bluuebunny/crossref_metadata_2025 huggingface dataset:
Caspase-2 Mediates Neuronal Cell Death Induced by β-Amyloid
Authors: Troy Carol M. , Rabacchi Sylvia A. , Friedman Wilma J. , Frappier Thierry F. , Brown Kristy , Shelanski Michael L.
Published: April 2018

β-amyloid (Aβ) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble Aβ are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that Aβ induces death by oxidative stress, possibly through the generation of peroxynitrite from superoxide and nitric oxide. In our current study, treatment with nitric oxide generators protected against Aβ-induced death, whereas inhibition of nitric oxide synthase afforded no protection, suggesting that formation of peroxynitrite is not critical for Aβ-mediated death. Previous studies have shown that aggregated Aβ can induce caspase-dependent apoptosis in cultured neurons. In all of the neuronal populations studied here (hippocampal neurons, sympathetic neurons, and PC12 cells), cell death was blocked by the broad spectrum caspase inhibitorN-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone and more specifically by the downregulation of caspase-2 with antisense oligonucleotides. In contrast, downregulation of caspase-1 or caspase-3 did not block Aβ1–42-induced death. Neurons from caspase-2 null mice were totally resistant to Aβ1–42toxicity, confirming the importance of this caspase in Aβ-induced death. The results indicate that caspase-2 is necessary for Aβ1–42-induced apoptosisin vitro.
Interstitial Cells of Cajal Mediate Cholinergic Neurotransmission from Enteric Motor Neurons
Authors: Ward Sean M. , Beckett Elizabeth A. H. , Wang XuanYu , Baker Fred , Khoyi Mohammad , Sanders Kenton M.
Published: April 2018

Interstitial cells of Cajal (ICC) are interposed between enteric neurons and smooth muscle cells in gastrointestinal muscles. The role of intramuscular ICC (IC-IM) in mediating enteric excitatory neural inputs was studied using gastric fundus muscles of wild-type animals andW/Wvmutant mice, which lack IC-IM. Excitatory motor neurons, labeled with antibodies to vesicular acetylcholine transporter or substance-P, were closely associated with IC-IM. Immunocytochemistry showed close contacts between enteric neurons and IC-IM. IC-IM also formed gap junctions with smooth muscle cells. Electrical field stimulation yielded fast excitatory junction potentials in the smooth muscle that were blocked by atropine. Neural responses were greatly reduced in muscles ofW/Wvanimals. Loss of cholinergic responses inW/Wvmuscles seemed to be caused by the loss of close synaptic contacts between motor neurons and IC-IM, because these muscles were not less responsive to exogenous acetylcholine than were wild-type muscles.W/Wvmuscles also responded to excitatory nerve stimulation when the breakdown of acetylcholine was blocked by neostigmine. The density of cholinergic nerve bundles within the muscles was not significantly different in wild-type andW/Wvmuscles, and similar amounts of14[C]choline were released from preloaded wild-type andW/Wvmuscles in response to nerve stimulation. The impact of losing IC-IM on gastric compliance was also evaluated in intact stomachs. Pressure increased as a function of fluid volume and infusion rate in wild-type animals, butW/Wvanimals showed little basal tone and minimal increases in pressure with fluid infusions. These data suggest that IC-IM play a major role in receiving cholinergic excitatory inputs from the enteric nervous system in the murine fundus.
Discharge Properties of Juxtacellularly Labeled and Immunohistochemically Identified Cholinergic Basal Forebrain Neurons Recorded in Association with the Electroencephalogram in Anesthetized Rats
Authors: Manns Ian D. , Alonso Angel , Jones Barbara E.
Published: April 2018

Multiple lines of evidence indicate that cholinergic basal forebrain neurons play an important role in the regulation of cortical activity and state. However, the discharge properties of cholinergic cells in relation to the electroencephalogram (EEG) are not yet known. In the present study, cells were recorded in the basal forebrain in association with cortical EEG activity in urethane-anesthetized rats, and their discharge was examined during EEG irregular slow activity and during stimulation-induced cortical activation, characterized by rhythmic slow (theta) and high-frequency (gamma) activities. Recorded cells were labeled with Neurobiotin (Nb), using the juxtacellular technique and identified as cholinergic by immunohistochemical staining for choline acetyltransferase (ChAT). Nb-positive/ChAT-positive neurons were distinctive and significantly different from Nb-positive/ChAT-negative neurons, which were heterogeneous in their discharge properties. All Nb+/ChAT+cells increased their discharge rate with stimulation, and most shifted from an irregular tonic discharge during EEG slow irregular activity to a rhythmic burst discharge during rhythmic slow activity. The stimulation-induced rhythmic discharge was cross-correlated with the EEG rhythmic slow activity. In some units the rhythmic discharge matched the rhythmic slow activity of the retrosplenial cortex; in others, it matched that of the prefrontal cortex, which occurred at a slower frequency, suggesting that subsets of cholinergic neurons may influence their cortical target areas rhythmically at particular frequencies. Cholinergic basal forebrain neurons thus may evoke and enhance cortical activation via both an increase in rate and a change in pattern to rhythmic bursting that would stimulate rhythmic slow (theta-like) activity in cortical fields during active waking and paradoxical sleep states.
α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression
Authors: Fekete Csaba , Légrádi Gábor , Mihály Emese , Huang Qin-Heng , Tatro Jeffrey B. , Rand William M. , Emerson Charles H. , Lechan Ronald M.
Published: April 2018

The hypothalamic arcuate nucleus has an essential role in mediating the homeostatic responses of the thyroid axis to fasting by altering the sensitivity of prothyrotropin-releasing hormone (pro-TRH) gene expression in the paraventricular nucleus (PVN) to feedback regulation by thyroid hormone. Because agouti-related protein (AGRP), a leptin-regulated, arcuate nucleus-derived peptide with α-MSH antagonist activity, is contained in axon terminals that terminate on TRH neurons in the PVN, we raised the possibility that α-MSH may also participate in the mechanism by which leptin influences pro-TRH gene expression. By double-labeling immunocytochemistry, α-MSH-IR axon varicosities were juxtaposed to ∼70% of pro-TRH neurons in the anterior and periventricular parvocellular subdivisions of the PVN and to 34% of pro-TRH neurons in the medial parvocellular subdivision, establishing synaptic contacts both on the cell soma and dendrites. All pro-TRH neurons receiving contacts by α-MSH-containing fibers also were innervated by axons containing AGRP. The intracerebroventricular infusion of 300 ng of α-MSH every 6 hr for 3 d prevented fasting-induced suppression of pro-TRH in the PVN but had no effect on AGRP mRNA in the arcuate nucleus. α-MSH also increased circulating levels of free thyroxine (T4) 2.5-fold over the levels in fasted controls, but free T4 did not reach the levels in fed controls. These data suggest that α-MSH has an important role in the activation of pro-TRH gene expression in hypophysiotropic neurons via either a mono- and/or multisynaptic pathway to the PVN, but factors in addition to α-MSH also contribute to the mechanism by which leptin administration restores thyroid hormone levels to normal in fasted animals.
Chronic Stress Induces Impairment of Spatial Working Memory Because of Prefrontal Dopaminergic Dysfunction
Authors: Mizoguchi Kazushige , Yuzurihara Mitsutoshi , Ishige Atsushi , Sasaki Hiroshi , Chui De-Hua , Tabira Takeshi
Published: April 2018

Although the mechanism responsible for cognitive deficits in stress-related neuropsychiatric disorders has been obscure, prefrontal cortical (PFC) dopaminergic dysfunction is thought to be involved. In animals, the mesoprefrontal dopaminergic system is particularly vulnerable to stress, and chronic stress induces working memory impairment. However, the relation between the working memory impairment and altered dopaminergic activity in chronically stressed rats is unclear. Furthermore, the change of dopaminergic activity in the PFC induced by stress is thought to express as a stress response, not as a disorder of organic function. We have previously reported that chronic stress administered by water immersion and restraint for 4 weeks induces a organic disorder such as hippocampal neuronal degeneration. We therefore examined whether chronically stressed (4 weeks) and recovered (10 d) rats show a working memory impairment caused by reduced dopamine (DA) transmission in the PFC, as suspected in the neuropsychiatric disorders. The stress impaired the spatial working memory evaluated by T-maze task and induced a marked reduction of DA transmission concomitant with an increase in DA D1 receptor density in the PFC. This memory impairment was sufficiently ameliorated by intra-PFC infusion of 10 ng SKF 81297, a D1 receptor-specific agonist. Pretreatment with intraperitoneal injection of 20 μg/kg SCH 23390, a D1 receptor antagonist, reversed the SKF 81297 response. These results indicate that chronic stress induces working memory impairment through a D1 receptor-mediated hypodopaminergic mechanism in the PFC. These findings provide important information for understanding of the mechanisms underlying PFC dysfunction in stress-related neuropsychiatric disorders.
Learning Performance of Normal and MutantDrosophilaafter Repeated Conditioning Trials with Discrete Stimuli
Authors: Beck C. D. O. , Schroeder Bradley , Davis Ronald L.
Published: April 2018

A new olfactory conditioning procedure is described using short training trials with discrete presentation of conditioned stimuli (CS) and unconditioned stimuli (US). A short odor presentation along with a single-shock stimulus produced modest but reliable and reproducible learning. Multiple trials presented sequentially improved performance with increasing trial number. Trial spacing had a significant impact on performance. Two trials presented with a short intertrial interval (ITI) produced no improvement over a single trial; two trials with a 15 min ITI significantly boosted performance. This effect required two associative trials, because substituting one of the trials with the CS alone, US alone, or an unpaired CS–US failed to boost performance. The increase in initial performance with two trials decayed within 15 min after training. Thus, the effect is short-lived. The utility of using a battery of tests, including a single short trial, two massed trials, and two spaced trials, to investigate parameters of memory formation in several mutants was demonstrated.
Modeling of Spontaneous Activity in Developing Spinal Cord Using Activity-Dependent Depression in an Excitatory Network
Authors: Tabak Joël , Senn Walter , O'Donovan Michael J. , Rinzel John
Published: April 2018

Spontaneous episodic activity is a general feature of developing neural networks. In the chick spinal cord, the activity comprises episodes of rhythmic discharge (duration 5–90 sec; cycle rate 0.1–2 Hz) that recur every 2–30 min. The activity does not depend on specialized connectivity or intrinsic bursting neurons and is generated by a network of functionally excitatory connections. Here, we develop an idealized, qualitative model of a homogeneous, excitatory recurrent network that could account for the multiple time-scale spontaneous activity in the embryonic chick spinal cord. We show that cycling can arise from the interplay between excitatory connectivity and fast synaptic depression. The slow episodic behavior is attributable to a slow activity-dependent network depression that is modeled either as a modulation of cellular excitability or as synaptic depression. Although the two descriptions share many features, the model with a slow synaptic depression accounts better for the experimental observations during blockade of excitatory synapses.
Presynaptic Mitochondrial Calcium Sequestration Influences Transmission at Mammalian Central Synapses
Authors: Billups Brian , Forsythe Ian D.
Published: April 2018

Beyond their role in generating ATP, mitochondria have a high capacity to sequester calcium. The interdependence of these functions and limited access to presynaptic compartments makes it difficult to assess the role of sequestration in synaptic transmission. We addressed this important question using the calyx of Held as a model glutamatergic synapse by combining patch-clamp with a novel mitochondrial imaging method. Presynaptic calcium current, mitochondrial calcium concentration ([Ca2+]mito, measured using rhod-2 or rhod-FF), cytoplasmic calcium concentration ([Ca2+]cyto, measured using fura-FF), and the postsynaptic current were monitored during synaptic transmission. Presynaptic [Ca2+]cytorose to 8.5 ± 1.1 μmand decayed rapidly with a time constant of 45 ± 3 msec; presynaptic [Ca2+]mitoalso rose rapidly to >5 μmbut decayed slowly with a half-time of 1.5 ± 0.4 sec. Mitochondrial depolarization with rotenone and carbonyl cyanidep-trifluoromethoxyphenylhydrazone abolished mitochondrial calcium rises and slowed the removal of [Ca2+]cytoby 239 ± 22%. Using simultaneous presynaptic and postsynaptic patch clamp, combined with presynaptic mitochondrial and cytoplasmic imaging, we investigated the influence of mitochondrial calcium sequestration on transmitter release. Depletion of ATP to maintain mitochondrial membrane potential was blocked with oligomycin, and ATP was provided in the patch pipette. Mitochondrial depolarization raised [Ca2+]cytoand reduced transmitter release after short EPSC trains (100 msec, 200 Hz); this effect was reversed by raising mobile calcium buffering with EGTA. Our results suggest a new role for presynaptic mitochondria in maintaining transmission by accelerating recovery from synaptic depression after periods of moderate activity. Without detectable thapsigargin-sensitive presynaptic calcium stores, we conclude that mitochondria are the major organelle regulating presynaptic calcium at central glutamatergic terminals.
Intrinsic Program for Migration of Cerebellar Granule CellsIn Vitro
Authors: Yacubova Elina , Komuro Hitoshi
Published: April 2018

Cerebellar granule cells exhibit distinct modes of migration in different cortical layers. The role of external cues in controlling these alterations has been suggested, but the significance of internal programs is not well understood. In the present study, we examined autonomous changes of migratory behavior of isolated granule cells in microexplant cultures of the postnatal mouse cerebellum. We found that isolated granule cells sequentially go through three characteristic phases of migration without cell–cell contact. In the first phase (0–20 hrin vitro) granule cells exhibit the highest rate of turning behavior and have multiple short processes. The length of the movement cycle is shortest. In the second phase (20–40 hrin vitro), granule cells extend a long and thick process and exhibit an elongated cycle of movement. Their speed is fastest, whereas the rate of turning is lowest. In the third phase (40–60 hrin vitro), granule cells slow down their movement and slightly increase their turnings. The length of the movement cycle further increases. At the end, the cells become permanently stationary, extend a lamellipodium around the soma, and emit several thin processes. Interestingly, granule cells sequentially develop four different modes of turning. These results indicate that internal (intrinsic) programs control alterations of granule cell behavior in a stage-dependent manner, suggesting that such programs independent of local cell–cell contacts may be essential for granule cell translocation in the developing cerebellum.
The Projections of Early Enteric Neurons Are Influenced by the Direction of Neural Crest Cell Migration
Authors: Young H. M. , Jones B. R. , McKeown S. J.
Published: April 2018

The enteric nervous system arises from the neural crest. In embryonic mice, vagal neural crest cells enter the developing foregut at approximately embryonic day 9.5 (E9.5) and then migrate rostrocaudally to colonize the entire gastrointestinal tract by E14.5. This study showed that a subpopulation of vagal crest-derived cells, very close to the migratory wavefront, starts to differentiate into neurons early, as shown by the expression of neuron-specific proteins and the absence of Sox10. Many of the early differentiating neurons transiently exhibited tyrosine hydroxylase (TH) immunoreactivity. The TH cells were demonstrated to be the progenitors of nitric oxide synthase (NOS) neurons. Immunohistochemistry, lesions, and DiI tracing were used to examine the projections of developing enteric neurons. The axons of first neurons in the gut (the TH–NOS neurons) projected in the same direction (caudally), and traversed the same pathways through the mesenchyme, as the migrating, undifferentiated, vagal crest-derived cells. To examine if the direction of migration and direction of axon projection are linked, coculture experiments were set up in which vagal crest-derived cells migrated either rostrocaudally (as they doin vivo), or caudorostrally (which they do not normally do), to colonize explants of embryonic aneural hindgut. The direction in which neurons projected was correlated with the direction of cell migration, but migration direction appears to be not the only mechanism influencing axon projection. Peristaltic reflexes involve both orally (rostrally) projecting neurons and anally (caudally) projecting neurons. Because few rostrally projecting neurons could be detected before birth, the full circuitry for peristaltic reflexes appears to develop after birth.
The Type 1 Interleukin-1 Receptor Is Essential for the Efficient Activation of Microglia and the Induction of Multiple Proinflammatory Mediators in Response to Brain Injury
Authors: Basu Anirban , Krady J. Kyle , O'Malley Mark , Styren Scott D. , DeKosky Steven T. , Levison Steven W.
Published: April 2018

Interleukin-1 (IL-1) is induced immediately after insults to the brain, and elevated levels of IL-1 have been strongly implicated in the neurodegeneration that accompanies stroke, Alzheimer's disease, and multiple sclerosis. In animal models, antagonizing IL-1 has been shown to reduce cell death; however, the basis for this protection has not been elucidated. Here we analyzed the response to penetrating brain injury in mice lacking the type 1 IL-1 receptor (IL-1R1) to determine which cellular and molecular mediators of tissue damage require IL-1 signaling. At the cellular level, fewer amoeboid microglia/macrophages appeared adjacent to the injured brain tissue in IL-1R1 null mice, and those microglia present at early postinjury intervals retained their resting morphology. Astrogliosis also was mildly abrogated. At the molecular level, cyclooxygenase-2 (Cox-2) and IL-6 expression were depressed and delayed. Interestingly, basal levels of Cox-2, IL-1, and IL-6 were significantly lower in the IL-1R1 null mice. In addition, stimulation of vascular cell adhesion molecule-1 mRNA was depressed in the IL-1R1 null mice, and correspondingly, there was reduced diapedesis of peripheral macrophages in the IL-1R1 null brain after injury. This observation correlated with a reduced number of Cox-2+amoeboid phagocytes adjacent to the injury. In contrast, several molecular aspects of the injury response were normal, including expression of tumor necrosis factor-α and the production of nerve growth factor. Because antagonizing IL-1 protects neural cells in experimental models of stroke and multiple sclerosis, our data suggest that cell preservation is achieved by abrogating microglial/macrophage activation and the subsequent self-propagating cycle of inflammation.
D1 Dopamine Receptor Regulation of Microtubule-Associated Protein-2 Phosphorylation in Developing Cerebral Cortical Neurons
Authors: Song Z.-M. , Undie A. S. , Koh P. O. , Fang Y.-Y. , Zhang L. , Dracheva S. , Sealfon S. C. , Lidow M. S.
Published: April 2018

This study addresses the hypothesis that the previously described capacity of D1 dopamine receptors (D1Rs) to regulate dendritic growth in developing cortical neurons may involve alterations in the phosphorylation state of microtubule-associated protein-2 (MAP2). The changes in phosphorylation of this protein are known to affect its ability to stabilize the dendritic cytoskeleton. The study involved two systems: primary cultures of mouse cortical neurons grown in the presence of the D1R agonists, SKF82958 orA77636, and the cortex of neonatal transgenic mice overexpressing the D1A subtype of D1R. In both models, a decrease in dendritic extension corresponded with an elevation in MAP2 phosphorylation. This phosphorylation occurred on all three amino acid residues examined in this study: serine, threonine, and tyrosine. In cultured cortical neurons, D1R stimulation-induced increase in MAP2 phosphorylation was blocked by the protein kinase A (PKA) inhibitor, H-89, and mimicked by the PKA activator, Sp-cAMPS. This indicates that D1Rs modulate MAP2 phosphorylation through PKA-associated intracellular signaling pathways. We also observed that the elevations in MAP2 phosphorylation in neuronal cultures in the presence of D1R agonists (or Sp-cAMPS) were maintained for a prolonged time (up to at least 96 hr). Moreover, MAP2 phosphorylation underwent a substantial increase between 24 and 72 hr of exposure to these drugs. Our findings are consistent with the idea that D1Rs can modulate growth and maintenance of dendrites in developing cortical cells by regulating the phosphorylation of MAP2. In addition, our observations suggest that MAP2 phosphorylation by long-term activation of D1Rs (and PKA) can be divided into two phases: the initial ∼24-hr-long phase of a relatively weak elevation in phosphorylation and the delayed phase of a much more robust phosphorylation increase taking place during the next ∼48 hr.
Diets Enriched in Foods with High Antioxidant Activity Reverse Age-Induced Decreases in Cerebellar β-Adrenergic Function and Increases in Proinflammatory Cytokines
Authors: Gemma Carmelina , Mesches Michael H. , Sepesi Boris , Choo Kevin , Holmes Douglas B. , Bickford Paula C.
Published: April 2018

Antioxidants and diets supplemented with foods high in oxygen radical absorbance capacity (ORAC) reverse age-related decreases in cerebellar β-adrenergic receptor function. We examined whether this effect was related to the antioxidant capacity of the food supplement and whether an antioxidant-rich diet reduced the levels of proinflammatory cytokines in the cerebellum. Aged male Fischer 344 rats were given apple (5 mg dry weight), spirulina (5 mg), or cucumber (5 mg) either in 0.5 ml water by oral gavage or supplied in the rat chow daily for 14 d. Electrophysiologic techniques revealed a significant decrease in β-adrenergic receptor function in aged control rats. Spirulina reversed this effect. Apple (a food with intermediate ORAC) had an intermediate effect on cerebellar β-adrenergic receptor physiology, and cucumber (low ORAC) had no effect, indicating that the reversal of β-adrenergic receptor function decreases might be related to the ORAC dose. The mRNA of the proinflammatory cytokines tumor necrosis factor-α (TNFα) and TNFβ was also examined. RNase protection assays revealed increased levels of these cytokines in the aged cerebellum. Spirulina and apple significantly downregulated this age-related increase in proinflammatory cytokines, whereas cucumber had no effect, suggesting that one mechanism by which these diets work is by modulation of an age-related increase in inflammatory responses. Malondialdehyde (MDA) was measured as a marker of oxidative damage. Apple and spirulina but not cucumber decreased MDA levels in the aged rats. In summary, the improved β-adrenergic receptor function in aged rats induced by diets rich in antioxidants is related to the ORAC dose, and these diets reduce proinflammatory cytokine levels.
Detection and Discrimination of Relative Spatial Phase by V1 Neurons
Authors: Mechler Ferenc , Reich Daniel S. , Victor Jonathan D.
Published: April 2018

Edge-like and line-like features result from spatial phase congruence, the local phase agreement between harmonic components of a spatial waveform. Psychophysical observations and models of early visual processing suggest that human visual feature detectors are specialized for edge-like and line-like phase congruence. To test whether primary visual cortex (V1) neurons account for such specificity, we made tetrode recordings in anesthetized macaque monkeys. Stimuli were drifting equal-energy compound gratings composed of four sinusoidal components. Eight congruence phases (one-dimensional features) were tested, including line-like and edge-like waveforms. Many of the 137 single V1 neurons (recorded at 45 sites) could reliably signal phase congruence by any of several response measures. Across neurons, the preferred spatial feature had only a modest bias for line-like waveforms. Information-theoretic analysis showed that congruence phase was temporally encoded in the frequency band present in the stimuli. The most sensitive neurons had feature discrimination thresholds that approached psychophysical levels, but typical neurons were substantially less sensitive. In single V1 neurons, feature discrimination exhibited various dependences on the congruence phase of the reference waveform. Simple cells were over-represented among the most sensitive neurons and on average carried twice as much feature information as complex cells. However, the distribution of the indices of optimal tuning and discrimination of relative phase was indistinguishable in simple and complex cells. Our results suggest that phase-sensitive pooling of responses is required to account for human psychophysical performance, although variation in feature selectivity among nearby neurons is considerable.
Space and Time Maps of Cone Photoreceptor Signals in Macaque Lateral Geniculate Nucleus
Authors: Reid R. Clay , Shapley Robert M.
Published: April 2018

We studied neurons in the central visual field representation of the lateral geniculate nucleus (LGN) in macaque monkeys by mapping their receptive fields in space and time. The mapping was performed by reverse correlation of a spike train of a neuron with pseudorandom, binary level stimuli (m-sequence grids). Black and white m-sequence grids were used to map the receptive field for luminance. The locations of receptive field center and surround were determined from this luminance map. To map the contribution of each cone class to the receptive field, we designed red–green or blue–yellow m-sequence grids to isolate the influence of that cone (long, middle, or short wavelength-sensitive: L, M, or S). Magnocellular neurons generally received synergistic input from L and M cones in both the center and the surround. A minority had cone-antagonistic (M–L) input to the surround. Red–green opponent parvocellular neurons received opponent cone input (L+M− or M+L−) that overlapped in space, as sampled by our stimulus grid, but that had somewhat different extents. For example, an L+ center parvocellular neuron would be L+/M− in both center and surround, but the L+ signal would be stronger in the center and the M− signal stronger in the surround. Accordingly, the luminance receptive field would be spatially antagonistic: on-center/off-surround. The space–time maps also characterized LGN dynamics. For example, magnocellular responses were transient, red–green parvocellular responses were more sustained, and blue-on responses were the most sustained for both luminance and cone-isolating stimuli. For all cell types the surround response peaked 8–10 msec later than the center response.
Metabotropic Glutamate 2 Receptors Modulate Synaptic Inputs and Calcium Signals in Striatal Cholinergic Interneurons
Authors: Pisani Antonio , Bonsi Paola , Catania Maria Vincenza , Giuffrida Raffaella , Morari Michele , Marti Matteo , Centonze Diego , Bernardi Giorgio , Kingston Ann E. , Calabresi Paolo
Published: April 2018

Striatal cholinergic interneurons were recorded from a rat slice preparation. Synaptic potentials evoked by intrastriatal stimulation revealed three distinct components: a glutamatergic EPSP, a GABAA-mediated depolarizing potential, and an acetylcholine (ACh)-mediated IPSP. The responses to group II metabotropic glutamate (mGlu) receptor activation were investigated on the isolated components of the synaptic potentials. Each pharmacologically isolated component was reversibly reduced by bath-applied LY379268 and ((2S,1′R,2′R,3′R)-2-(2,3-dicarboxylcyclopropyl)-glycine, group II agonists. In an attempt to define the relevance of group II mGlu receptor activation on cholinergic transmission, we focused on the inhibitory effect on the IPSP, which was mimicked and occluded by ω-agatoxin IVA (ω-Aga-IVA), suggesting a modulation on P-type high-voltage-activated calcium channels. Spontaneous calcium-dependent plateau-potentials (PPs) were recorded with cesium-filled electrodes plus tetraethylammonium and TTX in the perfusing solution, and measurements of intracellular calcium [Ca2+]ichanges were obtained simultaneously. PPs and the concomitant [Ca2+]ielevations were significantly reduced in amplitude and duration by LY379268. The mGlu-mediated inhibitory effect on PPs was mimicked by ω-Aga-IVA, suggesting an involvement of P-type channels. Moreover, electrically induced ACh release from striatal slices was reduced by mGlu2 receptor agonists and occluded by ω-Aga-IVA in a dose-dependent manner. Finally, double-labeling experiments combining mGlu2 receptorin situhybridization and choline acetyltransferase immunocytochemistry revealed a strong mGlu2 receptor labeling on cholinergic interneurons, whereas single-label isotopicin situhybridization for mGlu3 receptors did not show any labeling in these large striatal interneurons. These results suggest that the mGlu2 receptor-mediated modulatory action on cell excitability would tune striatal ACh release, representing an interesting target for pharmacological intervention in basal ganglia disorders.
Interneuronal Basis of the Generation of Related but Distinct Motor Programs inAplysia: Implications for Current Neuronal Models of Vertebrate Intralimb Coordination
Authors: Jing Jian , Weiss Klaudiusz R.
Published: April 2018

Coordination of two sets of movements, protraction–retraction versus opening–closing, of the feeding apparatus (the radula) in ingestive and egestive motor programs ofAplysiaresembles vertebrate intralimb coordination in that the relative timing of the two sets of movements differs in the two motor programs. In both ingestion and egestion, radula protraction and retraction alternate, whereas radula closure shifts its phase relative to protraction–retraction. In egestion, the radula closes in protraction; in ingestion, the radula closes in retraction. In both ingestive and egestive motor programs elicited by the command-like neuron, cerebral-buccal interneuron-2 (CBI-2), the protraction and retraction movements are mediated by the same sets of controller interneurons. In contrast, radula closure is mediated by two controller interneurons, B20 and B40, that are preferentially active in egestion and ingestion, respectively. In egestion, B20, active in protraction, drives closure motorneuron B8 in protraction, whereas in ingestion, B40, also active in protraction, uses a functionally novel mechanism, fast inhibition and slow excitation, to drive B8 in retraction. Our findings are summarized in a neural model that permits a conceptual comparison of our model with two previous hypothetical models of intralimb coordination in spinal circuits that were proposed by Grillner (1981,1985) and Berkowitz and Stein (1994). Although our model supports the existence of separate controllers for different movements as in theGrillner (1981, 1985) model; in terms of basic mechanisms, our model is similar to the Berkowitz and Stein (1994) model because the closure movement is mediated by separate controllers in different programs, and thus both models can be classified as recruitment models.
Phrenic Long-Term Facilitation Requires Spinal Serotonin Receptor Activation and Protein Synthesis
Authors: Baker-Herman Tracy. L. , Mitchell Gordon S.
Published: April 2018

Respiratory long-term facilitation (LTF) is a form of serotonin-dependent plasticity induced by intermittent hypoxia. LTF is manifested as a long-lasting increase in respiratory amplitude (and frequency) after the hypoxic episodes have ended. We tested the hypotheses that LTF of phrenic amplitude requires spinal serotonin receptor activation and spinal protein synthesis. A broad-spectrum serotonin receptor antagonist (methysergide) or protein synthesis inhibitors (emetine or cycloheximide) were injected intrathecally in the cervical spinal cord of anesthetized rats. Control rats, injected with vehicle (artificial CSF), exhibited an augmented phrenic burst amplitude after three 5 min episodes of hypoxia (78 ± 15% above baseline, 60 min after hypoxia;p< 0.05), indicating LTF. Pretreatment with methysergide, emetine, or cycloheximide attenuated or abolished phrenic LTF (20 ± 4, 0.2 ± 11, and 20 ± 2%, respectively; allp> 0.05). With protein synthesis inhibitors, phrenic LTF differed from control by 15 min after intermittent hypoxia. As an internal control against unintended drug distribution, we measured respiratory LTF in hypoglossal (XII) motor output. At 60 min after intermittent hypoxia, all treatment groups exhibited similar XII LTF (artificial CSF, 44 ± 10%; methysergide, 40 ± 5%; emetine, 35 ± 9%; and cycloheximide, 57 ± 29%; allp< 0.05), suggesting that drugs were restricted at effective doses to the spinal cord. We conclude that phrenic LTF requires spinal serotonin receptor activation and protein synthesis. Serotonin receptors on phrenic motoneuron dendrites may induce new protein synthesis, thereby giving rise to phrenic LTF.
Dopamine Release in the Dorsal Striatum during Cocaine-Seeking Behavior under the Control of a Drug-Associated Cue
Authors: Ito Rutsuko , Dalley Jeffrey W. , Robbins Trevor W. , Everitt Barry J.
Published: April 2018

Compulsive drug use is characterized by a pattern of drug seeking and consumption that becomes progressively habitual and less and less modifiable by external and internal factors. Although traditional views would posit that nigrostriatal dopamine (DA) neurons originating in the substantia nigra and innervating the dorsal striatum are primarily concerned with motor functions, recent studies have implicated the dorsal striatum in mediating stimulus–response (habit) learning. In this study,in vivomicrodialysis in combination with a second-order schedule of cocaine reinforcement was used to investigate the role of the dorsal striatal dopamine innervation in well established drug-seeking behavior under the control of a drug-associated cue [light conditioned stimulus (CS+)]. Rats were initially trained to self-administer cocaine under a continuous reinforcement schedule where a response on one of two identical levers led to a 20 sec presentation of a light CS+ and an intravenous cocaine infusion (0.75 mg/kg). The response requirement for the CS+ and cocaine was then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented with the cocaine-associated CS+ either noncontingently or contingent on responding during a session of cocaine-seeking behavior. The results showed a marked increase in DA release in the dorsal striatum during drug-seeking, when cocaine cues were presented contingently, but not when the same cue was presented noncontingently. These data indicate a possible involvement of the dopaminergic innervation of the dorsal striatum in well established, or habitual, cocaine-seeking behavior.
An Unbiased cDNA Library Prepared from IsolatedAplysiaSensory Neuron Processes Is Enriched for Cytoskeletal and Translational mRNAs
Authors: Moccia Robert , Chen Dillon , Lyles Vlasta , Kapuya Estreya , E Yaping , Kalachikov Sergey , Spahn Christian M. T. , Frank Joachim , Kandel Eric R. , Barad Mark , Martin Kelsey C.
Published: April 2018

Local protein synthesis is required for long-lasting synapse-specific plasticity in culturedAplysiasensorimotor synapses. To identify synaptically localized mRNAs, we prepared a cDNA library from isolated sensory neurites. By sequence analysis, we estimate that the library contains 263 distinct mRNAs, with 98 of these mRNAs constituting 70% of all clones. The localized transcripts are enriched for mRNAs encoding cytoskeletal elements and components of the translational machinery.In situhybridization confirms that the mRNAs for at least eight of these transcripts are present in distal neurites. Immunocytochemistry reveals that serotonin regulates the translation of one of the localized mRNAs, that encoding α1-tubulin. Our identification of mRNAs encoding cytoskeletal elements suggests that local protein synthesis is required for the growth of new synaptic connections associated with persistent synaptic strengthening. Our finding of mRNAs encoding components of the translational machinery suggests that local protein synthesis serves to increase the translational capacity of synapses.
Human Hippocampal and Parahippocampal Activity during Visual Associative Recognition Memory for Spatial and Nonspatial Stimulus Configurations
Authors: Düzel Emrah , Habib Reza , Rotte Michael , Guderian Sebastian , Tulving Endel , Heinze Hans-Jochen
Published: April 2018

Evidence from animal studies points to the importance of the parahippocampal region (PHR) [including entorhinal, perirhinal, and parahippocampal (PHC) cortices] for recognition of visual stimuli. Recent findings in animals suggest that PHR may also be involved in visual associative recognition memory for configurations of stimuli. Thus far, however, such involvement has not been demonstrated in humans. In fact, it has been argued that associative recognition in humans is critically dependent on the hippocampal formation (HF). To better understand the division of function between HF and PHR during recognition memory in humans, we measured the activity of both areas in healthy young adults during an associative recognition memory task using functional magnetic resonance imaging. To more precisely characterize the nature of the associations that might be coded by the HF and PHR during recognition, subjects were required to learn and were later tested for associations based on either the spatial arrangements of two stimuli or the identity of two stimuli (a face and a tool). An area in the PHC was found to be more active for recognized old configurations than new configurations in both the spatial and identity conditions. The HF, on the other hand, was more active for recognition of new configurations than old configurations and also more active in the spatial than the identity condition. These data highlight the involvement of PHR in the long-term coding of associative relationships between stimuli and help to clarify the nature of its functional distinction from the HF.
Complement Activation Contributes to Hypoxic-Ischemic Brain Injury in Neonatal Rats
Authors: Cowell Rita M. , Plane Jennifer M. , Silverstein Faye S.
Published: April 2018

Conflicting data have emerged regarding the role of complement activation in the pathophysiology of cerebral ischemia. On the basis of considerable evidence implicating inflammatory mediators in the progression of neonatal brain injury, we evaluated the contribution of complement activation to cerebral hypoxic-ischemic (HI) injury in the neonatal rat. To elicit unilateral forebrain HI injury, 7-d-old rats underwent right carotid ligation followed by 1.5-2 hr of exposure to 8% oxygen. Using immunoprecipitation and Western blot assays, we determined that HI induces local complement cascade activation as early as 8 hr post-HI; there was an eightfold increase in the activation fragment inactivated C3b at 16 hr. With immunofluorescence assays and confocal microscopy, both C3 and C9 were localized to injured neurons 16 and 24 hr post-HI. To investigate the contribution of systemic complement to brain injury, we administered the complement-depleting agent cobra venom factor (CVF) 24 hr before HI lesioning and evaluated both acute HI-induced complement deposition and the extent of resulting tissue injury 5 d after lesioning. CVF depleted both systemic and brain C3 by the time of surgery and reduced infarct size. Analysis of lesioned, CVF-treated animals demonstrated minimal neuronal C3 deposition but no reduction in C9 deposition. C3-immunoreactive microglia were identified in injured areas. These results indicate that complement activation contributes to HI injury in neonatal rat brain, systemic administration of CVF does not eliminate complement deposition within injured brain, and microglia may represent an important local source of C3 after acute brain injury.
Human Episodic Memory Retrieval Is Accompanied by a Neural Contiguity Effect
Authors: Folkerts Sarah , Rutishauser Ueli , Howard Marc W.
Published: April 2018

Cognitive psychologists have long hypothesized that experiences are encoded in a temporal context that changes gradually over time. When an episodic memory is retrieved, the state of context is recovered—a jump back in time. We recorded from single units in the medial temporal lobe of epilepsy patients performing an item recognition task. The population vector changed gradually over minutes during presentation of the list. When a probe from the list was remembered with high confidence, the population vector reinstated the temporal context of the original presentation of that probe during study, a neural contiguity effect that provides a possible mechanism for behavioral contiguity effects. This pattern was only observed for well remembered probes; old probes that were not well remembered showed an anti-contiguity effect. These results constitute the first direct evidence that recovery of an episodic memory in humans is associated with retrieval of a gradually changing state of temporal context, a neural “jump back in time” that parallels the act of remembering.

SIGNIFICANCE STATEMENTEpisodic memory is the ability to relive a specific experience from one's life. For decades, researchers have hypothesized that, unlike other forms of memory that can be described as simple associations between stimuli, episodic memory depends on the recovery of a neural representation of spatiotemporal context. During study of a sequence of stimuli, the brain state of epilepsy patients changed slowly over at least a minute. When the participant remembered a particular event from the list, this gradually changing state was recovered. This provides direct confirmation of the prediction from computational models of episodic memory. The resolution of this point means that the study of episodic memory can focus on the mechanisms by which this representation of spatiotemporal context is maintained and sometimes recovered.
Neuronostatin exerts actions on pituitary that are unique from its sibling peptide somatostatin
Authors: Luque Raúl M , Kineman Rhonda D
Published: April 2018

Neuronostatin, a somatostatin gene-encoded peptide, exerts important physiological and metabolic actions in diverse tissues. However, the direct biological effects of neuronostatin on pituitary function of humans and primates are still unknown. This study used baboon (Papio anubis) primary pituitary cell cultures, a species that closely models human physiology, to demonstrate that neuronostatin inhibits basal, but not ghrelin-/GnRH-stimulated, growth hormone (GH) and luteinizing hormone (LH) secretion in a dose- and time-dependent fashion, without affecting the secretion of other pituitary hormones (prolactin, ACTH, FSH, thyroid-stimulating hormone (TSH)) or changing mRNA levels. Actions of neuronostatin differs from somatostatin which in this study reduced GH/PRL/ACTH/LH/TSH secretion and GH/PRL/POMC/LH gene expression. Remarkably, we found that inhibitory actions of neuronostatin are likely mediated through: (1) the orphan receptor GPCR107 (found to be highly expressed in pituitary compared to somatostatin-receptors), (2) common (i.e. adenylyl cyclase/protein kinase A/MAPK/extra-/intracellular Ca2+ mobilization, but not phospholipase C/protein kinase C/mTOR) and distinct (i.e. PI3K) signaling pathways than somatostatin and; (3) dissimilar molecular mechanisms than somatostatin (i.e. upregulation of GPCR107 and downregulation of GHS-R/Kiss1-R expression by neuronostatin and, upregulation of sst1–5 expression by somatostatin). Altogether, the results of this study provide the first evidence that there is a functional neuronostatin signaling circuit, unique from somatostatin, which may work in concert with somatostatin to fine-tune hormone release from somatostropes and gonadotropes.
A poststernotomiás sebfertőzések kezelési sikertelenségének prediktív faktorai
Authors: Rashed Aref , Gombocz Károly , Frenyó Magdolna , Alotti Nasri , Verzár Zsófia
Published: April 2018

Abstract:

Introduction and aim: Post-sternotomy wound infection is still a major concern and it affects morbidity, mortality, and hospital costs. Reconstruction failure may further increase these risks with significant financial implications. Method: Here, we attempted to verify some factors that may significantly influence the success of the surgical treatment. We performed a single-center retrospective analysis of data from 3177 consecutive patients who underwent midline sternotomy. The diagnostic signs of post-sternotomy wound infections were observed in 60 patients (1.9%). These data were thoroughly analyzed. Results: Beside late diagnosis, the positive microbiological culture of the wounds, radical surgical intervention and peripheral vascular disease were found to significantly contribute to the development of surgical reconstruction failure. Radical surgical reconstruction was associated with a higher success rate (81.8 vs. 11.1%), p<0.001. Conclusion: Identification of the predictive factors that may lead to treatment failure can assist in developing treatment algorithms and improving the success rates of surgical reconstructions. Orv Hetil. 2018; 159(14): 566–570.