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J Neurosci [journal]
- Sleep restriction impairs blood-brain barrier function. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14697-706.
The blood-brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice.
- Munc13-3 Superprimes Synaptic Vesicles at Granule Cell-to-Basket Cell Synapses in the Mouse Cerebellum. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14687-96.
Munc13-3 is a presynaptic protein implicated in vesicle priming that is strongly expressed in cerebellar granule cells (GCs). Mice deficient of Munc13-3 (Munc13-3(-/-)) show an increased paired-pulse ratio (PPR), which led to the hypothesis that Munc13-3 increases the release probability (pr) of vesicles. In the present study, we analyzed unitary synaptic connections between GCs and basket cells in acute cerebellar slices from wild-type and Munc13-3(-/-) mice. Unitary EPSCs recorded from Munc13-3(-/-) GCs showed normal kinetics and synaptic latency but a significantly increased PPR and fraction of synaptic failures. A quantal analysis revealed that neither the charge of single quanta nor the binominal parameter N were affected by loss of Munc13-3 but that pr was almost halved in Munc13-3(-/-). Neither presynaptic Ca(2+) influx was affected by deletion of Munc13-3 nor replenishment of the readily releasable vesicle pool. However, a high concentration of EGTA led to a reduction in EPSCs that was significantly stronger in Munc13-3(-/-). We conclude that Munc13-3 is responsible for an additional step of molecular and/or positional "superpriming" that substantially increases the efficacy of Ca(2+)-triggered release.
- Difference in the gain in the phototransduction cascade between rods and cones in carp. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14682-6.
In the vertebrate retina, there are two types of photoreceptors, rods and cones. Rods are highly light-sensitive and cones are less light-sensitive. One of the possible mechanisms accounting for the lower light-sensitivity in cones would be lower signal amplification, i.e., lower gain in the phototransduction cascade in cones. In this study, we compared the difference in the gain between rods and cones electrophysiologically in carp. The initial rising phases of the light responses were analyzed to determine an index of the gain, G, a parameter that can be used to compare the gain among cells of varying outer segment volumes. G (in fL · sec(-2)) was 91.2 ± 14.8 (n = 5) in carp rods and 25.3 ± 3.2 (n = 4) in carp red cones, so that the gain in carp red cones is ∼1/4 of that in carp rods. G was also determined in bullfrog rods and was 81.0 ± 17.2 (n = 3) which was very similar to that in carp rods. The difference in the gain between rods and cones in carp determined in this study (∼1/4 in cones compared with rods) is consistent with that we recently determined biochemically (∼1/5 in cones compared with rods). Together with the result obtained in bullfrog rods in this study and the results obtained by others, we concluded that the gain in the cascade is several-fold lower in cones than in rods in carp and probably in other animal species also.
- Schwann cells and deleted in colorectal carcinoma direct regenerating motor axons towards their original path. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14668-81.
After complete nerve transection, a major challenge for regenerating peripheral axons is to traverse the injury site and navigate toward their original trajectory. Denervated Schwann cells distal to the lesion site secrete factors promoting axonal growth and serve as an axonal substrate, yet whether Schwann cells also actively direct axons toward their original trajectory is unclear. Using live-cell imaging in zebrafish, we visualize for the first time how in response to nerve transection distal Schwann cells change morphology as axons fragment, and how Schwann cell morphology reverses once regenerating growth cones have crossed the injury site and have grown along distal Schwann cells outlining the original nerve path. In mutants lacking Schwann cells, regenerating growth cones extend at rates comparable with wild type yet frequently fail to cross the injury site and instead stray along aberrant trajectories. Providing growth-permissive yet Schwann cell-less scaffolds across the injury site was insufficient to direct regenerating growth cones toward the original path, providing compelling evidence that denervated Schwann cells actively direct regenerating axons across the injury site toward their original trajectory. To identify signals that guide regenerating axons in vivo, we examined mutants lacking the deleted in colorectal carcinoma (DCC) guidance receptor. In these dcc mutants, a significant fraction of regenerating motor axons extended along aberrant trajectories, similar to what we observe in mutants lacking Schwann cells. Thus, Schwann cell and dcc-mediated guidance are critical early during regeneration to direct growth cones across the transection gap and onto their original axonal trajectory.
- Dissociable Roles of Right Inferior Frontal Cortex and Anterior Insula in Inhibitory Control: Evidence from Intrinsic and Task-Related Functional Parcellation, Connectivity, and Response Profile Analyses across Multiple Datasets. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14652-67.
The right inferior frontal cortex (rIFC) and the right anterior insula (rAI) have been implicated consistently in inhibitory control, but their differential roles are poorly understood. Here we use multiple quantitative techniques to dissociate the functional organization and roles of the rAI and rIFC. We first conducted a meta-analysis of 70 published inhibitory control studies to generate a commonly activated right fronto-opercular cortex volume of interest (VOI). We then segmented this VOI using two types of features: (1) intrinsic brain activity; and (2) stop-signal task-evoked hemodynamic response profiles. In both cases, segmentation algorithms identified two stable and distinct clusters encompassing the rAI and rIFC. The rAI and rIFC clusters exhibited several distinct functional characteristics. First, the rAI showed stronger intrinsic and task-evoked functional connectivity with the anterior cingulate cortex, whereas the rIFC had stronger intrinsic and task-evoked functional connectivity with dorsomedial prefrontal and lateral fronto-parietal cortices. Second, the rAI showed greater activation than the rIFC during Unsuccessful, but not Successful, Stop trials, and multivoxel response profiles in the rAI, but not the rIFC, accurately differentiated between Successful and Unsuccessful Stop trials. Third, activation in the rIFC, but not rAI, predicted individual differences in inhibitory control abilities. Crucially, these findings were replicated in two independent cohorts of human participants. Together, our findings provide novel quantitative evidence for the dissociable roles of the rAI and rIFC in inhibitory control. We suggest that the rAI is particularly important for detecting behaviorally salient events, whereas the rIFC is more involved in implementing inhibitory control.
- Oncogenic signaling is dominant to cell of origin and dictates astrocytic or oligodendroglial tumor development from oligodendrocyte precursor cells. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14644-51.
Stem cells, believed to be the cellular origin of glioma, are able to generate gliomas, according to experimental studies. Here we investigated the potential and circumstances of more differentiated cells to generate glioma development. We and others have shown that oligodendrocyte precursor cells (OPCs) can also be the cell of origin for experimental oligodendroglial tumors. However, the question of whether OPCs have the capacity to initiate astrocytic gliomas remains unanswered. Astrocytic and oligodendroglial tumors represent the two most common groups of glioma and have been considered as distinct disease groups with putatively different origins. Here we show that mouse OPCs can give rise to both types of glioma given the right circumstances. We analyzed tumors induced by K-RAS and AKT and compared them to oligodendroglial platelet-derived growth factor B-induced tumors in Ctv-a mice with targeted deletions of Cdkn2a (p16(Ink4a-/-), p19(Arf-/-), Cdkn2a(-/-)). Our results showed that glioma can originate from OPCs through overexpression of K-RAS and AKT when combined with p19(Arf) loss, and these tumors displayed an astrocytic histology and high expression of astrocytic markers. We argue that OPCs have the potential to develop both astrocytic and oligodendroglial tumors given loss of p19(Arf), and that oncogenic signaling is dominant to cell of origin in determining glioma phenotype. Our mouse data are supported by the fact that human astrocytoma and oligodendroglioma display a high degree of overlap in global gene expression with no clear distinctions between the two diagnoses.
- Maturational conversion of dendritic early endosomes and their roles in l1-mediated axon growth. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14633-43.
The function of endosomes is intricately linked to cellular function in all cell types, including neurons. Intriguingly, neurons express cell type-specific proteins that localize to endosomes, but little is known about how these neuronal proteins interface with canonical endosomes and ubiquitously expressed endosomal components, such as EEA1 (Early Endosomal Antigen 1). NEEP21 (Neuronal Early Endosomal Protein 21 kDa) localizes to somatodendritic endosomes, and downregulation of NEEP21 perturbs the correct trafficking of multiple receptors, including glutamate receptors (GluA2) during LTP and amyloidogenic processing of βAPP. Our own work implicated NEEP21 in correct trafficking of the axonal cell adhesion molecule L1/neuron-glia cell adhesion molecule (NgCAM). NEEP21 dynamically localizes with EEA1-positive early endosomes but is also found in EEA1-negative endosomes. Live imaging reveals that NEEP21-positive, EEA1-negative endosomes arise as a consequence of maturational conversion of EEA1/NEEP21 double-positive endosomes. Interfering with EEA1 function causes missorting of L1/NgCAM, axon outgrowth defects on the L1 substrate, and disturbance of NEEP21 localization. Last, we uncover evidence that functional interference with NEEP21 reduces axon and dendrite growth of primary rat hippocampal neurons on L1 substrate but not on N-cadherin substrate, thus implicating endosomal trafficking through somatodendritic early endosomes in L1-mediated axon growth.
- Genetic or Pharmacological Reduction of PERK Enhances Cortical-Dependent Taste Learning. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14624-32.
Protein translation initiation is controlled by levels of eIF2α phosphorylation (p-eIF2α) on Ser51. In addition, increased p-eIF2α levels impair long-term synaptic plasticity and memory consolidation, whereas decreased levels enhance them. Levels of p-eIF2α are determined by four kinases, of which protein kinase RNA-activated (PKR), PKR-like endoplastic reticulum kinase (PERK), and general control nonderepressible 2 are extensively expressed in the mammalian mature brain. Following identification of PERK as the major kinase to determine basal levels of p-eIF2α in primary neuronal cultures, we tested its function as a physiological constraint of memory consolidation in the cortex, the brain structure suggested to store, at least in part, long-term memories in the mammalian brain. To that aim, insular cortex (IC)-dependent positive and negative forms of taste learning were used. Genetic reduction of PERK expression was accomplished by local microinfusion of a lentivirus harboring PERK Short hairpin RNA, and pharmacological inhibition was achieved by local microinfusion of a PERK-specific inhibitor (GSK2606414) to the rat IC. Both genetic reduction of PERK expression and pharmacological inhibition of its activity reduced p-eIF2α levels and enhanced novel taste learning and conditioned taste aversion, but not memory retrieval. Moreover, enhanced extinction was observed together with enhanced associative memory, suggesting increased cortical-dependent behavioral plasticity. The results suggest that, by phosphorylating eIF2α, PERK functions in the cortex as a physiological constraint of memory consolidation, and its downregulation serves as cognitive enhancement.
- Interaction of the Cell Adhesion Molecule CHL1 with Vitronectin, Integrins, and the Plasminogen Activator Inhibitor-2 Promotes CHL1-Induced Neurite Outgrowth and Neuronal Migration. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14606-23.
The cell adhesion molecule close homolog of L1 (CHL1) plays important functional roles in the developing and adult nervous system. In search of the binding partners that mediate the diverse and sometimes opposing functions of CHL1, the extracellular matrix-associated proteins vitronectin and plasminogen activator inhibitor-2 (PAI-2) were identified as novel CHL1 interaction partners and tested for involvement in CHL1-dependent functions during mouse cerebellar development. CHL1-induced cerebellar neurite outgrowth and cell migration at postnatal days 6-8 were inhibited by a CHL1-derived peptide comprising the integrin binding RGD motif, and by antibodies against vitronectin or several integrins, indicating a vitronectin-dependent integrin-mediated pathway. A PAI-2-derived peptide, or antibodies against PAI-2, urokinase type plasminogen activator (uPA), uPA receptor, and several integrins reduced cell migration. CHL1 colocalized with vitronectin, PAI-2, and several integrins in cerebellar granule cells, suggesting an association among these proteins. Interestingly, at the slightly earlier age of 4-5 d, cerebellar neurons did not depend on CHL1 for neuritogenesis and cell migration. However, differentiation of progenitor cells into neurons at this stage was dependent on homophilic CHL1-CHL1 interactions. These observations indicate that homophilic CHL1 trans-interactions regulate differentiation of neuronal progenitor cells at early postnatal stages, while heterophilic trans-interactions of CHL1 with vitronectin, integrins, and the plasminogen activator system regulate neuritogenesis and neuronal cell migration at a later postnatal stage of cerebellar morphogenesis. Thus, within very narrow time windows in postnatal cerebellar development, distinct types of molecular interactions mediated by CHL1 underlie the diverse functions of this protein.
- Stimulus Dependence of Local Field Potential Spectra: Experiment versus Theory. [Journal Article]
- J Neurosci 2014 Oct 29; 34(44):14589-605.
The local field potential (LFP) captures different neural processes, including integrative synaptic dynamics that cannot be observed by measuring only the spiking activity of small populations. Therefore, investigating how LFP power is modulated by external stimuli can offer important insights into sensory neural representations. However, gaining such insight requires developing data-driven computational models that can identify and disambiguate the neural contributions to the LFP. Here, we investigated how networks of excitatory and inhibitory integrate-and-fire neurons responding to time-dependent inputs can be used to interpret sensory modulations of LFP spectra. We computed analytically from such models the LFP spectra and the information that they convey about input and used these analytical expressions to fit the model to LFPs recorded in V1 of anesthetized macaques (Macaca mulatta) during the presentation of color movies. Our expressions explain 60%-98% of the variance of the LFP spectrum shape and its dependency upon movie scenes and we achieved this with realistic values for the best-fit parameters. In particular, synaptic best-fit parameters were compatible with experimental measurements and the predictions of firing rates, based only on the fit of LFP data, correlated with the multiunit spike rate recorded from the same location. Moreover, the parameters characterizing the input to the network across different movie scenes correlated with cross-scene changes of several image features. Our findings suggest that analytical descriptions of spiking neuron networks may become a crucial tool for the interpretation of field recordings.