bluuebunny/crossref_metadata_2025 huggingface dataset:
Connexin35 Mediates Electrical Transmission at Mixed Synapses on Mauthner Cells
Authors: Pereda A. , O'Brien J. , Nagy J. I. , Bukauskas F. , Davidson K. G. V. , Kamasawa N. , Yasumura T. , Rash J. E.
Published: April 2018

Auditory afferents terminating as “large myelinated club endings” on goldfish Mauthner cells are identifiable “mixed” (electrical and chemical) synaptic terminals that offer the unique opportunity to correlate physiological properties with biochemical composition and specific ultrastructural features of individual synapses. By combining confocal microscopy and freeze-fracture replica immunogold labeling (FRIL), we demonstrate that gap junctions at these synapses contain connexin35 (Cx35). This connexin is the fish ortholog of the neuron-specific human and mouse connexin36 that is reported to be widely distributed in mammalian brain and to be responsible for electrical coupling between many types of neurons. Similarly, connexin35 was found at gap junctions between neurons in other brain regions, suggesting that connexin35-mediated electrical transmission is common in goldfish brain. Conductance of gap junction channels at large myelinated club endings is known to be dynamically modulated by the activity of their colocalized glutamatergic synapses. We show evidence by confocal microscopy for the presence of the NR1 subunit of the NMDA glutamate receptor subtype, proposed to be a key regulatory element, at these large endings. Furthermore, we also show evidence by FRIL double-immunogold labeling that the NR1 subunit of the NMDA glutamate receptor is present at postsynaptic densities closely associated with gap junction plaques containing Cx35 at mixed synapses across the goldfish hindbrain. Given the widespread distribution of electrical synapses and glutamate receptors, our results suggest that the plastic properties observed at these identifiable junctions may apply to other electrical synapses, including those in mammalian brain.
Deafness Disrupts Chloride Transporter Function and Inhibitory Synaptic Transmission
Authors: Vale Carmen , Schoorlemmer Jon , Sanes Dan H.
Published: April 2018

Loss of sensory function leads to atrophy or death within the developing CNS, yet little is known about the physiology of remaining synapses. After bilateral deafening, gramicidin-perforated-patch recordings were obtained from gerbil inferior colliculus neurons in a brain slice preparation. Afferent-evoked IPSPs had a diminished ability to block current-evoked action potentials in deafened neurons. This change could be attributed, in part, to a loss of potassium-dependent chloride transport function, with little change in K-Cl cotransporter expression. Treatments that suppressed chloride cotransport (bumetanide, cesium, and genistein) had little or no effect on neurons from deafened animals. These same treatments depolarized theEIPSCof control neurons. Semiquantitative RT-PCR and immunohistochemical staining indicated no change in the expression of chloride cotransporter mRNA or protein after deafness. Therefore, profound hearing loss leads rapidly to the disruption of chloride homeostasis, which is likely attributable to the dysfunction of the potassium-dependent chloride cotransport mechanism, rather than a downregulation of its expression. This results in inhibitory synapses that are less able to block excitatory events.
Neural Noise and Movement-Related Codes in the Macaque Supplementary Motor Area
Authors: Averbeck Bruno B. , Lee Daeyeol
Published: April 2018

We analyzed the variability of spike counts and the coding capacity of simultaneously recorded pairs of neurons in the macaque supplementary motor area (SMA). We analyzed the mean-variance functions for single neurons, as well as signal and noise correlations between pairs of neurons. All three statistics showed a strong dependence on the bin width chosen for analysis. Changes in the correlation structure of single neuron spike trains over different bin sizes affected the mean-variance function, and signal and noise correlations between pairs of neurons were much smaller at small bin widths, increasing monotonically with the width of the bin. Analyses in the frequency domain showed that the noise between pairs of neurons, on average, was most strongly correlated at low frequencies, which explained the increase in noise correlation with increasing bin width.

The coding performance was analyzed to determine whether the temporal precision of spike arrival times and the interactions within and between neurons could improve the prediction of the upcoming movement. We found that in ∼62% of neuron pairs, the arrival times of spikes at a resolution between 66 and 40 msec carried more information than spike counts in a 200 msec bin. In addition, in 19% of neuron pairs, inclusion of within (11%)- or between-neuron (8%) correlations in spike trains improved decoding accuracy. These results suggest that in some SMA neurons elements of the spatiotemporal pattern of activity may be relevant for neural coding.
Time Course and Time-Distance Relationships for Surround Suppression in Macaque V1 Neurons
Authors: Bair Wyeth , Cavanaugh James R. , Movshon J. Anthony
Published: April 2018

Iso-orientation surround suppression is a powerful form of visual contextual modulation in which a stimulus of the preferred orientation of a neuron placed outside the classical receptive field (CRF) of the neuron suppresses the response to stimuli within the CRF. This suppression is most often attributed to orientation-tuned signals that propagate laterally across the cortex, activating local inhibition. By studying the temporal properties of surround suppression, we have uncovered characteristics that challenge standard notions of surround suppression. We found that the latency of suppression depended on its strength. Across cells, strong suppression arrived on average 30 msec earlier than weak suppression, and suppression sometimes arrived faster than the excitatory CRF response. We compared the relative latency of CRF response onset and offset with the relative latency of suppression onset and offset. Response onset was delayed relative to response offset in the CRF but not in the surround. This is not the expected result if neurons targeted by suppression are like those that generate it. We examined the time course of suppression as a function of distance of the surround stimulus from the CRF and found that suppression was predominantly sustained for nearby stimuli and predominantly transient for distant stimuli. By comparing the latency of suppression for nearby and distant stimuli, we found that orientation-tuned suppression could effectively propagate across 6 - 8 mm of cortex at ∼1 m/sec. This is considerably faster than expected for horizontal cortical connections previously implicated in surround suppression. We offer refinements to circuits for surround suppression that account for these results and describe how feedback from cells with large CRFs can account for the rapid propagation of suppression within V1.
Preserved Sensitivity to Outcome Value after Lesions of the Basolateral Amygdala
Authors: Blundell Pam , Hall Geoffrey , Killcross Simon
Published: April 2018

Recent work (Blundell et al., 2001; Balleine et al., 2003) has suggested that the basolateral region of the amygdala (BLA) is important in the representation of the sensory and incentive aspects of motivationally significant events. In common with other theories of function of the BLA, this predicts that lesions of the BLA will interfere with reinforcer devaluation after appetitive Pavlovian or instrumental conditioning. However, this hypothesis also predicts that BLA lesions will be without effect on postconditioning changes in reinforcer value if initial learning is only about the sensory aspects of otherwise neutral events. This interpretation is supported by evidence for significant detrimental effects of BLA lesions on reinforcer devaluation in a Pavlovian autoshaping procedure, but no effect of postconditioning devaluation using a sensory preconditioning procedure. These results demonstrate that animals with BLA lesions can remain sensitive to post-training changes in the motivational value of outcomes.
Developmental Learning in a Pain-Related System: Evidence for a Cross-Modality Mechanism
Authors: Waldenström Alexandra , Thelin Jonas , Thimansson Erik , Levinsson Anders , Schouenborg Jens
Published: April 2018

The nociceptive spinal reflex system performs highly precise sensorimotor transformations that require functionally specified synaptic strengths. The specification is gradually attained during early development and appears to be learning dependent. Here we determine the time course of this specification for heat-nociceptive tail withdrawal reflexes and analyze which types of primary afferents are important for the learning by applying various forms of noninvasive sensory deprivations. The percentage of erroneous heat-nociceptive tail withdrawal reflexes (i.e., movements directed toward the stimulation) decreased gradually from 64.1 ± 2.5% (mean ± SEM) to <10% during postnatal days 10-21. This improvement was completely blocked by anesthetizing the tail during the adaptation period, confirming that an experience-dependent mechanism is involved in the specification of synaptic strengths. However, the results show that the adaptation occurs to a significant extent despite local analgesia and protection of the tail from noxious input, provided that tactile sensitivity is preserved. Therefore, it appears that a nociceptive input is not necessary for the adaptation, and that input from tactile receptors can be used to guide the nociceptive synaptic organization during development. Sensory deprivation in the adult rat failed to affect the heat-nociceptive withdrawal reflex system, indicating that the adaptation has a “critical period” during early development. These findings provide a key to the puzzle of how pain-related systems can be functionally adapted through experience despite the rare occurrence of noxious input during early life.
Differentiation of Marrow Stromal Cells into Photoreceptors in the Rat Eye
Authors: Kicic Anthony , Shen Wei-Yong , Wilson Ann S. , Constable Ian J. , Robertson Terry , Rakoczy P. Elizabeth
Published: April 2018

Retinal degenerations and dystrophies are the major causes of genetically inherited blindness that are characterized by the apoptotic death of the photoreceptor cell layer of the retina. To date, no treatment exists for these diseases and only recently have they been considered as candidates for gene and stem cell therapies. Here we report the ability of adult CD90+marrow stromal cells (MSCs) to be induced by activin A, taurine, and EGF into cells (20-32%) expressing photoreceptor-specific markers rhodopsin, opsin, and recoverinin vitro. CD90+cells were either transduced with recombinant adeno-associated virus expressing green fluorescent protein (GFP) or bromodeoxyuridine (BrdU) labeled and then injected into the subretinal space of adult Royal College of Surgeons rats. Fundus photography and angiography showed no adverse effects of CD90+MSC transplantation. GFP-expressing cells or BrdU-positive cells covered ∼30% of the entire retinal area. By 2 weeks after injection, CD90+MSCs integrated into the host retina, forming structures similar to the photoreceptor layer and expressed a photoreceptor-specific marker. No teratoma formation was observed in the recipient retina. The subretinally delivered CD90+MSCs did not stain for proliferating cell nuclear antigen, indicating that they primarily undergo differentiation rather than proliferation. In addition, we established that transplanted cells can attract synaptic vesicles and hence are potentially capable of signal transduction. This study demonstrates for the first time the partial differentiation of adult CD90+MSCs into photoreceptorsin vitroandin vivo. Our results establish a proof of concept for CD90+MSC differentiation with autologous transplantation, which may provide a promising therapeutic strategy for the treatment of some forms of genetically inherited retinal degenerations.
Submillisecond Precision of the Input-Output Transformation Function Mediated by Fast Sodium Dendritic Spikes in Basal Dendrites of CA1 Pyramidal Neurons
Authors: Ariav Gal , Polsky Alon , Schiller Jackie
Published: April 2018

The ability of cortical neurons to perform temporally accurate computations has been shown to be important for encoding of information in the cortex; however, cortical neurons are expected to be imprecise temporal encoders because of the stochastic nature of synaptic transmission and ion channel gating, dendritic filtering, and background synaptic noise. Here we show for the first time that fast local spikes in basal dendrites can serve to improve the temporal precision of neuronal output. Integration of coactivated, spatially distributed synaptic inputs produces temporally imprecise output action potentials within a time window of several milliseconds. In contrast, integration of closely spaced basal inputs initiates local dendritic spikes that amplify and sharpen the summed somatic potential. In turn, these fast basal spikes allow precise timing of output action potentials with submillisecond temporal jitter over a wide range of activation intensities and background synaptic noise. Our findings indicate that fast spikes initiated in individual basal dendrites can serve as precise “timers” of output action potentials in various network activity states and thus may contribute to temporal coding in the cortex.
Increased Morphological Diversity of Microglia in the Activated Hypothalamic Supraoptic Nucleus
Authors: Ayoub Albert E. , Salm A. K.
Published: April 2018

Microglia are the immune cells of the CNS. In the normal adult mammalian brain, the majority of these cells is quiescent and exhibits a ramified morphology. Microglia are perhaps best known for their swift transformation to an activated ameboid morphology in response to pathological insults. Here we have observed the responsiveness of these cells to events surrounding the normal activation of neurosecretory neurons in the hypothalamic supraoptic nucleus (SON), a well studied model of structural plasticity in the CNS. Neurons in the SON were activated by substituting 2% saline for drinking water. Brain sections were collected from four experimental groups [controls (C), 2 d-dehydrated (2D), 7 d-dehydrated (D7), and 7 d-dehydrated/21 d-rehydrated animals (R21)] and stained with Isolectin-B4-HRP to visualize microglial cells. Based on morphological criteria, we quantified ramified, hypertrophied, and ameboid microglia using unbiased stereological techniques. Statistical analyses showed significant increases in the number of hypertrophied microglia in the D2 and D7 groups. Moreover, there was a significant increase in the number of ameboid microglia in the D7 group. No changes were seen across conditions in the number of ramified cells, nor did we observe any significant phenotypic changes in a control area of the cingulate gyrus. Hence, increased morphological diversity of microglia was found specifically in the SON and was reversible with the cessation of stimulation. These results indicate that phenotypic plasticity of microglia may be a feature of the normal structural remodeling that accompanies neuronal activation in addition to the activation that accompanies brain pathology.
Palmitoylethanolamide Increases after Focal Cerebral Ischemia and Potentiates Microglial Cell Motility
Authors: Franklin Allyn , Parmentier-Batteur Sophie , Walter Lisa , Greenberg David A. , Stella Nephi
Published: April 2018

Focal cerebral ischemia (FCI) induces rapid neuronal death in the ischemic core, which gradually expands toward the penumbra, partly as the result of a neuroinflammatory response. It is known that propagation of neuroinflammation involves microglial cells, the resident macrophages of the brain, which are highly motile when activated by specific signals. However, the signals that increase microglial cell motility in response to FCI remain mostly elusive.

Here, we tested the hypothesis that endocannabinoids mediate neuroinflammation propagation by increasing microglial cell motility. We found that, in mouse cerebral cortex, FCI greatly increases palmitoylethanolamide (PEA), only moderately increases anandamide [arachidonylethanolamide (AEA)], and does not affect 2-arachidonoylglycerol levels. We also found that PEA potentiates AEA-induced microglial cell migration, without affecting other steps of microglial activation, such as proliferation, particle engulfment, and nitric oxide production. This potentiation of microglial cell migration by PEA involves reduction in cAMP levels. In line with this, we provide evidence that PEA acts through Gi/o-coupled receptors. Interestingly, these receptors engaged by PEA are pharmacologically distinct from CB1and CB2cannabinoid receptors, as well as from the WIN and abn-CBD (abnormal-cannabidiol) receptors, two recently identified cannabinoid receptors.

Our results show that PEA and AEA increase after FCI and synergistically enhance microglial cell motility. Because such a response could participate in the propagation of the FCI-induced neuroinflammation within the CNS, and because PEA is likely to act through its own receptor, a better understanding of the receptor engaged by PEA may help guide the search for improved therapies against neuroinflammation.
Ephrin-B2 and EphB2 Regulation of Astrocyte-Meningeal Fibroblast Interactions in Response to Spinal Cord Lesions in Adult Rats
Authors: Bundesen Liza Q. , Scheel Tracy Aber , Bregman Barbara S. , Kromer Lawrence F.
Published: April 2018

The present study provides the first evidence that signaling occurs between B-ephrins and EphB receptors in the adult CNS in response to injury. Specifically, our combined histological and biochemical data indicate that two members of the B-class of ephrins and Eph receptors, ephrin-B2 and EphB2, are expressed by astrocytes and meningeal fibroblasts, respectively, in the adult spinal cord. In response to thoracic spinal cord transection lesions, ephrin-B2 and EphB2 protein levels exhibit an initial decrease (1 d after lesion), followed by a significant increase by day 14. Immunohistochemical data indicate that ephrin-B2 is expressed by reactive CNS astrocytes, and EphB2 is present on fibroblasts invading the lesion site from the adjacent meninges. During the first 3 d after injury, there is intermingling of ephrin-B2-expressing reactive astrocytes at the lesion surface with EphB2-containing fibroblasts that is concurrent with bidirectional activation (phosphorylation) of ephrin-B2 and EphB2. By 7 d, both cell types are establishing restricted cellular domains containing dense networks of cells and interweaving processes. This astroglial-meningeal fibroblast scar is fully developed by day 14 when there is strict segregation of ephrin-B2-expressing astrocytes from EphB2-positive meningeal fibroblasts. These morphological changes are concomitant with a simultaneous decrease in ephrin-B2 and EphB2 activation. These observations provide strong evidence that cell contact-mediated bidirectional signaling between ephrin-B2 on reactive astrocytes and EphB2 on meningeal fibroblasts is an early event in the cellular cascades that result in the development of the glial scar and the exclusion of meningeal fibroblasts from the injured spinal cord.
Secretory Vesicles Membrane Area Is Regulated in Tandem with Quantal Size in Chromaffin Cells
Authors: Gong Liang-Wei , Hafez Ismail , Alvarez de Toledo Guillermo , Lindau Manfred
Published: April 2018

The number of transmitter molecules released in a quantal event can be regulated, and recent studies suggest that the modulation of quantal size is associated with corresponding changes in vesicle volume (Colliver et al., 2000; Pothos et al., 2002). If so, this could occur either by distension of the vesicle membrane or by incorporation and removal of vesicle membrane. We performed simultaneous measurements of vesicle membrane area and catecholamine release in individual quantal events from chromaffin cells using cell-attached patch amperometry. Cells were treated with reserpine, a vesicular monoamine transport blocker that decreases quantal size, orl-dopa, a catecholamine precursor that increases quantal size. We show that decrease and increase in quantal size are associated with a respective decrease and increase in vesicle membrane area. These results point to a novel mechanism of vesicle membrane dynamics by which vesicles physically change their membrane area in response to changes in transmitter content such that the intravesicular concentration of transmitter is maintained.
Roles of α1- and α2-Adrenoceptors in the Nucleus Raphe Magnus in Opioid Analgesia and Opioid Abstinence-Induced Hyperalgesia
Authors: Bie B. , Fields H. L. , Williams J. T. , Pan Z. Z.
Published: April 2018

Noradrenaline and α-adrenoceptors have been implicated in the modulation of pain in various behavioral conditions. Noradrenergic neurons and synaptic inputs are present in neuronal circuits critical for pain modulation, but their actions on neurons in those circuits and consequently the mechanisms underlying noradrenergic modulation of pain remain unclear. In this study, both recordingsin vitroand behavioral analysesin vivowere used to examine cellular and behavioral actions mediated by α1- and α2-adrenoceptors on neurons in the nucleus raphe magnus. We found that α1- and α2-receptors were colocalized in the majority of a class of neurons (primary cells) that inhibit spinal pain transmission and are excited during opioid analgesia. Activation of the α1-receptor depolarized whereas α2-receptor activation hyperpolarized these neurons through a decrease and an increase, respectively, in potassium conductance. Blockade of the excitatory α1-receptor or activation of the inhibitory α2-receptor significantly attenuated the analgesia induced by local opioid application, suggesting that α1-receptor-mediated synaptic inputs in these primary cells contribute to their excitation during opioid analgesia. In the other cell class (secondary cells) that is thought to facilitate spinal nociception and is inhibited by analgesic opioids, only α1-receptors were present. Blocking the α1-receptor in these cells significantly reduced the hyperalgesia (increased pain) induced by opioid abstinence. Thus, state-dependent activation of α1-mediated synaptic inputs onto functionally distinct populations of medullary pain-modulating neurons contributes to opioid-induced analgesia and opioid withdrawal-induced hyperalgesia.
Ischemic Preconditioning by Caspase Cleavage of Poly(ADP-Ribose) Polymerase-1
Authors: Garnier Philippe , Ying Weihai , Swanson Raymond A.
Published: April 2018

A transient, sublethal ischemic interval confers resistance to a subsequent, otherwise lethal ischemic insult, in a process termed ischemic preconditioning. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but extensive PARP-1 activation is a major cause of ischemic cell death. Because PARP-1 can be cleaved and inactivated by caspases, we investigated the possibility that caspase cleavage of PARP-1 could contribute to ischemic preconditioning. Murine cortical cultures were treated with glucose deprivation combined with 0.5 mm2-deoxyglucose and 5 mmazide (“chemical ischemia”) to model the reversible energy failure that occurs during transient ischemiain vivo. Cortical cultures preconditioned with 15 min of chemical ischemia showed increased resistance to subsequent, longer periods of chemical ischemia. These cultures were also more resistant to the PARP-1 activating agent,N-methyl-N′-nitro-N-nitrosoguanidine, suggesting reduced capacity for PARP-1 activation after preconditioning. Immunostaining for the 89 kDa PARP-1 cleavage fragment and for poly(ADP-ribose) formation confirmed that PARP-1 was cleaved and PARP-1 activity was attenuated in the preconditioned neurons. Preconditioning also produced an increase in activated caspase-3 peptide and an increase in caspase-3 activity in the cortical cultures. A cause-effect relationship between caspase activation, PARP-1 cleavage, and ischemic preconditioning was supported by studies using the caspase inhibitor Ac-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO). Cultures treated with DEVD-CHO after preconditioning showed reduced PARP-1 cleavage and reduced resistance to subsequent ischemia. These findings suggest a novel interaction between the caspase- and PARP-1-mediated cell death pathways in which sublethal caspase activation leads to PARP-1 cleavage, thereby increasing resistance to subsequent ischemic stress.
Molecular-Imaging Probe 2-(1-{6-[(2-Fluoroethyl)(Methyl) Amino]-2-Naphthyl}Ethylidene) Malononitrile Labels Prion PlaquesIn Vitro
Authors: Bresjanac Mara , Smid Lojze M. , Vovko Tomaz D. , Petrič Andrej , Barrio Jorge R. , Popovic Mara
Published: April 2018

The study aimed to evaluate the fluorescent molecular-imaging probe 2-(1-{6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) for its ability to selectively and reproducibly label prion plaques in fixed, paraffin-embedded cerebellar sections from patients of confirmed Gerstmann-Sträussler-Scheinker disease, sporadic Creutzfeldt-Jacob disease (CJD) with kuru plaques, and variant CJD (vCJD). FDDNP is a highly hydrophobic, viscosity-sensitive, solvent-sensitive, fluorescent substance, whose radiofluorinated analog [18F]FDDNP has recently been successfully used to label senile plaques and neurofibrillary tangles in the living brain of Alzheimer's disease patients with positron emission tomography. Our results show that FDDNP reliably identifies all prion plaques, including small cluster-plaques in vCJD. This finding may open newin vivodiagnostic possibilities for vCJD.
Functional–Anatomic Correlates of Sustained and Transient Processing Components Engaged during Controlled Retrieval
Authors: Velanova Katerina , Jacoby Larry L. , Wheeler Mark E. , McAvoy Mark P. , Petersen Steve E. , Buckner Randy L.
Published: April 2018

Controlled processing is central to episodic memory retrieval. In the present study, neural correlates of sustained, as well as transient, processing components were explored during controlled retrieval using a mixed blocked event-related functional magnetic resonance imaging paradigm. Results from 29 participants suggest that certain regions in prefrontal cortex, including anterior left inferior prefrontal cortex near Brodmann's Area (BA) 45/47 and more posterior and dorsal left prefrontal cortex near BA 44, increase activity on a trial-by-trial basis when high levels of control are required during retrieval. Providing direct evidence for control processes that participate on an ongoing basis, right frontal-polar cortex was strongly associated with a sustained temporal profile during high control retrieval conditions, as were several additional posterior regions, including those within left parietal cortex. These results provide evidence for functional dissociation within prefrontal cortex. Frontal-polar regions near BA 10 associate with temporally extended control processes that may underlie an attentional set, or retrieval mode, during controlled retrieval, whereas more posterior prefrontal regions associate with individual retrieval attempts. In particular, right frontal-polar cortex involvement in sustained processes reconciles a number of disparate findings that have arisen when contrasting blocked-trial paradigms with event-related paradigms.
Identification of Individual Neurons Reflecting Short- and Long-Term Visual Memory in an Arthropodo
Authors: Tomsic Daniel , Berón de Astrada Martén , Sztarker Julieta
Published: April 2018

Ideally, learning-related changes should be investigated while they occurin vivo, but physical accessibility and stability limit intracellular studies. Experiments with insects and crabs demonstrate their remarkable capacity to learn and memorize visual features. However, the location and physiology of individual neurons underlying these processes is unknown. A recently developed crab preparation allows stable intracellular recordings from the optic ganglia to be performed in the intact animal during learning. In the crabChasmagnathus, a visual danger stimulus (VDS) elicits animal escape, which declines after a few stimulus presentations. The long-lasting retention of this decrement is mediated by an association between contextual cues of the training site and the VDS, therefore, called context-signal memory (CSM). CSM is achieved only by spaced training. Massed training, on the contrary, produces a decline of the escape response that is short lasting and, because it is context independent, is called signal memory (SM). Here, we show that movement detector neurons (MDNs) from the lobula (third optic ganglion) of the crab modify their response to the VDS during visual learning. These modifications strikingly correlate with the rate of acquisition and with the duration of retention of both CSM and SM. Long-term CSM is detectable from the response of the neuron 1 d after training. In contrast to MDNs, identified neurons from the medulla (second optic ganglion) show no changes. Our results indicate that visual memory in the crab, and possibly other arthropods, including insects, is accounted for by functional changes occurring in neurons originating in the optic lobes.
Efficacy of Retinal Spikes in Driving Cortical Responses
Authors: Kara Prakash , Reid R. Clay
Published: April 2018

How does a single retinal ganglion cell (RGC) affect the firing of simple cells in the visual cortex? Although much is known of the functional connections between the retina and the lateral geniculate nucleus (LGN) and between LGN and visual cortex, it is hard to infer the effect of disynaptic connections from retina to visual cortex. Most importantly, there is considerable divergence from retina to LGN, so cortical neurons might be influenced by ganglion cells through multiple feedforward pathways. We recorded simultaneously from ganglion cells in the retina and cortical simple cells in the striate cortex with overlapping receptive fields and evaluated disynaptic connections with cross-correlation analysis. In all disynaptically connected pairs, the retinal receptive field center and overlapping cortical subregion always shared the same sign (either both ON or both OFF). Connected pairs were similar in other respects, such as relative position and timing of their receptive fields, and thus obeyed the same rules of connectivity found previously for retinothalamic and thalamocortical connections. We found that a single RGC directly contributed on average to ∼3% of the activity of its cortical target. The relative timing of pairs of spikes from the retinal cell affected their efficacy in driving the cortical cell. When two retinal spikes were closely spaced (<10 msec), the second spike was several times more likely to drive the cortical target. The relative magnitude of this disynaptic paired spike enhancement was considerably larger than has been found previously for retinogeniculate and geniculocortical connections. The amplified paired spike enhancement from retina to cortex ensures that signal transmission from retina to cortex is particularly effective when the retina fires a series of closely spaced action potentials.
Response of Mitochondrial Traffic to Axon Determination and Differential Branch Growth
Authors: Ruthel Gordon , Hollenbeck Peter J.
Published: April 2018

Mitochondria are concentrated in regions of the neuron where the demand for mitochondrial function is high, such as nodes of Ranvier, synapses, and active growth cones. Does mitochondrial transport respond to changes in neuronal energy consumption and architecture, or does it precede and perhaps predict them? We have used axon determination, elongation, and alternating branch growth in hippocampal neurons to analyze the cellular cues that control mitochondrial traffic. During the stage 2–3 transition, when one minor process becomes the axon and accelerates its growth, mitochondria do not uniformly cluster at the base of the prospective axon. There is increased entry of mitochondria into the nascent axon, but this does not require accumulation near the axon. After axonal elongation is under way, the mitochondrial density of the minor processes decreases. Axonal towing experiments showed that elongation alone does not result in transport of mitochondria into the axon; thus, cytoplasmic flow cannot explain the entry of mitochondria into growing axons. Analysis of mitochondrial transport during alternating growth of axonal branches showed that mitochondrial traffic responds to changes in growth through regulation of entry into, but not exit from, branches. Branch-towing experiments showed that this response is not caused by axonal elongation alone, nor does it require an active growth cone. We propose that mitochondrial traffic in axons responds to changes in axonal outgrowth, and that the mechanism by which sorting at branch points occurs is different from the mechanism responsible for concentrating mitochondria at the growth cone.
Representation of Auditory Space by Cortical Neurons in Awake Cats
Authors: Mickey Brian J. , Middlebrooks John C.
Published: April 2018

We evaluated the spatial selectivity of auditory cortical neurons in awake cats. Single- and multiunit activity was recorded in primary auditory cortex as the animals performed a nonspatial auditory discrimination or sat idly. Their heads were unrestrained, and head position was tracked. Broadband sounds were delivered from locations throughout 360° on the horizontal plane, and source locations were expressed in head-centered coordinates. As in anesthetized animals, the firing rates of most units were modulated by sound location, and most units responded best to sounds in the contralateral hemifield. Tuning was sharper than in anesthetized cats, in part because of suppression at nonoptimal locations. Nonetheless, spatial receptive fields typically spanned 150-180°. Units exhibited diverse temporal response patterns that often depended on sound location. An information-theoretic analysis showed that information transmission was reduced by ∼10% when the precision of spike timing was disrupted by 16-32 msec, and by ∼50% when all location-related variation of spike timing was removed. Spikes occurring within 60 msec of stimulus onset transmitted the most location-related information, but later spikes also carried information. The amount of information transmitted by ensembles of units increased with the number of units, indicating some degree of mutual independence in the spatial information transmitted by various units. Spatial tuning and information transmission were changed little by an increase in sound level of 20-30 dB. For the vast majority of units, receptive fields showed no significant change with the cat's head position or level of participation in the auditory task.
Postsynaptic Protein Kinase A Reduces Neuronal Excitability in Response to Increased Synaptic Excitation in theDrosophilaCNS
Authors: Baines Richard A.
Published: April 2018

Previous work has identified a role for synaptic activity in the development of excitable properties of motoneurons in theDrosophilaembryo. In this study the underlying mechanism that enables two such neurons, termed aCC and RP2, to respond to increased exposure to synaptic excitation is characterized. Synaptic excitation is increased in genetic backgrounds that lack either a cAMP-specific phosphodiesterase (EC:3.1.4,dunce) or acetylcholinesterase (EC:3.1.1.7,ace), the enzyme that terminates the endogenous cholinergic excitation of these motoneurons. Analysis of membrane excitability in aCC/RP2, in either background, shows that these neurons have a significantly reduced capability to fire action potentials (APs) in response to injection of depolarizing current. Analysis of underlying voltage-gated currents show that this effect is associated with a marked reduction in magnitude of the voltage-dependent inward Na+current (INa). Partially blockingINain these motoneurons, using low concentrations of TTX, demonstrates that a reduction ofINais, by itself, sufficient to reduce membrane excitability. An analysis of firing implicates an increased AP threshold to underlie the reduction in membrane excitability observed because of heightened exposure to synaptic excitation. Genetic or pharmacological manipulations that either elevate cAMP or increase protein kinase A (PKA) activity in wild-type aCC/RP2 mimic both the reductions in membrane excitability andINa.In comparison, increasing cAMP catabolism or inhibition of PKA activity is sufficient to block the induction of these activity-dependent changes. The induced changes in excitability can be rapid, occurring within 5 min of exposure to a membrane-permeable cAMP analog, indicative that threshold can be regulated in these neurons by a post-translational mechanism that is dependent on phosphorylation.
Neurodegeneration in Striatum Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Role of Matrix Metalloproteinase-9 in Early Blood-Brain Barrier Disruption?
Authors: Kim Gyung W. , Gasche Yvan , Grzeschik Susanna , Copin Jean-Christophe , Maier Carolina M. , Chan Pak H.
Published: April 2018

Blood-brain barrier (BBB) dysfunction is a potential mechanism involved in progressive striatal damage induced by the mitochondrial excitotoxin, 3-nitropropionic acid (3-NP). After activation by proteases and free radicals, matrix metalloproteinases (MMPs), particularly MMP-9 and -2, can digest the endothelial basal lamina leading to BBB opening. Using CD-1 mice, we show that MMP-9 expression by zymography is increased in the injured striatum compared with the contralateral striatum 2 hr after 3-NP injection [133.50 ± 57.17 vs 50.25 ± 13.56; mean ± SD of optical densities in arbitrary units (A.U.);p< 0.005] and remains elevated until 24 hr (179.33 ± 78.24 A.U.). After 4 hr, MMP-9 expression and activation are accompanied by an increase in BBB permeability. MMP inhibition attenuates BBB disruption, swelling, and lesion volume compared with vehicle-treated controls. There is a clear spatial relationship between MMP-9 expression and oxidized hydroethidine, indicating reactive oxygen species (ROS) production. Furthermore, transgenic mice that overexpress copper/zinc-superoxide dismutase (SOD1) show decreased lesion size and edema along with decreased immunoreactivity for MMP-9, compared with wild-type littermates (lesion: 38.8 ± 15.1 and 53.3 ± 10.3, respectively,p≤ 0.05; edema: 21.8 ± 11.2 and 35.28 ± 11, respectively,p≤ 0.05; MMP-9-positive cells: 352 ± 57 and 510 ± 45, respectively,p≤ 0.005), whereas knock-out mice deficient in SOD1 display significantly greater swelling (48.65 ± 17;p≤ 0.05). We conclude that early expression and activation of MMP-9 by ROS may be involved in early BBB disruption and progressive striatal damage after 3-NP treatment.
Dual Effect of High-Frequency Stimulation on Subthalamic Neuron Activity
Authors: Garcia Liliana , Audin Jacques , D'Alessandro Giampaolo , Bioulac Bernard , Hammond Constance
Published: April 2018

Although it is well known that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) alleviates the cardinal symptoms of Parkinson's disease, the underlying mechanisms are not fully understood. We investigated the effect of stimulation from low to high frequencies on rat STN neurons in naive and dopamine-depleted slices using whole-cell, current-clamp techniques and on-line artifact suppression. Stimulation at 10 Hz evoked 10 Hz single spikes but did not significantly modify ongoing STN activity. In contrast, at therapeutically relevant frequencies (80-185 Hz), stimulation had a dual effect: it fully suppressed STN spontaneous activity and generated a robust pattern of recurrent bursts of spikes, with each spike being time-locked to a stimulus pulse. Neither the suppression of spontaneous activity nor the generation of spikes was prevented by the antagonists of the metabotropic and ionotropic receptors of glutamate and γ-aminobutyric acid. Tetrodotoxin, the Na+channel blocker, suppressed all HFS-evoked spikes, whereas nifedipin, an L-type Ca2+-channel blocker, abolished the membrane oscillations underlying bursts. Therefore, we conclude that HFS drives the STN neuronal activity by directly activating the neuronal membrane. We suggest that this pattern may remove the deleterious activity of the basal ganglia network in the parkinsonian state and drive target neurons to a high-frequency state of activity, dependent on the characteristics of STN efferent synapses and resonant properties of target membranes.
Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex
Authors: González-Maeso Javier , Yuen Tony , Ebersole Barbara J. , Wurmbach Elisa , Lira Alena , Zhou Mingming , Weisstaub Noelia , Hen Rene , Gingrich Jay A. , Sealfon Stuart C.
Published: April 2018

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results ofin vitrosignal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit.In vitrostudies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicablein vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patternsin vivothat are reflected in unique changes in the somatosensory cortex transcriptome.
Cardiotrophin-Like Cytokine/Cytokine-Like Factor 1 is an Essential Trophic Factor for Lumbar and Facial MotoneuronsIn Vivo
Authors: Forger Nancy G. , Prevette David , deLapeyrière Odile , de Bovis Béatrice , Wang Siwei , Bartlett Perry , Oppenheim Ronald W.
Published: April 2018

The ciliary neurotrophic factor α-receptor (CNTFRα) is required for motoneuron survival during development, but the relevant ligand(s) has not been determined. One candidate is the heterodimer formed by cardiotrophin-like cytokine (CLC) and cytokine-like factor 1 (CLF). CLC/CLF binds to CNTFRα and enhances the survival of developing motoneuronsin vitro; whether this novel trophic factor plays a role in neural developmentin vivohas not been tested. We examined motor and sensory neurons in embryonic chicks treated with CLC and in mice with a targeted deletion of theclfgene. Treatment with CLC increased the number of lumbar spinal cord motoneurons that survived the cell death period in chicks. However, this effect was regionally specific, because brachial and thoracic motoneurons were unaffected. Similarly, newbornclf-/- mice exhibited a significant reduction in lumbar motoneurons, with no change in the brachial or thoracic cord.Clfdeletion also affected brainstem motor nuclei in a regionally specific manner; the number of motoneurons in the facial but not hypoglossal nucleus was significantly reduced. Sensory neurons of the dorsal root ganglia were not affected by either CLC treatment orclfgene deletion. Finally, mRNA for bothclcandclfwas found in skeletal muscle fibers of embryonic mice during the motoneuron cell death period. These findings support the view that CLC/CLF is a target-derived factor required for the survival of specific pools of motoneurons. Thein vivoactions of CLC and CLF can account for many of the effects of CNTFRα on developing motoneurons.
A Molecular Mechanism for mRNA Trafficking in Neuronal Dendrites
Authors: Shan Jianguo , Munro Trent P. , Barbarese Elisa , Carson John H. , Smith Ross
Published: April 2018

Specific neuronal mRNAs are localized in dendrites, often concentrated in dendritic spines and spine synapses, where they are translated. The molecular mechanism of localization is mostly unknown. Here we have explored the roles of A2 response element (A2RE), acis-acting signal for oligodendrocyte RNA trafficking, and its cognatetrans-acting factor, heterogeneous nuclear ribonucleoprotein (hnRNP) A2, in neurons. Fluorescently labeled chimeric RNAs containing A2RE were microinjected into hippocampal neurons, and RNA transport followed using confocal laser scanning microscopy. These RNA molecules, but not RNA lacking the A2RE sequence, were transported in granules to the distal neurites. hnRNP A2 protein was implicated as the cognatetrans-acting factor: it was colocalized with RNA in cytoplasmic granules, and RNA trafficking in neurites was compromised by A2RE mutations that abrogate hnRNP A2 binding. Coinjection of antibodies to hnRNP A2 halved the number of trafficking cells, and treatment of neurons with antisense oligonucleotides also disrupted A2RE-RNA transport. Colchicine inhibited trafficking, whereas cells treated with cytochalasin were unaffected, implicating involvement of microtubules rather than microfilaments. A2RE-like sequences are found in a subset of dendritically localized mRNAs, which, together with these results, suggests that a molecular mechanism based on thiscis-acting sequence may contribute to dendritic RNA localization.
The Tissue Plasminogen Activator-Plasminogen Proteolytic Cascade Accelerates Amyloid-β (Aβ) Degradation and Inhibits Aβ-Induced Neurodegeneration
Authors: Melchor Jerry P. , Pawlak Robert , Strickland Sidney
Published: April 2018

Accumulation of the amyloid-β (Aβ) peptide depends on both its generation and clearance. To better define clearance pathways, we have evaluated the role of the tissue plasminogen activator (tPA)-plasmin system in Aβ degradationin vivo. In two different mouse models of Alzheimer's disease, chronically elevated Aβ peptide in the brain correlates with the upregulation of plasminogen activator inhibitor-1 (PAI-1) and inhibition of the tPA-plasmin system. In addition, Aβ injected into the hippocampus of mice lacking either tPA or plasminogen persists, inducing PAI-1 expression and causing activation of microglial cells and neuronal damage. Conversely, Aβ injected into wild-type mice is rapidly cleared and does not cause neuronal degeneration. Thus, the tPA-plasmin proteolytic cascade aids in the clearance of Aβ, and reduced activity of this system may contribute to the progression of Alzheimer's disease.