bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurons Regulate Extracellular Levels of Amyloid β-Protein via Proteolysis by Insulin-Degrading Enzyme
Authors: Vekrellis Konstantinos , Ye Zhen , Qiu Wei Qiao , Walsh Dominic , Hartley Dean , Chesneau Valérie , Rosner Marsha Rich , Selkoe Dennis J.
Published: April 2018

Progressive cerebral accumulation of amyloid β-protein (Aβ) is an early and invariant feature of Alzheimer's disease. Little is known about how Aβ, after being secreted, is degraded and cleared from the extracellular space of the brain. Defective Aβ degradation could be a risk factor for the development of Alzheimer's disease in some subjects. We reported previously that microglial cells release substantial amounts of an Aβ-degrading protease that, after purification, is indistinguishable from insulin-degrading enzyme (IDE). Here we searched for and characterized a role for IDE in Aβ degradation by neurons, the principal cell type that produces Aβ. Whole cultures of differentiated pheochromocytoma (PC12) cells and primary rat cortical neurons actively degraded endogenously secreted Aβ via IDE. However, unlike that in microglia, IDE in differentiated neurons was not released but localized to the cell surface, as demonstrated by biotinylation. Undifferentiated PC12 cells released IDE into their medium, whereas after differentiation, IDE was cell associated but still degraded Aβ in the medium. Overexpression of IDE in mammalian cells markedly reduced the steady-state levels of extracellular Aβ40and Aβ42, and the catalytic site mutation (E111Q) abolished this effect. We observed a novel membrane-associated form of IDE that is ∼5 kDa larger than the known cytosolic form in a variety of cells, including differentiated PC12 cells. Our results support a principal role for membrane-associated and secreted IDE isoforms in the degradation and clearance of naturally secreted Aβ by neurons and microglia.
Declines in mRNA Expression of Different Subunits May Account for Differential Effects of Aging on Agonist and Antagonist Binding to the NMDA Receptor
Authors: Magnusson Kathy R.
Published: April 2018

The purpose of the present study was to determine whether some of the age-related changes that occur in binding to the NMDA receptor complex can be accounted for by changes in subunit expression during the aging process.In situhybridization for the NMDA subunits ζ1, ε1, and ε2, and receptor autoradiography, using the agonist glutamate and the competitive antagonist [(±)-2-carboxypiperazin-4-yl] propyl-1-phosphonic acid (CPP), were performed on sections from C57Bl/6 mice representing three different age groups (3, 10, and 30 months of age). There was a significant overall decrease between 3 and 30 month olds in the density of mRNA for the ζ1 subunit in the cortex and hippocampus, but only a few individual brain regions exhibited significant declines. The mRNA for the ε2 subunit was significantly decreased in a majority of cortical regions and in the dentate granule cells. Emulsion analysis indicated that the change in the density of ε2 subunit mRNA in the inner frontal cortex was primarily attributable to a decrease in the amount of messages per cell. Age-related changes in mRNA density of the ε2 subunit correlated with changes in NMDA-displaceable [3H]glutamate binding, and mRNA density changes in the ζ1 subunit showed a significant relationship with changes in [3H]CPP binding in the 30-month-old mice. These results suggest that changes during aging in the expression of different subunits of the NMDA receptor may account for the differential effects of aging on agonist versus antagonist binding to the NMDA binding site.
Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K+Channels That Underlie the Neuronal M Current
Authors: Shapiro Mark S. , Roche John P. , Kaftan Edward J. , Cruzblanca Humberto , Mackie Ken , Hille Bertil
Published: April 2018

Channels from KCNQ2 and KCNQ3 genes have been suggested to underlie the neuronal M-type K+current. The M current is modulated by muscarinic agonists via G-proteins and an unidentified diffusible cytoplasmic messenger. Using whole-cell clamp, we studied tsA-201 cells in which cloned KCNQ2/KCNQ3 channels were coexpressed with M1muscarinic receptors. Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons. Oxo-M also produced obvious intracellular Ca2+transients, observed by using indo-1 fluorescence. However, modulation of the current remained strong even when Ca2+signals were abolished by the combined use of strong intracellular Ca2+buffers, an inhibitor of IP3receptors, and thapsigargin to deplete Ca2+stores. Muscarinic modulation was not blocked by staurosporine, a broad-spectrum protein kinase inhibitor, arguing against involvement of protein kinases. The modulation was not associated with a shift in the voltage dependence of channel activation. Homomeric KCNQ2 and KCNQ3 channels also expressed well and were modulated individually by oxo-M, suggesting that the motifs for modulation are present on both channel subtypes. Homomeric KCNQ2 and KCNQ3 currents were blocked, respectively, at very low and at high concentrations of tetraethylammonium ion. Finally, when KCNQ2 subunits were overexpressed by intranuclear DNA injection in sympathetic neurons, total M current was fully modulated by the endogenous neuronal muscarinic signaling mechanism. Our data further rule out Ca2+as the diffusible messenger. The reconstitution of muscarinic modulation of the M current that uses cloned components should facilitate the elucidation of the muscarinic signaling mechanism.
A Fundamental Role for the Nitric Oxide-G-Kinase Signaling Pathway in Mediating Intercellular Ca2+Waves in Glia
Authors: Willmott Nicholas J. , Wong Kay , Strong Anthony J.
Published: April 2018

In this study, we highlight a role for the nitric oxide–cGMP-dependent protein kinase (NO–G-kinase) signaling pathway in glial intercellular Ca2+wave initiation and propagation. Addition of the NO donor molsidomine (100–500 μm) or puffing aqueous NO onto primary glial cell cultures evoked an increase in [Ca2+]iin individual cells and also local intercellular Ca2+waves, which persisted after removal of extracellular Ca2+. High concentrations of ryanodine (100–200 μm) and antagonists of the NO–G-kinase signaling pathway essentially abrogated the NO-induced increase in [Ca2+]i, indicating that NO mobilizes Ca2+from a ryanodine receptor-linked store, via the NO–G-kinase signaling pathway. Addition of 10 μmnicardipine to cells resulted in a slowing of the molsidomine-induced rise in [Ca2+]i, and inhibition of Mn2+quench of cytosolic fura-2 fluorescence mediated by a bolus application of 2 μmaqueous NO to cells, indicating that NO also induces Ca2+influx in glia. Mechanical stress of individual glial cells resulted in an increase in intracellular NO in target and neighboring cells and intercellular Ca2+waves, which were NO, cGMP, and G-kinase dependent, because incubating cells with nitric oxide synthase, guanylate cyclase, and G-kinase inhibitors, or NO scavengers, reduced Δ[Ca2+]iand the rate of Ca2+wave propagation in these cultures. Results from this study suggest that NO–G-kinase signaling is coupled to Ca2+mobilization and influx in glial cells and that this pathway plays a fundamental role in the generation and propagation of intercellular Ca2+waves in glia.
Mechanisms of Glutamate Metabolic Signaling in Retinal Glial (Müller) Cells
Authors: Poitry Serge , Poitry-Yamate Carol , Ueberfeld Joern , MacLeish Peter R. , Tsacopoulos Marcos
Published: April 2018

Retinal Müller (glial) cells metabolize glucose to lactate, which is preferentially taken up by photoreceptor neurons as fuel for their oxidative metabolism. We explored whether lactate supply to neurons is a glial function controlled by neuronal signals. For this, we used subcellular fluorescence imaging and either amperometric or optical biosensors to monitor metabolic responses simultaneously from mitochondrial and cytosolic compartments of individual Müller cells from salamander retina. Our results demonstrate that lactate production and release is controlled by the combined action of glutamate and NH4+, both at micromolar concentrations. Transport of glutamate by a high-affinity carrier can produce in Müller cells a rapid rise of glutamate concentration. In our isolated Müller cells, glutamine synthetase (GS) converted transported glutamate to glutamine that was released. This reaction, predominant when enough NH4+is available, was limited at micromolar concentrations of NH4+, and more glutamate entered then as substrate into the mitochondrial tricarboxylic acid cycle (TCA). Increased production of glutamine by GS leads to increased utilization of ATP, some of which is generated glycolytically. Methionine sulfoximine, a specific inhibitor of GS, suppressed the stimulatory effect of glutamate and NH4+on glycolysis and induced massive entry of glutamate into the TCA cycle. The rate of glutamine production also determined the amount of pyruvate transaminated by glutamate to alanine. Lactate, alanine, and glutamine can be taken up and metabolized by photoreceptor neurons. We conclude that a major function of Müller glial cells is to nourish retinal neurons and to metabolize the neurotoxic ammonia and glutamate.
Impaired Axonal Regeneration in α7 Integrin-Deficient Mice
Authors: Werner Alexander , Willem Michael , Jones Leonard L. , Kreutzberg Georg W. , Mayer Ulrike , Raivich Gennadij
Published: April 2018

The interplay between growing axons and the extracellular substrate is pivotal for directing axonal outgrowth during development and regeneration. Here we show an important role for the neuronal cell adhesion molecule α7β1 integrin during peripheral nerve regeneration. Axotomy led to a strong increase of this integrin on regenerating motor and sensory neurons, but not on the normally nonregenerating CNS neurons. α7 and β1 subunits were present on the axons and their growth cones in the regenerating facial nerve. Transgenic deletion of the α7 subunit caused a significant reduction of axonal elongation. The associated delay in the reinnervation of the whiskerpad, a peripheral target of the facial motor neurons, points to an important role for this integrin in the successful execution of axonal regeneration.
Surviving Granule Cells of the Sclerotic Human Hippocampus Have Reduced Ca2+Influx Because of a Loss of Calbindin-D28kin Temporal Lobe Epilepsy
Authors: Nägerl U. Valentin , Mody Istvan , Jeub Monika , Lie Ailing A. , Elger Christian E. , Beck Heinz
Published: April 2018

In mesial temporal lobe epilepsy (mTLE), the predominant form of epilepsy in adults, and in animal models of the disease, there is a conspicuous loss of the intracellular Ca2+-binding protein calbindin-D28k(CB) from granule cells (GCs) of the dentate gyrus. The role of this protein in nerve cell function is controversial, but here we provide evidence for its role in controlling Ca2+influx into human neurons. In patients with Ammon's horn sclerosis (AHS), the loss of CB from GCs markedly increased the Ca2+-dependent inactivation of voltage-dependent Ca2+currents (ICa), thereby diminishing Ca2+influx during repetitive neuronal firing. Introducing purified CB into GCs restored Ca2+current inactivation to levels observed in cells with normal CB content harvested from mTLE patients without AHS. Our data are consistent with the possibility of neuroprotection secondary to the CB loss. By limiting Ca2+influx through an enhanced Ca2+-dependent inactivation of voltage-dependent Ca2+channels during prolonged neuronal discharges, the loss of CB may contribute to the resistance of surviving human granule cells in AHS.
Embryonic and Early Fetal Development of the Human Neocortex
Authors: Meyer Gundela , Schaaps Jean Pierre , Moreau Louis , Goffinet André M.
Published: April 2018

Early corticogenesis was studied in human embryos and early fetuses from Carnegie stages 16 to 22 (5–8 gestational weeks) by using immunohistochemistry for Reelin (Reln), calretinin (CR), and glutamic acid decarboxylase (GAD). A first population of Reln-positive cells appears in the neocortical anlage at stage 16 and increases in number at stages 17–18. At stages 19–20, a monolayer of horizontal CR- and GAD-positive, Reln-negative neurons forms in the preplate, whereas Reln-positive cells shift into a subpial position. Another cell class, the pioneer projection neuron, is CR-positive but GAD- and Reln-negative; pioneer cells contribute early corticofugal axons. Pioneer cells first appear below the monolayer at stage 20 and form a pioneer plate at stage 21. The cortical plate (CP) proper emerges at stage 21 and inserts itself within the pioneer plate, which is thus split into a minor superficial component and a larger deep component that presumably corresponds to the subplate. Initial CP neurons are radially organized and mostly CR-negative. Reln-positive cells remain consistently segregated from the pioneer cells and are thus not directly involved in preplate partition. Our data indicate that the neuronal composition of the human neocortical preplate is more complex than generally described and that various neurons participate in a sequence of events that precede the emergence of the CP.
In VivoStructure–Function Analyses ofCaenorhabditis elegansMEC-4, a Candidate Mechanosensory Ion Channel Subunit
Authors: Hong Kyonsoo , Mano Itzhak , Driscoll Monica
Published: April 2018

Mechanosensory signaling mediated by mechanically gated ion channels constitutes the basis for the senses of touch and hearing and contributes fundamentally to the development and homeostasis of all organisms. Despite this profound importance in biology, little is known of the molecular identities or functional requirements of mechanically gated ion channels. We report a genetically based structure–function analysis of the candidate mechanotransducing channel subunit MEC-4, a core component of a touch-sensing complex inCaenorhabditis elegansand a member of the DEG/ENaC superfamily. We identify molecular lesions in 40 EMS-inducedmec-4alleles and further probe residue and domain function using site-directed approaches. Our analysis highlights residues and subdomains critical for MEC-4 activity and suggests possible roles of these in channel assembly and/or function. We describe a class of substitutions that disrupt normal channel activity in touch transduction but remain permissive for neurotoxic channel hyperactivation, and we show that expression of an N-terminal MEC-4 fragment interferes within vivochannel function. These data advance working models for the MEC-4 mechanotransducing channel and identify residues, unique to MEC-4 or the MEC-4 degenerin subfamily, that might be specifically required for mechanotransducing function. Because many other substitutions identified by our study affect residues conserved within the DEG/ENaC channel superfamily, this work also provides a broad view of structure–function relations in the superfamily as a whole. Because theC. elegansgenome encodes representatives of a large number of eukaryotic channel classes, we suggest that similar genetic-based structure–activity studies might be generally applied to generate insight into thein vivofunction of diverse channel types.
Spontaneous Acetylcholine Secretion from Developing Growth Cones ofDrosophilaCentral Neurons in Culture: Effects of cAMP-Pathway Mutations
Authors: Yao Wei-Dong , Rusch Jannette , Poo Mu-ming , Wu Chun-Fang
Published: April 2018

We describe a novel bioassay system that usesXenopusembryonic myocytes (myoballs) to detect the release of acetylcholine fromDrosophilaCNS neurons. When a voltage-clampedXenopusmyoball was manipulated into contact with culturedDrosophila“giant” neurons, spontaneous synaptic current-like events were registered. These events were observed within seconds after contact and were blocked by curare and α-bungarotoxin, but not by TTX and Cd2+, suggesting that they are caused by the spontaneous quantal release of acetylcholine (ACh). The secretion occurred not only at the growth cone, but also along the neurite and at the soma, with significantly different release parameters among various regions. The amplitude of these currents displayed a skewed distribution. These features are distinct from synaptic transmission at more mature synapses or autapses formed in this culture system and are reminiscent of the transmitter release process during early development in other preparations. The usefulness of this coculture system in studying presynaptic secretion mechanisms is illustrated by a series of studies on the cAMP pathway mutations,dunce(dnc) andPKA-RI, which disrupt a cAMP-specific phosphodiesterase and the regulatory subunit of cAMP-dependent protein kinase A, respectively. We found that these mutations affected the ACh current kinetics, but not the quantal ACh packet, and that the release frequency was greatly enhanced by repetitive neuronal activity indnc,but not wild-type, growth cones. These results suggest that the cAMP pathway plays an important role in the activity-dependent regulation of transmitter release not only in mature synapses as previously shown, but also in developing nerve terminals before synaptogenesis.
A Role for Somatosensory Cortices in the Visual Recognition of Emotion as Revealed by Three-Dimensional Lesion Mapping
Authors: Adolphs Ralph , Damasio Hanna , Tranel Daniel , Cooper Greg , Damasio Antonio R.
Published: April 2018

Although lesion and functional imaging studies have broadly implicated the right hemisphere in the recognition of emotion, neither the underlying processes nor the precise anatomical correlates are well understood. We addressed these two issues in a quantitative study of 108 subjects with focal brain lesions, using three different tasks that assessed the recognition and naming of six basic emotions from facial expressions. Lesions were analyzed as a function of task performance by coregistration in a common brain space, and statistical analyses of their joint volumetric density revealed specific regions in which damage was significantly associated with impairment. We show that recognizing emotions from visually presented facial expressions requires right somatosensory-related cortices. The findings are consistent with the idea that we recognize another individual's emotional state by internally generating somatosensory representations that simulate how the other individual would feel when displaying a certain facial expression. Follow-up experiments revealed that conceptual knowledge and knowledge of the name of the emotion draw on neuroanatomically separable systems. Right somatosensory-related cortices thus constitute an additional critical component that functions together with structures such as the amygdala and right visual cortices in retrieving socially relevant information from faces.
Neurosteroid Modulation of GABA IPSCs Is Phosphorylation Dependent
Authors: Fáncsik András , Linn David M. , Tasker Jeffrey G.
Published: April 2018

The neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) facilitates GABAAreceptor-mediated ionic currents via allosteric modulation of the GABAAreceptor. Accordingly, allopregnanolone caused an increase in the slow decay time constant of spontaneous GABA-mediated IPSCs in magnocellular neurons recorded in hypothalamic slices. The allopregnanolone effect on IPSCs was inhibited by a G-protein antagonist as well as by blocking protein kinase C and, to a lesser extent, cAMP-dependent protein kinase activities. G-protein and protein kinase C activation in the absence of the neurosteroid had no effect on spontaneous IPSCs but enhanced the effect of subsequent allopregnanolone application. These findings together suggest that the neurosteroid modulation of GABA-mediated IPSCs requires G-protein and protein kinase activation, although not via a separate G-protein-coupled steroid receptor.
Molecular Cloning of a Novel Membrane Glycoprotein, Pal, Specifically Expressed in Photoreceptor Cells of the Retina and Containing Leucine-Rich Repeat
Authors: Gomi Fumi , Imaizumi Kazunori , Yoneda Takunari , Taniguchi Manabu , Mori Yasutake , Miyoshi Ko , Hitomi Junichi , Fujikado Takashi , Tano Yasuo , Tohyama Masaya
Published: April 2018

We have isolated a novel retina-specific gene in a screen for genes of which expression is not apparent neonatally in rat retina but is abundant postnatally on day 14 (P14). This gene, named Pal, encodes a putative type I transmembrane protein containing five leucine-rich repeats (LRRs), a single C2-type Ig-like domain, and a single fibronectin type III domain and is considered to be a new member of the LRR and Ig superfamily. No expression of Pal was found in rat retina at P1, but it was detected at P7 and markedly increased with subsequent development. These expression patterns of Pal appeared to be correlated with the development of the photoreceptor outer segments, because in the adult rat retina it was specifically localized in these segments. Ultrastructually, Pal immunoreactivity was distributed diffusely on the disk membrane in the lamellar regions. On the basis of its structural features and localization pattern, Pal may act as a receptor for a certain trophic factor or for an adhesion molecule participating in morphogenesis. The human homolog of Pal was mapped to chromosome 10q23.2–23.3 using fluorescencein situhybridization.
The Precision of Single Neuron Responses in Cortical Area V1 during Stereoscopic Depth Judgments
Authors: Prince Simon J. D. , Pointon Andrew D. , Cumming Bruce G. , Parker Andrew J.
Published: April 2018

The performance of single neurons in cortical area V1 of alert macaque monkeys was compared against the animals' psychophysical performance during a binocular disparity discrimination task. Performance was assessed with stimuli that consisted of a patch of dynamic random dots, whose disparity varied from trial to trial, surrounded by an annulus of similar dots at a fixed disparity. On each trial, the animals indicated whether the depth of the central patch was in front of or behind the annulus. For each disparity of the center patch, neural performance was assessed by calculating the probability that the response of the neuron was greater or less than the response when the center disparity was the same as that of the annulus. Initially the animals performed the task simultaneously with the neural recording. However, the range of disparities used, which was appropriate for the neuronal recording, may have affected performance, because the thresholds were substantially lower (2.6×) when the psychophysical measurements were repeated later. Average neuronal thresholds were ∼4× poorer than these behavioral thresholds, although the best neurons were marginally better than the animals' behavior. Thus, the well known precision of relative depth judgments can be supported with signals from a small number of V1 neurons. Interference with the relative depth information in the stimulus profoundly affected behavioral thresholds, which were ∼10× poorer when the surround was absent or contained binocularly uncorrelated dots. In this case, single V1 neurons consistently outperform the observer: presumably here, psychophysical thresholds are limited by other factors (such as uncertainty about vergence eye position).
A Role for Complement in the Rejection of Porcine Ventral Mesencephalic Xenografts in a Rat Model of Parkinson's Disease
Authors: Barker Roger A. , Ratcliffe Emma , Mclaughlin Megan , Richards Andrew , Dunnett Stephen B.
Published: April 2018

Vascularized whole organ discordant xenografts placed in the periphery are rejected by a rapid “hyperacute” process that involves preformed antibody binding to the xeno-antigens on the donor endothelial cells with complement activation. In the CNS, xenografts are classically thought to be rejected more slowly by a T-cell-dependent process. We now report that xenografts of embryonic porcine ventral mesencephalic tissue in the 6-hydroxydopamine-lesioned, nonimmunosuppressed rat induce both a humoral and a cell-mediated response. Over the first 10 d after implantation, the xenografts matured with identifiable TH neurons and pig-specific neurofilament fibers extending along host white matter tracts. During this period of time, IgM and complement binding were observed within the graft, as well as a CD8 cellular infiltrate, leading to rejection of the transplant over the next 25 d. These intracerebral xenografts were not associated with an early systemic antibody response. A role for complement in this rejection process was further investigated using cobra venom factor (CVF), which systemically depleted the rats of complement for 7 d. CVF treatment, when given in the period immediately before and after grafting, delayed but did not prevent the cellular immune response induced by the graft, demonstrating that xenografted neural tissue can activate the humoral arm of the rejection process, in particular the complement cascade. This suggests that interventions targeting this aspect of the immune rejection process may be of great importance for the future development of xenotransplantation for neurodegenerative conditions.
A Novel Selective Melanocortin-4 Receptor Agonist Reduces Food Intake in Rats and Mice without Producing Aversive Consequences
Authors: Benoit Stephen C. , Schwartz Michael W. , Lachey Jennifer L. , Hagan Mary M. , Rushing Paul A. , Blake Kathleen A. , Yagaloff Keith A. , Kurylko Grazyna , Franco Lucia , Danhoo Waleed , Seeley Randy J.
Published: April 2018

Studies using nonselective agonists and antagonists of melanocortin-3 receptor (MC3R) and MC4R point to the importance of the CNS melanocortin system in the control of food intake. We describe here a novel compound that is highly selective as an agonist at the MC4 receptor but has minimal activity at the MC3 receptor. When administered centrally to rats, this selective agonist increased Fos-like immunoreactivity in the paraventricular nucleus, central nucleus of the amygdala, nucleus of the solitary tract, and area postrema, a pattern of neuronal activation that is similar to that induced by a nonselective MC3/4R agonist. Additionally, it suppresses food intake when administered centrally to rats or peripherally todb/dbmice that lack functional leptin receptors via a mechanism that is not accompanied by illness or other nonspecific effects. Conversely, a related compound that is a selective MC4R antagonist potently increased food intake when administered centrally in rats. These results support the hypothesis that the brain MC4R is intimately involved in the control of food intake and body weight and provide evidence that selective activation of MC4R causes anorexia that is not secondary to aversive effects.
Role of Microglial-Derived Tumor Necrosis Factor in Mediating CD14 Transcription and Nuclear Factor κ B Activity in the Brain during Endotoxemia
Authors: Nadeau Sylvain , Rivest Serge
Published: April 2018

Systemic injection of the endotoxin lipopolysaccharide (LPS) upregulates the gene encoding CD14 early in the circumventricular organs (CVOs) and later in the brain parenchyma. The present study tested the hypothesis that the parenchymal production of the proinflammatory cytokine tumor necrosis factor α (TNF-α) by microglial cells is responsible for triggering CD14 transcription in an autocrine/paracrine loop-like manner. In a first set of experiments, Sprague Dawley rats were killed 1, 3, 6, and 12 hr after an intracerebroventricular administration of recombinant rat TNF-α or vehicle solution. Second, anti-rat TNF-α-neutralizing antibody or vehicle solution was administrated into the lateral ventricle 10 hr before an intraperitoneal injection of LPS. Central administration of the cytokine caused a strong induction of IκBα, TNF-α, and CD14 mRNA in parenchymal microglial cells. The hybridization signal for these transcripts was localized to the edge of the ventricles and the site of infusion. The time-related expression of each mRNA suggested that TNF-α has the ability to trigger its own production followed by the transcription of the LPS receptor; the signal for IκBα, TNF-α, and CD14 peaked at 1, 3, and 6 hr, respectively. The genes encoding TNF-α and mCD14 were also induced in the CVOs and within microglial cells across the brain parenchyma in response to intraperitoneal LPS administration. This induction in parenchymal cells of the brain was prevented in animals that received the anti-TNF-antisera intracerebroventricularly 10 hr before the systemic treatment with the endotoxin. The present data provide the evidence that microglial-derived TNF-α is responsible for the production of the LPS receptor CD14 during endotoxemia. This autocrine/paracrine stimulatory loop may be of great importance in controlling the inflammatory events that take place in the CNS during innate immune response as well as under pathological conditions.
A Site of Auditory Experience-Dependent Plasticity in the Neural Representation of Auditory Space in the Barn Owl's Inferior Colliculus
Authors: Gold Joshua I. , Knudsen Eric I.
Published: April 2018

The barn owl's optic tectum contains a map of auditory space that is based, in part, on a map of interaural time difference (ITD). Previous studies have shown that this ITD map is shaped by auditory experience. In this study, we investigated whether the plasticity responsible for experience-induced changes in ITD tuning in the tectum occurs within the tectum itself or at an earlier stage in the auditory pathway.

We altered auditory experience in young owls by implanting an acoustic filtering device in one ear that caused frequency-dependent changes in sound timing and level. We analyzed the representation of ITD in normal and device-reared owls in two nuclei in the ascending pathway: the external nucleus of the inferior colliculus (ICX), the primary source of ascending auditory input to the tectum, and the lateral shell of the central nucleus of the inferior colliculus (ICCls), the primary source of input to the ICX. In the ICX, device rearing caused adaptive, frequency-dependent changes in ITD tuning, as well as changes in frequency tuning. These changes in tuning were similar to changes that occurred in the optic tectum in the same owls. In contrast, in the ICCls, tuning for ITD and frequency was unaffected by device rearing. The data indicate that plasticity at the level of the ICX is largely responsible for the adaptive adjustments in ITD tuning and frequency tuning that are observed in the optic tecta of owls raised with abnormal auditory experience.
Retroviral Inhibition of cAMP-Dependent Protein Kinase Inhibits Myelination But Not Schwann Cell Mitosis Stimulated by Interaction with Neurons
Authors: Howe Douglas G. , McCarthy Ken D.
Published: April 2018

Schwann cells are the myelinating glia of the peripheral nervous system. Neuron–Schwann cell contact profoundly affects several aspects of Schwann cell phenotype, including stimulation of mitosis and myelin formation. Many reports suggest that neuronal contact exerts this influence on Schwann cells by elevating Schwann cell cAMP and activating cAMP-dependent protein kinase A (PKA). To elucidate the importance of Schwann cell PKA in neuronal stimulation of Schwann cell mitosis and myelination, the gene encoding the PKA inhibitory protein RIαAB or PKIEGFP was delivered to Schwann cells using retroviral vectors. PKA inhibitory retroviral vectors effectively blocked forskolin-stimulated Schwann cell mitosis and morphological change, demonstrating the ability of the vectors to inhibit PKA in infected Schwann cells. Treatment of dorsal root ganglia neuron–Schwann cell cocultures with H-89 (10 μm) or KT5720 (1–10 μm), chemical inhibitors selective for PKA, significantly inhibited neuronal stimulation of Schwann cell mitosis. In contrast, retrovirus-mediated inhibition of Schwann cell PKA had no effect on the ability of neurons to stimulate Schwann cell mitosis. However, markedly fewer myelin segments were formed by Schwann cells expressing PKA inhibitory proteins compared with controls. These results suggest that activation of Schwann cell PKA is required for myelin formation but not for Schwann cell mitosis stimulated by interaction with neurons.
Projections from the Rat Prefrontal Cortex to the Ventral Tegmental Area: Target Specificity in the Synaptic Associations with Mesoaccumbens and Mesocortical Neurons
Authors: Carr David B. , Sesack Susan R.
Published: April 2018

Excitatory projections from the prefrontal cortex (PFC) to the ventral tegmental area (VTA) play an important role in regulating the activity of VTA neurons and the extracellular levels of dopamine (DA) within forebrain regions. Previous investigations have demonstrated that PFC terminals synapse on the dendrites of DA and non-DA neurons in the VTA. However, the projection targets of these cells are not known. To address whether PFC afferents innervate different populations of VTA neurons that project to the nucleus accumbens (NAc) or to the PFC, a triple labeling method was used that combined peroxidase markers for anterograde and retrograde tract-tracing with pre-embedding immunogold–silver labeling for either tyrosine hydroxylase (TH) or GABA. Within the VTA, PFC terminals formed asymmetric synapses onto dendritic shafts that were immunoreactive for either TH or GABA. PFC terminals also synapsed on VTA dendrites that were retrogradely labeled from the NAc or the PFC. Dendrites retrogradely labeled from the NAc and postsynaptic to PFC afferents were sometimes immunoreactive for GABA but were never TH-labeled. Conversely, dendrites retrogradely labeled from the PFC and postsynaptic to PFC afferents were sometimes immunoreactive for TH but were never GABA-labeled. These results provide the first demonstration of PFC afferents synapsing on identified cell populations in the VTA and indicate a considerable degree of specificity in the targets of the PFC projection. The unexpected finding of selective PFC synaptic input to GABA-containing mesoaccumbens neurons and DA-containing mesocortical neurons suggests novel mechanisms through which the PFC can influence the activity of ascending DA and GABA projections.
Postnatal Handling Increases the Expression of cAMP-Inducible Transcription Factors in the Rat Hippocampus: The Effects of Thyroid Hormones and Serotonin
Authors: Meaney Michael J. , Diorio Josie , Francis Darlene , Weaver Shelley , Yau Joyce , Chapman Karen , Seckl Jonathan R.
Published: April 2018

Postnatal handling increases glucocorticoid receptor expression in the rat hippocampus, thus altering the regulation of hypothalamic synthesis of corticotropin-releasing hormone and the hypothalamic–pituitary–adrenal response to stress. The effect on glucocorticoid receptor gene expression represents one mechanism by which the early environment can exert a long-term effect on neural development. The handling effect on hippocampal glucocorticoid receptor expression is dependent on peripheral thyroid hormone release and the activation of ascending serotonergic pathways. In primary hippocampal cell cultures, serotonin (5-HT) increases glucocorticoid receptor expression, and this effect appears to be mediated by increased cAMP levels. In the current studies we examined thein vivoeffects of handling on hippocampal cAMP–protein kinase A (PKA) activity. In 7-d-old rat pups, we found that (1) postnatal handling increased adenylyl cyclase activity and hippocampal cAMP levels, (2) the effect of handling on cAMP levels was completely blocked by treatment with either propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, or the 5-HT receptor antagonist, ketanserin, and (3) handling also increased hippocampal PKA activity. We then examined the effects of handling on cAMP-inducible transcription factors. Handling rapidly increased levels of the mRNAs for nerve growth factor-inducible factor A (NGFI-A) (zif268,krox24) and activator protein-2 (AP-2) as well as for NGFI-A and AP-2 immunoreactivity throughout the hippocampus. Finally, we found that the effects of handling on NGFI-A and AP-2 expression were significantly reduced by concurrent treatment with either PTU or ketanserin, effects that paralleled those on cAMP formation. NGFI-A and AP-2 have been implicated in the regulation of glucocorticoid receptor expression during development. Thus, these findings suggest that postnatal handling might alter glucocorticoid receptor gene expression via cAMP–PKA pathways involving the activation of NGFI-A and AP-2.
GABA in the Deep Layers of the Superior Colliculus/Mesencephalic Reticular Formation Mediates the Enhancement of Startle by the Dopamine D1Receptor Agonist SKF 82958 in Rats
Authors: Meloni Edward G. , Davis Michael
Published: April 2018

GABA transmission in the deep layers of the superior colliculus/deep mesencephalic reticular formation (deep SC/Me) mediates several motor responses, including those expressed after systemic administration of dopamine agonists. In the present study we examined the role of the deep SC/Me in the modulation of the acoustic startle reflex and its enhancement by the dopamine D1agonist SKF 82958. Rats were implanted with bilateral cannulas into the deep SC/Me or superficial layers of the SC (super SC) and 1 week later were infused with various compounds. The GABAAantagonist bicuculline (0, 5, and 10 ng) produced a dose- and time-dependent enhancement of startle after infusion into the deep SC/Me, but not the super SC. Infusion of the GABAAagonist muscimol (0.1 μg) into the deep SC/Me, but not the super SC, blocked the enhancement of startle by systemic SKF 82958 (1 mg/kg) but had no effect on baseline startle by itself. This effect was not produced by infusion of the D1antagonist SCH 23390(1 μg) or the glutamate antagonist NBQX (0.1 μg). Deposits of FluoroGold into the deep SC/Me, combined with immunohistochemistry for glutamic acid decarboxylase (GAD), confirmed a direct GABAergic input from the substantia nigra pars reticulata (SNr) to the deep SC/Me. These results suggest that GABA tone in the deep SC/Me modulates the expression of startle as well as the enhancement of startle by dopamine D1agonists. On the basis of these data and previous work, we have proposed a striatonigral–tectal–reticular neural pathway mediating the effects of dopamine D1agonists on startle.
Temporal Coding of Visual Information in the Thalamus
Authors: Reinagel Pamela , Reid R. Clay
Published: April 2018

The amount of information a sensory neuron carries about a stimulus is directly related to response reliability. We recorded from individual neurons in the cat lateral geniculate nucleus (LGN) while presenting randomly modulated visual stimuli. The responses to repeated stimuli were reproducible, whereas the responses evoked by nonrepeated stimuli drawn from the same ensemble were variable. Stimulus-dependent information was quantified directly from the difference in entropy of these neural responses. We show that a single LGN cell can encode much more visual information than had been demonstrated previously, ranging from 15 to 102 bits/sec across our sample of cells. Information rate was correlated with the firing rate of the cell, for a consistent rate of 3.6 ± 0.6 bits/spike (mean ± SD). This information can primarily be attributed to the high temporal precision with which firing probability is modulated; many individual spikes were timed with better than 1 msec precision. We introduce a way to estimate the amount of information encoded in temporal patterns of firing, as distinct from the information in the time varying firing rate at any temporal resolution. Using this method, we find that temporal patterns sometimes introduce redundancy but often encode visual information. The contribution of temporal patterns ranged from −3.4 to +25.5 bits/sec or from −9.4 to +24.9% of the total information content of the responses.
Intrinsic and Extrinsic Contributions to Auditory Selectivity in a Song Nucleus Critical for Vocal Plasticity
Authors: Rosen Merri J. , Mooney Richard
Published: April 2018

The development, maintenance, and perception of learned vocalizations in songbirds are likely to require auditory neurons that respond selectively to song. Neurons with song-selective responses have been described in several brain nuclei critical to singing, but the mechanisms by which such response properties arise, are modified, and propagate are poorly understood. The lateral magnocellular nucleus of the anterior neostriatum (LMAN) is the output of an anterior forebrain pathway (AFP) essential for learning and maintenance of song, processes dependent on auditory feedback. Although neurons throughout this pathway respond selectively to auditory presentation of the bird's own song, LMAN is the last stage at which responses to this auditory information could be transformed before being transmitted to vocal motor areas, where such responses may influence vocal production. Indeed, previous extracellular studies have indicated that LMAN′s auditory selectivity is greater than that at earlier stages of the AFP. To determine whether LMAN local circuitry transforms or simply relays song-related auditory information to vocal control neurons, it is essential to distinguish local from extrinsic contributions to LMAN′s auditory selectivity.In vivointracellular recordings from LMAN projection neurons, coupled with local circuit inactivation, reveal that much of LMAN′s song selectivity is supplied by its extrinsic inputs, but selective blockade of GABA receptors indicates that local inhibition is required for the expression of song selectivity. Therefore, LMAN neurons receive highly song-selective information, but LMAN′s local circuitry can mask these selective inputs, providing a mechanism for context-dependent auditory feedback.
Periodicity and Firing Rate As Candidate Neural Codes for the Frequency of Vibrotactile Stimuli
Authors: Salinas Emilio , Hernández Adrián , Zainos Antonio , Romo Ranulfo
Published: April 2018

The flutter sensation is felt when mechanical vibrations between 5 and 50 Hz are applied to the skin. Neurons with rapidly adapting properties in the somatosensory system of primates are driven very effectively by periodic flutter stimuli; their evoked spike trains typically have a periodic structure with highly regular time differences between spikes. A long-standing conjecture is that, such periodic structure may underlie a subject's capacity to discriminate the frequencies of periodic vibrotactile stimuli and that, in primary somatosensory areas, stimulus frequency is encoded by the regular time intervals between evoked spikes, not by the mean rate at which these are fired. We examined this hypothesis by analyzing extracellular recordings from primary (S1) and secondary (S2) somatosensory cortices of awake monkeys performing a frequency discrimination task. We quantified stimulus-driven modulations in firing rate and in spike train periodicity, seeking to determine their relevance for frequency discrimination. We found that periodicity was extremely high in S1 but almost absent in S2. We also found that periodicity was enhanced when the stimuli were relevant for behavior. However, periodicity did not covary with psychophysical performance in single trials. On the other hand, rate modulations were similar in both areas, and with periodic and aperiodic stimuli, they were enhanced when stimuli were important for behavior, and were significantly correlated with psychophysical performance in single trials. Thus, the exquisitely timed, stimulus-driven spikes of primary somatosensory neurons may or may not contribute to the neural code for flutter frequency, but firing rate seems to be an important component of it.
cAMP-Dependent Protein Kinase Inhibits mGluR2 Coupling to G-Proteins by Direct Receptor Phosphorylation
Authors: Schaffhauser Hervé , Cai Zhaohui , Hubalek Frantisek , Macek Thomas A. , Pohl Jan , Murphy Thomas J. , Conn P. Jeffrey
Published: April 2018

One of the primary physiological roles of group II and group III metabotropic glutamate receptors (mGluRs) is to presynaptically reduce synaptic transmission at glutamatergic synapses. Interestingly, previous studies suggest that presynaptic mGluRs are tightly regulated by protein kinases. cAMP analogs and the adenylyl cyclase activator forskolin inhibit the function of presynaptic group II mGluRs in area CA3 of the hippocampus. We now report that forskolin has a similar inhibitory effect on putative mGluR2-mediated responses at the medial perforant path synapse and that this effect of forskolin is blocked by a selective inhibitor of cAMP-dependent protein kinase (PKA). A series of biochemical and molecular studies was used to determine the precise mechanism by which PKA inhibits mGluR2 function. Our studies reveal that PKA directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor. Site-directed mutagenesis combined with biochemical measures of mGluR2 function reveal that phosphorylation of this site inhibits coupling of mGluR2 from GTP-binding proteins
Neocortical Origin and Tangential Migration of Guidepost Neurons in the Lateral Olfactory Tract
Authors: Tomioka Naomi , Osumi Noriko , Sato Yasufumi , Inoue Takayoshi , Nakamura Shun , Fujisawa Hajime , Hirata Tatsumi
Published: April 2018

The early-generated neurons designated as lot cells specifically mark the future site of the lateral olfactory tract (LOT) and guide LOT axons. We investigated the mechanism of how lot cells develop and get localized in the LOT position. Lot cells differentiated from neuroepithelial cells in all regions of the neocortex but not from those in the ganglionic eminence in culture. Cell tracing analyses demonstrated that lot cells generated from the neocortex subsequently followed a tangential migration stream ventrally toward the LOT position. Mutant mouse embryos lacking the function of transcription factor Gli3 showed disturbances of the migration stream and translocation of lot cells in the dorsal telencephalon. These results reveal a new type of neuronal migration in the telencephalon and introduce an unexpected dramatic feature of the earliest regionalization of the telencephalon.
Developmental Regulation of a Local Positive Autocontrol of Supraoptic Neurons
Authors: Chevaleyre Vivien , Dayanithi Govindan , Moos Françoise C. , Desarménien Michel G.
Published: April 2018

Mature oxytocin (OT) and vasopressin (AVP) magnocellular neurons of the hypothalamic supraoptic nuclei (SON) autocontrol their electrical activity via somatodendritic release of their respective peptides. Because OT and AVP are synthesized early in development and could play an important role in the maturation of these neurons, we checked whether the peptides are released within the SON and act on their secreting neurons during 3 weeks of postnatal development. We used patch-clamp recordings from SON neurons in rat hypothalamic horizontal slices to show that the spontaneous electrical activity of immature SON neurons is blocked by OT or AVP receptor antagonists, demonstrating a basal somatodendritic release of the peptides. Application of OT or AVP depolarizes SON neurons and stimulates activity typical of the corresponding mature neurons. This effect is directly on SON neurons because it is recorded in dissociated neurons. Radioimmunoassays from isolated SON were used to show that each peptide facilitates its own release at a somatodendritic level, exhibiting a self-sustaining positive feedback loop. This autocontrol is not uniform during development because the proportion of neurons depolarized by the peptides, the amplitude of the depolarization, and the propensity of the peptides to facilitate their own release are maximal during the second postnatal week and decrease thereafter. These data are consistent with a role of autocontrol in the maturation of SON neurons because it is maximal during the delimited period of postnatal development that corresponds to the period of major synapse formation.