely to be caused by compensatory changes in GluR1. These results suggest that GluR2-containing AMPA receptors, possibly within the CeA, are critical for the formation of stimulus-reward associations necessary for PIT and conditioned approach, but are not involved in the plastic processes underlying the attribution of motivational value to the conditioned stimulus (CS).
Thalamocortical Angular Tuning Domains within Individual Barrels of Rat Somatosensory Cortex
Authors: Bruno Randy M. , Khatri Vivek , Land Peter W. , Simons Daniel J.
Published: April 2018

In the rodent somatosensory cortex, whisker-related barrels in layer IV are morphological counterparts of functional cortical columns that extend throughout the cortical depth. We used microelectrode recordings and spike-triggered averaging of field potentials evoked by single thalamic barreloid neurons to investigate functional thalamocortical microcircuits. The function of such circuits was probed by deflecting the principal whisker of a barrel in different angular directions. We found that individual barrels contain minicolumns of neurons preferring the same deflection angle. Angular tuning domains are established by convergent inputs from thalamocortical cells with corresponding angular preferences. Processing within such domains may depend on local connectivity among vertically aligned barrel neurons.
Prolonged Habituation of the Gill-Withdrawal Reflex inAplysiaDepends on Protein Synthesis, Protein Phosphatase Activity, and Postsynaptic Glutamate Receptors
Authors: Ezzeddine Youssef , Glanzman David L.
Published: April 2018

Despite representing perhaps the simplest form of memory, habituation is not yet well understood mechanistically. We used a reduced preparation to analyze the neurobiological mechanisms of persistent habituation of a simple behavior, the defensive withdrawal reflex of the marine snailAplysia californica. This preparation permits direct infusion of drugs into the abdominal ganglion during training via a cannula in the abdominal artery. Using siphon-elicited gill withdrawal, we demonstrate habituation of withdrawal that persists for 1-6 hr after repeated, spaced blocks of habituating stimulation. This form of habituation exhibits site specificity and requires protein synthesis because it is blocked by the presence of anisomycin, a protein synthesis inhibitor. We also find that habituation of gill withdrawal requires protein phosphatase activity, because it is blocked by okadaic acid, an inhibitor of protein phosphatase. Finally, habituation of gill withdrawal requires activation of NMDA-type and AMPA-type postsynaptic receptors within the abdominal ganglion, because it is blocked by infusion ofdl-2-amino-5-phosphonovaleric acid or 6,7-dinitroquinoxaline-2,3-dione. The requirement for activation of postsynaptic glutamatergic receptors indicates that homosynaptic depression, an exclusively presynaptic mechanism that has been implicated previously in habituation inAplysia, does not play a significant role in persistent habituation of the withdrawal reflex. Our results indicate that postsynaptic mechanisms, possibly including modulation of glutamate receptor function, play a major, heretofore unsuspected, role in habituation inAplysia.
A Mechanism for the Direct Regulation of T-Type Calcium Channels by Ca2+/Calmodulin-Dependent Kinase II
Authors: Welsby Philip J. , Wang Hongge , Wolfe Joshua T. , Colbran Roger J. , Johnson Michael L. , Barrett Paula Q.
Published: April 2018

Low-voltage-activated (LVA) Ca2+channels are widely distributed throughout the CNS and are important determinants of neuronal excitability, initiating dendritic and somatic Ca2+spikes that trigger and shape the pattern of action potential firing. Here, we define a molecular mechanism underlying the dynamic regulation of α1Hchannels (Cav3.2), by Ca2+/CaM-dependent protein kinase II (CaMKII). We show that channel regulation is selective for the LVA α1HCa2+channel subtype, depends on determinants in the α1HII-III intracellular loop, and requires the phosphorylation of a serine residue absent from unregulated α1G(Cav3.1) channels. These studies identify the α1Hchannel as a new substrate for CaMKII and provide the first molecular mechanism for the direct regulation of T-type Ca2+channels by a protein kinase. Our data suggest a novel mechanism for modulating the integrative properties of neurons.
Lidocaine Inactivation of Ventral Subiculum Attenuates Cocaine-Seeking Behavior in Rats
Authors: Sun WenLin , Rebec George V.
Published: April 2018

The role of the ventral subiculum in cocaine- or cue-induced cocaine-seeking behavior was investigated in rats tested on a between-session reinstatement model. Rats were trained to self-administer cocaine (0.25 mg/infusion, i.v.) in a lever-pressing operant task in a daily 2 hr session. Responding was reinforced contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after the lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Bilateral microinjections of lidocaine (100 μg) into the ventral subiculum decreased cocaine- or cue-induced reinstatement of cocaine-seeking behavior compared with saline microinjections into the same area in another group of rats. Lidocaine microinjections, however, had no effect on cocaine self-administration behavior or food-maintained or food-reinstated responding. Collectively, these results suggest that the ventral subiculum plays an important role in cocaine-seeking behavior. Considering the role of this structure in context learning, our data suggest that the full expression of cocaine- or cue-induced reinstatement may depend on the context in which the cocaine experience occurred.
Mediation of Amphetamine-Induced Long-Term Depression of Synaptic Transmission by CB1Cannabinoid Receptors in the Rat Amygdala
Authors: Huang Ya-Chun , Wang Su-Jane , Chiou Lih-Chu , Gean Po-Wu
Published: April 2018

The amygdala is thought to mediate memory consolidation of amphetamine-induced conditioned place preference, a behavioral paradigm that requires memory for an association between environmental cues and the affective state produced by the drug treatment. Here we show that amphetamine induces long-term synaptic depression (LTD) in the amygdala. Amphetamine LTD is not affected by dopamine, serotonin 1A, and norepinephrine α2 receptor antagonists but is blocked by the cannabinoid CB1receptor antagonist AM251. It is mimicked by the CB1agonistWIN55212-2 and facilitated and partially occluded by endocannabinoid uptake inhibitor AM404. Both amphetamine andWIN55212-2 LTDs are associated with an increase in the ratio of paired-pulse facilitation and a decrease in the frequency but not the amplitude of miniature EPSCs. They are also sensitive to block by P/Q type calcium channel blocker and occluded by each other, indicating that these two forms of synaptic plasticity share a common underlying mechanism. Loading postsynaptic neuron with calcium chelator blocked amphetamine LTD in some but not all neurons tested. However, in the presence of AM404, amphetamine LTD was present in all neurons recorded. These results suggest that amphetamine-induced endocannabinoid release depends on a rise in intracellular calcium and the incomplete block of LTD in some neurons may be attributable to the spillover of endocannabinoid from nearby cells. The finding that endocannabinoids underlie the synaptic actions of amphetamine may open a new avenue for the treatment of psychostimulants addiction.
Lesions of Mature Barrel Field Cortex Interfere with Sensory Processing and Plasticity in Connected Areas of the Contralateral Hemisphere
Authors: Rema V. , Ebner Ford F.
Published: April 2018

Lesions of primary sensory cortex produce impairments in brain function as an outcome of the direct tissue damage. In addition, indirect lesion effects have been described that consist of functional deficits in areas sharing neural connections with the damaged area. The present study characterizes interhemispheric deficits produced as a result of unilateral lesions of the entire vibrissa representation of S-I barrel field cortex (BFC) in adult rats using single-neuron recording under urethane anesthesia. After unilateral lesions of adult BFC, responses of neurons in the contralateral homotopic BFC are severely depressed. Background (spontaneous) activity is reduced by ∼80%, responses to test stimuli applied to the whiskers are reduced by ∼50%, and onset of synaptic plasticity induced by trimming all but two whiskers (“whisker-pairing plasticity”) is delayed over sevenfold compared with sham-lesion control animals. These deficits persist with only slight improvement for at least 4 months after lesion. Both fast-spiking and regular-spiking neuron responses are diminished contralateral to the lesion, as are cells above, below, and within the cortical barrels. Enriched environment experience increased the magnitude of responses and accelerated the rate of synaptic plasticity but did not restore response magnitude to control levels. Deficiencies in evoked responses and synaptic plasticity are primarily restricted to areas that share direct axonal connections with the lesioned cortex, because equivalently sized lesions of visual cortex produce minimal deficits in contralateral BFC function. These results indicate that interhemispheric deficits consist of remarkable and persistent decrements in sensory processing at the single-neuron level and support the idea that the deficits are somehow linked to the shared neural connections with the area of brain damage.
Barrages of Synaptic Activity Control the Gain and Sensitivity of Cortical Neurons
Authors: Shu Yousheng , Hasenstaub Andrea , Badoual Mathilde , Bal Thierry , McCormick David A.
Published: April 2018

Ongoing synaptic activity, ever present in cortical neurons, may vary widely in its amplitude and characteristics, potentially having a strong influence on neuronal processing. Intracellular recordings in layer 5 pyramidal cells in prefrontal and visual cortical slices maintainedin vitrorevealed spontaneous periods of synaptic bombardment. Testing the responsiveness of these cortical cells to synaptic inputs or the injection of artificial excitatory postsynaptic conductances of various amplitudes revealed that background synaptic activity dramatically increased the probability of response to small inputs, decreased the slope of the input-output curve, and decreased both the latency and jitter of action potential activation. Examining the effects of different components of synaptic barrages (namely, depolarization, increase in membrane conductance, and increase in membrane potential variance) revealed that the effects observed were dominated by the membrane depolarization and increase in variance. Depolarization increased the peak cross-correlation between injected complexin vivo-like waveforms through enhancement of responsiveness to small inputs, whereas increases in variance did so through a shift in firing mode from one of threshold detection to probabilistic discharge. These results indicate that rapid increases in neuronal responsiveness, as well as increases in spike timing precision, can be achieved through balanced barrages of excitatory and inhibitory synaptic activity.
Localization of a β-Actin Messenger Ribonucleoprotein Complex with Zipcode-Binding Protein Modulates the Density of Dendritic Filopodia and Filopodial Synapses
Authors: Eom Taesun , Antar Laura N. , Singer Robert H. , Bassell Gary J.
Published: April 2018

The dendritic transport and local translation of mRNA may be an essential mechanism to regulate synaptic growth and plasticity. We investigated the molecular mechanism and function of β-actin mRNA localization in dendrites of cultured hippocampal neurons. Previous studies have shown that β-actin mRNA localization to the leading edge of fibroblasts or the growth cones of developing neurites involved a specific interaction between a zipcode sequence in the 3′ untranslated region and the mRNA-binding protein zipcode-binding protein-1 (ZBP1). Here, we show that ZBP1 is required for the localization of β-actin mRNA to dendrites. Knock-down of ZBP1 using morpholino antisense oligonucleotides reduced dendritic levels of ZBP1 and β-actin mRNA and impaired growth of dendritic filopodia in response to BDNF treatment. Transfection of an enhanced green fluorescent protein (EGFP)-β-actin construct, which contained the zipcode, increased the density of dendritic filopodia and filopodial synapses. Transfection of an EGFP construct, also with the zipcode, resulted in recruitment of endogenous ZBP1 and β-actin mRNA into dendrites and similarly increased the density of dendritic filopodia. However, the β-actin zipcode did not affect filopodial length or the density of mature spines. These results reveal a novel function for an mRNA localization element and its binding protein in the regulation of dendritic morphology and synaptic growth via dendritic filopodia.
Regulation of Exocytosis from Single Visualized GABAergic Boutons in Hippocampal Slices
Authors: Brager Darrin H. , Luther Paul W. , Erdélyi Ferenc , Szabó Gabor , Alger Bradley E.
Published: April 2018

Regulation of GABA release is crucial for normal brain functioning, and GABAA-mediated IPSCs are strongly influenced by repetitive stimulation and neuromodulation. However, GABA exocytosis has not been examined directly in organized tissue. Important issues remain outside the realm of electrophysiological techniques or are complicated by postsynaptic factors. For example, it is not known whether all presynaptic modulators affect release from all boutons in the same way, or whether modulator effects depend on the presence of certain types of voltage-gated calcium channels (VGCCs). To address such issues, we used confocal imaging and styryl dyes to monitor exocytosis from identified GABAergic boutons in organotypic hippocampal slice cultures. Repetitively evoked IPSCs declined more rapidly and completely than exocytosis, suggesting that depletion of filled vesicles cannot fully account for IPSC depression and underscoring the usefulness of directly imaging exocytosis. Stimulation at 10 Hz produced a transient facilitation of exocytosis that was dependent on L-type VGCCs. Using specific toxins, we found that release mediated via N-type and P-type VGCCs had similar properties. Neither baclofen nor a cannabinoid receptor agonist, CP55940, affected all boutons uniformly; they slowed release from some but completely prevented detectable release from others. Increasing stimulus frequency overcame this blockade of release. However, baclofen and CP55940 did not act identically, because only baclofen reduced facilitation and affected bouton releasing via P/Q-type VGCCs. Direct observation thus revealed novel features of GABAergic exocytosis and its regulation that would have been difficult or impossible to detect electrophysiologically. These features advance the understanding of the regulation of synapses and networks by presynaptic inhibition.
Estradiol Differentially Regulates c-Fos after Focal Cerebral Ischemia
Authors: Rau Shane W. , Dubal Dena B. , Böttner Martina , Wise Phyllis M.
Published: April 2018

Estrogen replacement therapy enhances mood, delays cognitive decline, and reduces the risk of neurodegeneration. Our laboratory has shown previously that pretreatment with low physiological levels of estradiol protects against middle cerebral artery occlusion (MCAO)-induced brain injury during late phases of neuronal cell death. Immediate early genes (IEGs) are induced by various forms of brain injury, and their induction is known to be a critical step in programmed cell death. The current study tested the hypothesis that the ability of estradiol to reduce MCAO-induced cell death involves attenuation of expression of one or more IEGs. We examined the effects of MCAO on the temporospatial pattern of IEG expression and the modulation of this pattern by estradiol replacement. Rats were ovariectomized and treated with either vehicle or low physiological concentrations of estradiol. One week later, rats underwent MCAO and brains were collected 1, 4, 8, 16, and 24 hr later. We assessed IEG mRNAs in discrete regions of brain by RT-PCR at 24 hr. We examined expression of c-Fos mRNA and protein in greater detail usingin situhybridization and immunohistochemistry to delineate the time course and specific regions of cortex in which estradiol influenced its expression. Our results reveal thatc-fos, fosB, c-jun, andjunBlevels were upregulated at 24 hr. Furthermore, estradiol selectively affected the expression of c-Fos mRNA and protein by attenuating the injury-induced increase in a time- and region-specific manner. Our findings strongly suggest that the ability of estradiol to protect against MCAO-induced cell death involves attenuation of c-Fos induction.
Glutamate Spillover in the Striatum Depresses Dopaminergic Transmission by Activating Group I Metabotropic Glutamate Receptors
Authors: Zhang Hui , Sulzer David
Published: April 2018

Cortical glutamate and substantia nigra dopamine (DA) afferents converge onto the dendritic spines of medium spiny neurons (MSNs) in the striatum where they act to modulate motor and cognitive functions. The released DA spills over from its synapse and is thought to regulate glutamatergic input by acting on distal DA receptors located on corticostriatal axon terminals. By monitoring evoked DA release directly using fast-scan cyclic voltammetry, we report a reciprocal modulation by glutamate spillover on evoked striatal DA release, induced by either glutamate uptake blockade or high-frequency stimulation of corticostriatal tracts. We demonstrate that this modulation is attributable to the activation of group I metabotropic glutamate receptors. Thus, under conditions in which glutamate escapes the confines of its synapse, it can elicit the presynaptic suppression of dopaminergic neurotransmission.
Emerging Role for Autophagy in the Removal of Aggresomes in Schwann Cells
Authors: Fortun Jenny , Dunn William A. , Joy Shale , Li Jie , Notterpek Lucia
Published: April 2018

The presence of protein aggregates in the nervous system is associated with various pathological conditions, yet their contribution to disease mechanisms is poorly understood. One type of aggregate, the aggresome, accumulates misfolded proteins destined for degradation by the ubiquitin-proteasome pathway. Peripheral myelin protein 22 (PMP22) is a short-lived Schwann cell (SC) protein that forms aggresomes when the proteasome is inhibited or the protein is overexpressed. Duplication, deletion, or point mutations inPMP22are associated with a host of demyelinating peripheral neuropathies, suggesting that, for normal SC cell function, the levels of PMP22 must be tightly regulated. Therefore, we speculate that mutant, misfolded PMP22 might overload the proteasome and promote aggresome formation. To test this, sciatic nerves of Trembler J (TrJ) neuropathy mice carrying a leucine-to-proline mutation in PMP22 were studied. In TrJ neuropathy nerves, PMP22 has an extended half-life and forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes. On the basis of these characteristics, we hypothesized that PMP22 aggresomes are transitory, linking the proteasomal and lysosomal protein degradation pathways. Here we show that Schwann cells have the ability to eliminate aggresomes by a mechanism that is enhanced when autophagy is activated and is primarily prevented when autophagy is inhibited. This mechanism of aggresome clearance is not unique to peripheral glia, because L fibroblasts were also capable of removing aggresomes. Our results provide evidence for the involvement of the proteasome pathway in TrJ neuropathy and for the role of autophagy in the clearance of aggresomes.
Endophilin Promotes a Late Step in Endocytosis at Glial Invaginations inDrosophilaPhotoreceptor Terminals
Authors: Fabian-Fine Ruth , Verstreken Patrik , Hiesinger P. Robin , Horne Jane Anne , Kostyleva Rita , Zhou Yi , Bellen Hugo J. , Meinertzhagen Ian A.
Published: April 2018

Retrieval of synaptic vesicles from the membrane of neurons is crucial to maintain normal rates of neurotransmitter release. Photoreceptor terminals of the fly's eye release neurotransmitter in a tonic manner. They therefore rely heavily on vesicle regeneration. Null mutations inendophilin(endo) block clathrin-mediated endocytosis at theDrosophilaneuromuscular junction, where previous analysis of hypomorphic mutations has suggested a function for Endophilin (Endo) before vesicle fission, during membrane bending. Here, at fly photoreceptor synapses, we show that Endo is localized to synaptic vesicles at sites of endocytosis that are glial invaginations called capitate projections, and that when the photoreceptor synapses lack Endo they are impaired in their ability to release neurotransmitter. Detailed ultrastructural analysis ofendonull mutant photoreceptor synapses fails to reveal a defect at early stages of vesicle reformation but, instead, reveals an accumulation of clusters of electron-dense, apparently nonfunctional, late endocytotic vesicles. Usingdynamin;endodouble-mutant photoreceptors, we provide further evidence that ultimately the function of Endophilin is required late in endocytosis, allowing vesicles to progress through the synaptic vesicle cycle.
Molecular Basis for Ultraviolet Vision in Invertebrates
Authors: Salcedo Ernesto , Zheng Lijun , Phistry Meridee , Bagg Eve E. , Britt Steven G.
Published: April 2018

Invertebrates are sensitive to a broad spectrum of light that ranges from UV to red. Color sensitivity in the UV plays an important role in foraging, navigation, and mate selection in both flying and terrestrial invertebrate animals. Here, we show that a single amino acid polymorphism is responsible for invertebrate UV vision. This residue (UV: lysine vs blue:asparagine or glutamate) corresponds to amino acid position glycine 90 (G90) in bovine rhodopsin, a site affected in autosomal dominant human congenital night blindness. Introduction of the positively charged lysine in invertebrates is likely to deprotonate the Schiff base chromophore and produce an UV visual pigment. This same position is responsible for regulating UV versus blue sensitivity in several bird species, suggesting that UV vision has arisen independently in invertebrate and vertebrate lineages by a similar molecular mechanism.
The Development of a Single Frequency Place in the Mammalian Cochlea: The Cochlear Resonance in the Mustached BatPteronotus parnellii
Authors: Russell Ian J. , Drexl Markus , Foeller Elisabeth , Vater Marianne , Kössl Manfred
Published: April 2018

Cochlear microphonic potentials (CMs) were recorded from the sharply tuned, strongly resonant auditory foveae of 1- to 5-week-old mustached bats that were anesthetized with Rompun and Ketavet. The fovea processes Doppler-shifted echo responses of the constant-frequency component of echolocation calls. During development, the frequency and tuning sharpness of the cochlear resonance increases, and CM ringing persists for longer after the tone. CM is relatively insensitive at tone onset and grows linearly with increased stimulus level. During the tone, the CM is more sensitive and grows compressively with increased stimulus level and phase leads onset CM by 90° for frequencies below the resonance. CM during the ringing is also sensitive and compressive and phase leads onset CM by 180° below the resonance and lags it by 180° above the resonance. Throughout postnatal development, CMs measured during the tone and in the ringing increase both in sensitivity and compression. The cochlear resonance appears to be attributable to interaction between two oscillators. The more broadly tuned oscillator dominates the onset response, and the narrowly tuned oscillator dominates the ringing. Early in development, mechanical coupling between the oscillators results in a relatively broadly tuned system with several frequency modes in the CM at tone onset and in the CM ringing. Beating occurs between the resonance and the stimulus response during the tone and between two components of the narrowly tuned oscillator at tone offset. At maturity, the CM has three modes for frequencies within 10 kHz of the resonance at tone onset and a single, sharply tuned mode in the ringing.
Peptidergic Nociceptors of Both Trigeminal and Dorsal Root Ganglia Express Serotonin 1D Receptors: Implications for the Selective Antimigraine Action of Triptans
Authors: Potrebic Sonja , Ahn Andrew H. , Skinner Kate , Fields Howard L. , Basbaum Allan I.
Published: April 2018

Agonists at serotonin 1D (5-HT1D) receptors relieve migraine headache but are not clinically used as general analgesics. One possible explanation for this difference is that 5-HT1Dreceptors are preferentially expressed by cranial afferents of the trigeminal system. We compared the distribution of 5-HT1Dreceptor-immunoreactive (5-HT1D-IR) peripheral afferents within the trigeminal ganglion (TRG) and lumbar dorsal root ganglion (DRG) of the rat. We also examined the neurochemical identity of 5-HT1D-IR neurons with markers of primary afferent nociceptors, peripherin, isolectin B4, and substance P, and markers of myelinated afferents, N52 and SSEA3. We observed a striking similarity in the size, distribution, and neurochemical identity of 5-HT1D-IR neurons in TRG and lumbar DRG afferents. Furthermore, the vast majority of 5-HT1D-IR neurons are unmyelinated peptidergic afferents that distribute peripherally, including the dura, cornea, and the sciatic nerve. In the central projections of these afferents within the trigeminal nucleus caudalis and the spinal cord dorsal horn, 5-HT1D-IR fibers are concentrated in laminas I and outer II; a few axons penetrate to lamina V. At the ultrastructural level, 5-HT1Dreceptors in the spinal cord dorsal horn are localized exclusively within dense core vesicles of synaptic terminals. We observed scattered 5-HT1D-IR neurons in the nodose ganglia, and there was sparse terminal immunoreactivity in the solitary nucleus. The visceral efferents of the superior cervical ganglia did not contain 5-HT1Dimmunoreactivity. Our finding, that 5-HT1Dreceptors are distributed in nociceptors throughout the body, raises the possibility that triptans can regulate not only headache-associated pain but also nociceptive responses in extracranial tissues.