bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct Ontogeny of Glucocorticoid and Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Types I and II mRNAs in the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid Actions
Authors: Diaz Rochellys , Brown Roger W. , Seckl Jonathan R.
Published: April 2018

Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11β-hydroxysteroid dehydrogenases (11β-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11β-HSD type 1 (11β-HSD1) is a bidirectional enzymein vitrothat acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11β-HSD type 2 (11β-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivityin vivo. We have examined the ontogeny of 11β-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11β-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11β-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11β-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11β-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11β-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.
Behavioral and Neurobiological Consequences of Social Subjugation during Puberty in Golden Hamsters
Authors: Delville Yvon , Melloni Richard H. , Ferris Craig F.
Published: April 2018

In golden hamsters, offensive aggression is facilitated by vasopressin and inhibited by serotonin. We tested whether these neurotransmitter systems respond to modifications resulting from the stress of threat and attack (i.e., social subjugation) during puberty. Male golden hamsters were weaned at postnatal day 25 (P25), exposed daily to aggressive adults from P28 to P42, and tested for offensive aggression as young adults (P45). The results showed a context-dependent alteration in aggressive behavior. Subjugated animals were more likely to attack younger and weaker intruders than nonsubjugated controls. Conversely, subjugated animals were less likely to attack animals of similar size and age. After testing, the animals were killed, and their brains were collected to determine whether these behavioral changes are underlined by changes in the vasopressin and serotonin systems. Social subjugation resulted in a 50% decrease in vasopressin levels within the anterior hypothalamus, a site involved in the regulation of aggression. Furthermore, whereas the density of vasopressin-immunoreactive fibers within the area was not significantly altered in subjugated animals, the number of serotonin-immunoreactive varicosities within the anterior hypothalamus and lateral septum was 20% higher in subjugated animals than in their controls. These results establish puberty as a developmental period sensitive to environmental stressors. Furthermore, the results show that changes in the vasopressin and serotonin systems can correlate with behavioral alterations, supporting the role of these two neurotransmitters in the regulation of aggression.
Corticosteroid Regulation of Ion Channel Conductances and mRNA Levels in Individual Hippocampal CA1 Neurons
Authors: Nair Suresh M. , Werkman Taco R. , Craig Johanna , Finnell Richard , Joëls Marian , Eberwine James H.
Published: April 2018

Overexposure to corticosteroid hormones is harmful to hippocampal neuronal integrity, likely by perturbation of calcium homeostasis. To identify molecular mechanisms at the single-cell level, we characterized mRNA expression corresponding to voltage- and ligand-gated Ca channels in individual dissociated CA1 neurons in response to long-term corticosterone (CORT) exposure. Predominant mineralocorticoid receptor occupation (ADC-LO group) resulted in low levels of P/Q- and L-type Ca channel mRNAs, high levels of GluR-2 versus GluR-1, and a high ratio of NMDAR-2A to NMDAR-2B mRNA. Corresponding alterations in protein expression were consistent with the restriction of Ca influx. In contrast, additional glucocorticoid receptor occupation (ADC-HI group) altered the expression of these mRNAs in a manner consistent with enhanced Ca influx; interestingly, qualitatively similar alterations were seen in control ADX neurons. Electrophysiological data from the same neurons indicate that Ca current amplitudes also are modulated by CORT, although on a shorter time scale. Finally, principal components analysis (PCA) suggests that neuronal AMPA and NMDA receptor composition may be regulated by MR and GR activation in a complex manner. Therefore, our data implicate molecular events by which CORT may regulate Ca influx into CA1 hippocampal neurons.
Opioid Receptor Subtype Expression Defines Morphologically Distinct Classes of Hippocampal Interneurons
Authors: Svoboda Kurt R. , Adams Cathy E. , Lupica Carl R.
Published: April 2018

The inhibition of hippocampal pyramidal cells occurs via inhibitory interneurons making GABAergic synapses on distinct segments of the postsynaptic membrane. In area CA1 of the hippocampus, the activation of mu- and delta-opioid receptors inhibits these interneurons, thereby increasing the excitability of the pyramidal cells. Through the use of selective opioid agonists and biocytin-filled whole-cell electrodes, interneurons possessing somata located within stratum oriens of hippocampal slices were classified according to the location of their primary axon termination and the expression of mu- or delta-opioid receptors. Activation of these opioid receptor subtypes resulted in outward currents in the majority of interneurons, which is consistent with their inhibition.Post hocmorphological analysis revealed that those interneurons heavily innervating the pyramidal cell body layer were much more likely to express mu-opioid receptors, whereas cells with axons ramifying in the pyramidal neuron dendritic layers were more likely to express delta-opioid receptors, as defined by the generation of outward currents. This morphological segregation of interneuron projections suggests that mu receptor activation would diminish GABA release onto pyramidal neuron somata, thereby increasing their excitability and output. Conversely, inhibition of interneurons via delta receptor activation would amplify afferent signaling to pyramidal neuron dendrites by reducing GABAergic inhibition of these structures.
Relationship between Afferent and Central Temporal Patterns in the Locust Olfactory System
Authors: Wehr Michael , Laurent Gilles
Published: April 2018

Odors evoke synchronized oscillations and slow temporal patterns in antennal lobe neurons and fast oscillations in the mushroom body local field potential (LFP) of the locust. What is the contribution of primary afferents in the generation of these dynamics? We addressed this question in two ways. First, we recorded odor-evoked afferent activity in both isolated antennae and intact preparations. Odor-evoked population activity in the antenna and the antennal nerve consisted of a slow potential deflection, similar for many odors. This deflection contained neither oscillatory nor odor-specific slow temporal patterns, whereas simultaneously recorded mushroom body LFPs exhibited clear 20–30 Hz oscillations. This suggests that the temporal patterning of antennal lobe and mushroom body neurons is generated downstream of the olfactory receptor axons. Second, we electrically stimulated arrays of primary afferentsin vivo. A brief shock to the antennal nerve produced compound PSPs in antennal lobe projection neurons, with two peaks at an ∼50 msec interval. Prolonged afferent stimulation with step, ramp, or slow sine-shaped voltage waveforms evoked sustained 20–30 Hz oscillations in projection neuron membrane potential and in the mushroom body LFP. Projection neuron and mushroom body oscillations were phase-locked and reliable across trials. Synchronization of projection neurons was seen directly in paired intracellular recordings. Pressure injection of picrotoxin into the antennal lobe eliminated the oscillations evoked by electrical stimulation. Different projection neurons could express different temporal patterns in response to the same electrical stimulus, as seen for odor-evoked responses. Conversely, individual projection neurons could express different temporal patterns of activity in response to step stimulation of different spatial arrays of olfactory afferents. These patterns were reliable and remained distinct across different stimulus intensities. We conclude that oscillatory synchronization of olfactory neurons originates in the antennal lobe and that slow temporal patterns in projection neurons can arise in the absence of temporal patterning of the afferent input.
Identification of acis-Acting Dendritic Targeting Element in MAP2 mRNAs
Authors: Blichenberg Arne , Schwanke Birgit , Rehbein Monika , Garner Craig C. , Richter Dietmar , Kindler Stefan
Published: April 2018

In neurons, a limited number of mRNAs have been identified in dendritic processes, whereas other transcripts are restricted to the cell soma. Here we have investigated the molecular mechanisms underlying extrasomatic localization of mRNAs encoding microtubule-associated protein 2 (MAP2) in primary neuronal cultures. Vectors expressing recombinant mRNAs were introduced into hippocampal and sympathetic neurons using DNA transfection and microinjection protocols, respectively. Chimeric mRNAs containing the entire 3′ untranslated region of MAP2 transcripts fused to a nondendritic reporter mRNA are detected in dendrites. In contrast, RNAs containing MAP2 coding and 5′ untranslated regions or tubulin sequences are restricted to the cell soma. Moreover, 640 nucleotides from the MAP2 3′ untranslated region (UTR) are both sufficient and essential for extrasomatic localization of chimeric mRNAs in hippocampal and sympathetic neurons. Thus, acis-acting dendritic targeting element that is effective in two distinct neuronal cell types is contained in the 3′ UTR of MAP2 transcripts. The observation of RNA granules in dendrites implies that extrasomatic transcripts seem to assemble into multimolecular complexes that may function as transport units.
Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons
Authors: Hartley Dean M. , Walsh Dominic M. , Ye Chianping P. , Diehl Thekla , Vasquez Sara , Vassilev Peter M. , Teplow David B. , Selkoe Dennis. J.
Published: April 2018

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is thought to be caused in part by the age-related accumulation of amyloid β-protein (Aβ). The presence of neuritic plaques containing abundant Aβ-derived amyloid fibrils in AD brain tissue supports the concept that fibril accumulation per se underlies neuronal dysfunction in AD. Recent observations have begun to challenge this assumption by suggesting that earlier Aβ assemblies formed during the process of fibrillogenesis may also play a role in AD pathogenesis. Here, we present the novel finding that protofibrils (PF), metastable intermediates in amyloid fibril formation, can alter the electrical activity of neurons and cause neuronal loss. Both low molecular weight Aβ (LMW Aβ) and PF reproducibly induced toxicity in mixed brain cultures in a time- and concentration-dependent manner. No increase in fibril formation during the course of the experiments was observed by either Congo red binding or electron microscopy, suggesting that the neurotoxicity of LMW Aβ and PF cannot be explained by conversion to fibrils. Importantly, protofibrils, but not LMW Aβ, produced a rapid increase in EPSPs, action potentials, and membrane depolarizations. These data suggest that PF have inherent biological activity similar to that of mature fibrils. Our results raise the possibility that the preclinical and early clinical progression of AD is driven in part by the accumulation of specific Aβ assembly intermediates formed during the process of fibrillogenesis.
Cocaine Upregulates the Dopamine Transporter in Fetal Rhesus Monkey Brain
Authors: Fang Yuan , Rønnekleiv Oline K.
Published: April 2018

Cocaine is a highly addictive drug that binds to the dopamine transporter (DAT), inhibits the reuptake of dopamine, and initiates multiple actions within midbrain dopaminergic systems. Using the rhesus monkey, we have investigated the consequences ofin uterococaine exposure on the expression of DAT in the fetal brain. By using the selective DAT ligand [125I]RTI-121and tyrosine hydroxylase (TH) immunocytochemistry, we found that DAT binding sites are highly developed by day 70 of gestation and show a distribution pattern similar to TH. The rank order of specific 3β-(4-[125I]iodophenyl)tropane-2β-carboxylic acid isopropyl ester ([125I]RTI-121) binding densities was substantia nigra–ventral tegmental area > putamen > caudate > lateral hypothalamus > accumbens > linear/interfascicular nuclei ≥ globus pallidus > prefrontal cortex. Furthermore, we observed that DAT mRNA was differentially expressed within fetal midbrain dopamine neurons with the highest levels detected in the ventral tier of the substantia nigra pars compacta, and the lowest levels in the ventral tegmental area and the linear/interfascicular nuclei.In uterococaine exposure between days 22 and 70 significantly increased DAT mRNA expression, and the density of [125I]RTI-121 binding sites within midbrain dopamine neurons in the 70-d-old fetus. This increased DAT expression is accompanied by other presynaptic and postsynaptic neuronal changes, which collectively suggest that midbrain dopamine neurons are hypoactive after prolonged cocaine exposure, a state that may be a contributing factor in the development of attention deficit disorders observed in subjects exposed prenatally to cocaine.
Parametric Population Representation of Retinal Location: Neuronal Interaction Dynamics in Cat Primary Visual Cortex
Authors: Jancke Dirk , Erlhagen Wolfram , Dinse Hubert R. , Akhavan Amir C. , Giese Martin , Steinhage Axel , Schöner Gregor
Published: April 2018

Neuronal interactions are an intricate part of cortical information processing generating internal representations of the environment beyond simple one-to-one mappings of the input parameter space. Here we examined functional ranges of interaction processes within ensembles of neurons in cat primary visual cortex. Seven “elementary” stimuli consisting of small squares of light were presented at contiguous horizontal positions. The population representation of these stimuli was compared to the representation of “composite” stimuli, consisting of two squares of light at varied separations. Based on receptive field measurements and by application of an Optimal Linear Estimator, the representation of retinal location was constructed as a distribution of population activation (DPA) in visual space. The spatiotemporal pattern of the DPA was investigated by obtaining the activity of each neuron for a sequence of time intervals. We found that the DPA of composite stimuli deviates from the superposition of its components because of distance-dependent (1) early excitation and (2) late inhibition. (3) The shape of the DPA of composite stimuli revealed a distance-dependent repulsion effect. We simulated these findings within the framework of dynamic neural fields. In the model, the feedforward response of neurons is modulated by spatial ranges of excitatory and inhibitory interactions within the population. A single set of model parameters was sufficient to describe the main experimental effects. Combined, our results indicate that the spatiotemporal processing of visual stimuli is characterized by a delicate, mutual interplay between stimulus-dependent and interaction-based strategies contributing to the formation of widespread cortical activation patterns.
Effects of Gravitational Load on Jaw Movements in Speech
Authors: Shiller Douglas M. , Ostry David J. , Gribble Paul L.
Published: April 2018

External loads arising as a result of the orientation of body segments relative to gravity can affect the achievement of movement goals. The degree to which subjects adjust control signals to compensate for these loads is a reflection of the extent to which forces affecting motion are represented neurally. In the present study we assessed whether subjects, when speaking, compensate for loads caused by the orientation of the head relative to gravity. We used a mathematical model of the jaw to predict the effects of control signals that are not adjusted for changes to head orientation. The simulations predicted a systematic change in sagittal plane jaw orientation and horizontal position resulting from changes to the orientation of the head. We conducted an empirical study in which subjects were tested under the same conditions. With one exception, empirical results were consistent with the simulations. In both simulation and empirical studies, the jaw was rotated closer to occlusion and translated in an anterior direction when the head was in the prone orientation. When the head was in the supine orientation, the jaw was rotated away from occlusion. The findings suggest that the nervous system does not completely compensate for changes in head orientation relative to gravity. A second study was conducted to assess possible changes in acoustical patterns attributable to changes in head orientation. The frequencies of the first (F1) and second (F2) formants associated with the steady-state portion of vowels were measured. As in the kinematic study, systematic differences in the values of F1 and F2 were observed with changes in head orientation. Thus the acoustical analysis further supports the conclusion that control signals are not completely adjusted to offset forces arising because of changes in orientation.
Chronic Morphine Treatment Alters NMDA Receptor-Mediated Synaptic Transmission in the Nucleus Accumbens
Authors: Martin Gilles , Ahmed Serge H. , Blank Thomas , Spiess Joachim , Koob George F. , Siggins George R.
Published: April 2018

In a study of a possible substrate underlying morphine addiction, we examined NMDA receptor-mediated synaptic transmission of core nucleus accumbens neurons after chronic morphine treatment, using intracellular recording in a slice preparation of rat. We evoked pharmacologically isolated NMDA EPSCs by local stimulation and elicited inward currents by NMDA superfusion. In control slices, Mg2+and phorbol 12,13-diacetate (PDAc), a protein kinase C activator, strongly inhibited and increased, respectively, NMDA EPSC amplitudes. The PDAc effects were likely postsynaptic because PDAc enhanced the currents evoked by superfused NMDA to the same extent that it did the NMDA EPSCs. Chronic morphine treatment significantly decreased NMDA EPSC amplitudes and the sensitivity of NMDA EPSCs to Mg2+and PDAc, as well as the kinetics of the decay (inactivation rate) of the EPSCs (from 97 ± 2.5 msec in untreated rats to 78.7 ± 1.8 msec in slices from treated rats). One week after withdrawal, the Mg2+and PDAc effects were still significantly less than those in control slices. Interestingly, 1 week of withdrawal led to an increased NMDA EPSC inactivation rate compared with controls. These data demonstrate that chronic morphine treatment significantly alters NMDA receptor-mediated synaptic transmission in the accumbens, and these effects persist 1 week after withdrawal. These long-term effects may represent an important neuroadaptation in opiate dependence.
Behavioral and Neural Bases of Noncoincidence Learning inHermissenda
Authors: Britton Gabrielle , Farley Joseph
Published: April 2018

Neurobiological studies of associative learning and memory have focused nearly exclusively on the analysis of neural plasticity resulting from paired stimuli. A second major category of associative-learning processes, one that has been conspicuously neglected in cellular studies, is that of conditioned inhibition (CI), learning that one stimulus signals the absence of another. The physiological bases of CI are obscure and unexplored. To study the behavioral and neural bases of CI, we exposed the nudibranch molluscHermissenda crassicornisto explicitly unpaired (EU) presentations of light and rotation. We report here thatHermissendaexhibited persistent increases in phototactic behavior after EU training. Retardation-of-learning test results provided further evidence that EU animals learned that light signaled the absence of rotation. The increased phototactic behavior of EU animals was paralleled by selective decreases in the magnitude of ocular type B cell photoresponses and the frequency of light-elicited action potentials: the first report of a neural correlate of noncoincidence learning. Plasticity arising from explicitly unpaired stimulus presentations raises provocative questions as to how noncoincidence is detected and represented within the nervous system.
Functional Blockade of Tyrosine Kinase A in the Rat Basal Forebrain by a Novel Antagonistic Anti-Receptor Monoclonal Antibody
Authors: Cattaneo Antonino , Capsoni Simona , Margotti Elisa , Righi Massimo , Kontsekova Eva , Pavlik Peter , Filipcik Peter , Novak Michal
Published: April 2018

We have exploited a new monoclonal antibody against the tyrosine kinase A (TrkA) nerve growth factor (NGF) receptor to block the NGF–TrkA interaction in the rat basal forebrain. The monoclonal antibody MNAC13 is a potent antagonist that prevents the binding of NGF to TrkA in a variety of systems. This antibody was used to study the maintenance of the cholinergic phenotype in the rat basal forebrainin vivo, by the implant of antibody-secreting cells. Basal forebrain cholinergic neurons (BFCNs) are greatly affected by the antibody treatment, both in terms of cell number and of cell soma size. When antibody-secreting cells are implanted at postnatal day 2 (P2), the effects observed at P8 are as severe as those obtained with anti-NGF antibodies and, interestingly, are observed also if anti-TrkA cells are implanted at P8, when anti-NGF antibodies, delivered by the same route, are no longer effective (Molnar et al., 1998). The effects induced by anti-TrkA, as those induced by anti-NGF, are reversible, but the time required for recovery and the critical period in the sensitivity of BFCNs to the functional inactivation of TrkA is twice as long than that observed when NGF is intercepted. These results demonstrate that BFCNs are more sensitive to the block of TrkA activation than they are to the block of NGF. The cloning of MNAC13 variable regions and their assembly into a functional polypeptide of reduced size (single chain Fv fragment) will allow its use in gene transfer applications.
Ras Regulates Sympathetic Neuron Survival by Suppressing the p53-Mediated Cell Death Pathway
Authors: Mazzoni Irene E. , Saı̈d Farid A. , Aloyz Raquel , Miller Freda D. , Kaplan David
Published: April 2018

In this report, we examine how the Ras protein regulates neuronal survival, focusing on sympathetic neurons. Adenovirus-expressed constitutively activated Ras (RasV12) enhanced survival and the phosphorylation of Akt (protein kinase B) and MAP kinase (MAPK), two targets of Ras activity. Functional inhibition of endogenous Ras by adenovirus-expressed dominant-inhibitory Ras (N17Ras) decreased nerve growth factor (NGF)-dependent survival and both Akt and MAPK phosphorylation as well. To determine the signaling pathways through which Ras mediates survival, we used Ras effector mutants and pharmacological inhibitors that selectively suppress phosphatidylinositol 3-kinase (PI3-K)/Akt or MAP kinase kinase (MEK)/MAPK pathways. The Ras effector mutant RasV12Y40C, which selectively stimulates PI3-K and Akt, rescued survival in the absence of NGF, and the PI3-K inhibitor LY 294002 inhibited both Ras- and NGF-dependent survival. RasV12T35S, which activates MEK/MAPK but not PI3-K/Akt, was less effective at rescuing survival, whereas the MEK inhibitor PD 098059 also partially suppressed Ras-dependent survival. To investigate the mechanisms by which Ras suppresses neuronal death, we examined whether Ras functions by inhibiting the proapoptotic p53 pathway (Jun-N-terminal kinase/p53/BAX) that is necessary for neuronal death after NGF withdrawal and p75NTR activation. We found that RasV12 suppressed c-jun, BAX, and p53 levels, whereas inhibition of NGF-induced Ras-survival activity via N17Ras increased the levels of these proteins. Furthermore, the E1B55K protein, which suppresses p53 activity, blocked N17Ras-induced neuronal death. Together, these results indicate that Ras is, in part, both necessary and sufficient for survival of sympathetic neurons and that this effect is mediated by activation of both the PI3-K– and MEK-signaling cascades, which in turn suppress a proapoptotic p53 pathway.
Differential Expression of Small Heat Shock Proteins in Reactive Astrocytes after Focal Ischemia: Possible Role of β-Adrenergic Receptor
Authors: Imura Tetsuya , Shimohama Shun , Sato Masaaki , Nishikawa Hiroyuki , Madono Kenya , Akaike Akinori , Kimura Jun
Published: April 2018

Small heat shock proteins (sHSPs), a family of HSPs, are known to accumulate in the CNS, mainly in astrocytes, in several pathological conditions such as Alexander's disease, Alzheimer's disease, and Creutzfeldt-Jakob disease. sHSPs may act not only as molecular chaperones, protecting against various stress stimuli, but may also play a physiological role in regulating cell differentiation and proliferation. In the present study, we have demonstrated that transient focal ischemia in rats dramatically induced HSP27 but not α B-crystallin (αBC), both of which are members of sHSPs, in reactive astrocytes. In contrast,in vitrochemical ischemic stress induced both HSP27 and αBC in cultured glial cells to the same extent. Dibutyryl cAMP (dBcAMP) and isoproterenol, a β-adrenergic receptor (βAR) agonist, enhanced HSP27 expression but suppressed αBC, and changed the shape of the cells to a stellate form. dBcAMP and isoproterenol inhibited cell proliferation under normal conditions. An increase in βAR-like immunoreactivity was also observed in reactive astrocytesin vivo. These results, together with recent findings that βAR plays an important role in glial scar formationin vivo, raise the possibility that βAR activation modulates sHSP expression after focal ischemia and is involved in the transformation of astrocytes to their reactive form.
Protection from Oxidative Stress–Induced Apoptosis in Cortical Neuronal Cultures by Iron Chelators Is Associated with Enhanced DNA Binding of Hypoxia-Inducible Factor-1 and ATF-1/CREB and Increased Expression of Glycolytic Enzymes, p21waf1/cip1, and Erythropoietin
Authors: Zaman Khalequz , Ryu Hoon , Hall David , O'Donovan Kevin , Lin Kuo-I , Miller Matthew P. , Marquis John C. , Baraban Jay M. , Semenza Gregg L. , Ratan Rajiv R.
Published: April 2018

Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress–induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element–binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21waf1/cip1, and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress–induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress.
Activity-Driven Synapse Elimination Leads Paradoxically to Domination by Inactive Neurons
Authors: Barber Michael J. , Lichtman Jeff W.
Published: April 2018

In early postnatal life, multiple motor axons converge at individual neuromuscular junctions. However, during the first few weeks after birth, a competitive mechanism eliminates all the inputs but one. This phenomenon, known as synapse elimination, is thought to result from competition based on interaxonal differences in patterns or levels of activity (for review, see Lichtman, 1995). Surprisingly, experimental data support two opposite views of the role of activity: that active axons have a competitive advantage (Ribchester and Taxt, 1983; Ridge and Betz, 1984; Balice-Gordon and Lichtman, 1994) and that inactive axons have a competitive advantage (Callaway et al., 1987,1989). To understand this paradox, we have formulated a mathematical model of activity-mediated synapse elimination. We assume that the total amount of transmitter released, rather than the frequency of release, mediates synaptic competition. We further assume that the total synaptic area that a neuron can support is metabolically constrained by its activity level and size. This model resolves the paradox by showing that a competitive advantage of higher frequency axons early in development is overcome at later stages by greater synaptic efficacy of axons firing at a lower rate. This model both provides results consistent with experiments in which activity has been manipulated and an explanation for the origin of the size principle (Henneman, 1985).
Target-Specific Factors Regulate the Formation of Glutamatergic Transmitter Release Sites in Cultured Neocortical Neurons
Authors: Mohrmann Ralf , Werner Markus , Hatt Hanns , Gottmann Kurt
Published: April 2018

Synapse formation in the mammalian CNS is thought to involve specific target recognition processes between presynaptic and postsynaptic neurons leading to the establishment of defined neuronal circuits. To study the role of target neuron-specific factors in synaptogenesis, we used cocultures of presynaptic explants and dissociated target neurons from rat neocortex, which enabled us to selectively vary the postsynaptic target neurons. Cocultures containing target neurons that were obtained early during development [embryonic day 16 (E16)] were compared to cocultures containing target neurons that were obtained at a later embryonic stage (E19).

Postsynaptic currents (PSCs) were evoked in target neurons by maximal extracellular stimulation in the presynaptic explant. The mean amplitudes of AMPA and NMDA receptor-mediated PSCs were sixfold reduced in E16 target neurons, whereas the mean amplitudes of GABAAreceptor-mediated PSCs did not differ between E16 and E19 target neurons. This reduction was in part caused by an apparently twofold reduction in mean quantal amplitude, as shown by recording AMPA receptor-mediated miniature PSCs. In addition, a reduced number of glutamatergic release sites in E16 target neurons was revealed by synapsin I immunostaining of dendritic presynaptic terminals. No differences in mean release probability were observed between E16 and E19 target neurons.

Thus, the formation of glutamatergic transmitter release sites was strongly influenced by target neuron-specific factors. The formation of functional GABAergic synapses, however, was independent of the type of target neurons, suggesting specific retrograde signaling during the establishment of glutamatergic synapses.
Heat Stress and Protection from Permanent Acoustic Injury in Mice
Authors: Yoshida Naohiro , Kristiansen Arthur , Liberman M. Charles
Published: April 2018

The inner ear can be permanently damaged by overexposure to high-level noise; however, damage can be decreased by previous exposure to moderate level, nontraumatic noise (Canlon et al., 1988). The mechanism of this “protective” effect is unclear, but a role for heat shock proteins has been suggested. The aim of the present study was to directly test protective effects of heat stress in the ear. For physiological experiments, CBA/CaJ mice were exposed to an intense octave band of noise (8–16 kHz) at 100 dB SPL for 2 hr, either with or without previous whole-body heat stress (rectal temperature to 41.5 °C for 15 min). The interval between heat stress and sound exposure varied in different groups from 6 to 96 hr. One week later, inner ear function was assessed in each animal via comparison of compound action potential thresholds to mean values from unexposed controls. Permanent threshold shifts (PTSs) were ∼40 dB in the group sound-exposed without previous heat stress. Heat-stressed animals were protected from acoustic injury: mean PTS in the group with 6 hr heat-stress–trauma interval was reduced to ∼10 dB. This heat stress protection disappeared when the treatment-trauma interval surpassed 24 hr. A parallel set of quantitative PCR experiments measured heat-shock protein mRNA in the cochlea and showed 100- to 200-fold increase over control 30 min after heat treatment, with levels returning to baseline at 6 hr after treatment. Results are consistent with the idea that upregulation of heat shock proteins protects the ear from acoustic injury.
Attentional Orienting Is Impaired by Unilateral Lesions of the Thalamic Reticular Nucleus in the Rat
Authors: Weese G. Daniel , Phillips Janice M. , Brown Verity J.
Published: April 2018

The thalamic reticular nucleus (TRN) has been implicated in attentional processes based on its anatomical, electrophysiological, and neurochemical relationships with the sensory nuclei of the thalamus and corresponding sensory areas of cortex. This study examined the possibility that the TRN is involved in covert orienting of attention. Attention can be summoned to a spatial location in the absence of an overt orienting response. The reaction time to a visual target is faster when attention has been drawn to the location of the target by a preceding cue in that location (valid cue) compared with when the cue misdirects attention (invalid cue) away from the location of the subsequent target. This reaction time difference is referred to as the “validity effect.”

Rats were trained to perform such a reaction time task with visual cues and targets presented in poke holes to either side of the rat's head, which had to be maintained centrally and still. If the rat made an overt orienting response to the cue, the trial was aborted. Unilateral lesions were made by injection of ibotenic acid in the TRN. After surgery, there was no bias apparent in their responding; they were as likely to initiate responses and were equally accurate to either side. There was, however, a complete abolition of the validity effect for responses to contralateral targets. The data are discussed in terms of a role for the TRN in attentional processing.
Motor Skills Training Enhances Lesion-Induced Structural Plasticity in the Motor Cortex of Adult Rats
Authors: Jones Theresa A. , Chu Catherine J. , Grande Lucinda A. , Gregory Aurora D.
Published: April 2018

To assess behavioral experience effects on synaptic plasticity after brain damage, the present study examined the effects of complex motor skills training (the acrobatic task) on synaptic changes in layer V of the motor cortex opposite unilateral damage to the forelimb sensorimotor cortex (FLsmc). Adult male rats were given lesions or sham operations followed by 28 d of training on the acrobatic task [acrobat condition (AC)]. As a motor activity control [motor control (MC)], lesion and sham animals were given simple repetitive exercise. Previously, FLsmc lesions and acrobatic training have independently been found to result in increases in synapse to neuron ratios in the intact motor cortex relative to controls, and both of these effects were replicated in the present study. In addition, acrobat training after lesions significantly increased layer V synapses per neuron relative to sham–AC and lesion–MC rats. Thus, the combination of acrobatic training and lesions resulted in an enhanced synaptogenic response. Synapse subtypes were also differentially affected by the conditions. Lesion–MC and sham–AC primarily had increases in the number of synapses per neuron formed by multiple synaptic boutons in comparison to sham–MC. In contrast, lesion–AC had increases in both multiple and single synapses. Multiple synaptic spines and perforated synapses were also differentially affected by training versus lesions. On tests of coordinated forelimb use, lesion–AC rats performed better than lesion–MC rats. In addition to supporting a link between behavioral experience and structural plasticity after brain damage, these findings suggest that adaptive neural plasticity may be enhanced using behavioral manipulations as “therapy.”
A Novel Human Opsin in the Inner Retina
Authors: Provencio Ignacio , Rodriguez Ignacio R. , Jiang Guisen , Hayes William Pär , Moreira Ernesto F. , Rollag Mark D.
Published: April 2018

Here we report the identification of a novel human opsin, melanopsin, that is expressed in cells of the mammalian inner retina. The human melanopsin gene consists of 10 exons and is mapped to chromosome 10q22. This chromosomal localization and gene structure differs significantly from that of other human opsins that typically have four to seven exons. A survey of 26 anatomical sites indicates that, in humans, melanopsin is expressed only in the eye.In situhybridization histochemistry shows that melanopsin expression is restricted to cells within the ganglion and amacrine cell layers of the primate and murine retinas. Notably, expression is not observed in retinal photoreceptor cells, the opsin-containing cells of the outer retina that initiate vision. The unique inner retinal localization of melanopsin suggests that it is not involved in image formation but rather may mediate nonvisual photoreceptive tasks, such as the regulation of circadian rhythms and the acute suppression of pineal melatonin. The anatomical distribution of melanopsin-positive retinal cells is similar to the pattern of cells known to project from the retina to the suprachiasmatic nuclei of the hypothalamus, a primary circadian pacemaker.
Novel Mechanism of Massive Photoreceptor Degeneration Caused by Mutations in thetrpGene ofDrosophila
Authors: Yoon Jaeseung , Ben-Ami Hagit Cohen , Hong Young Seok , Park Soyeon , Strong Lydia L. R. , Bowman John , Geng Chaoxian , Baek Kwanghee , Minke Baruch , Pak William L.
Published: April 2018

TheDrosophila trpgene encodes a light-activated Ca2+channel subunit, which is a prototypical member of a novel class of channel proteins. Previously identifiedtrpmutants are all recessive, loss-of-function mutants characterized by a transient receptor potential and the total or near-total loss of functional TRP protein. Although retinal degeneration does occur in these mutants, it is relatively mild and slow in onset. We report herein a new mutant,TrpP365, that does not display the transient receptor potential phenotype and is characterized by a substantial level of the TRP protein and rapid, semi-dominant degeneration of photoreceptors. We show that, in spite of its unusual phenotypes,TrpP365is atrpallele because aTrpP365transgene induces the mutant phenotype in a wild-type background, and a wild-typetrptransgene in aTrpP365background suppresses the mutant phenotype. Moreover, amino acid alterations that could cause theTrpP365phenotype are found in the transmembrane segment region of the mutant channel protein. Whole-cell recordings clarified the mechanism underlying the retinal degeneration by showing that the TRP channels ofTrpP365are constitutively active. Although several genes, when mutated, have been shown to cause retinal degeneration inDrosophila, the underlying mechanism has not been identified for any of them. The present studies provide evidence for a specific mechanism for massive degeneration of photoreceptors inDrosophila. Insofar as some human homologs of TRP are highly expressed in the brain, a similar mechanism could be a major contributor to degenerative disorders of the brain.
Insulin-Like Growth Factor-I Protects Axotomized Rat Retinal Ganglion Cells from Secondary Death via PI3-K-Dependent Akt Phosphorylation and Inhibition of Caspase-3In Vivo
Authors: Kermer Pawel , Klöcker Nikolaj , Labes Monika , Bähr Mathias
Published: April 2018

Recently we have shown that the majority of retinal ganglion cells (RGCs) dies via activation of caspase-3 after transection of the optic nerve (ON) in the adult rat. In the present study we investigated whether insulin-like growth factor-I (IGF-I), an important factor in retinal development, prevents secondary death of RGCs after axotomy. Moreover, we studied potential intracellular mechanisms of IGF-mediated neuroprotection in more detail. Our results indicate that intraocular application of IGF-I protects RGCs from death after ON transection in a dose-dependent manner. We show reduced caspase-3 activity as one possible neuroprotective mechanism of IGF-I treatmentin vivo. Caspase-3 mRNA expression remained unchanged. Because caspase inhibition can be mediated by Aktin vitro,we examined phosphorylation of Akt after axotomy and under IGF treatment. Western blot analysis revealed decreased Akt phosphorylation after axotomy without treatment and an increased phosphorylation of Akt under treatment with IGF-I. This strong increase could be reduced by simultaneous injection of wortmannin (WM), a potent inhibitor of phosphatidylinositol 3-kinase (PI3-K). To prove the pathway suggested by these experiments as relevant for thein vivosituation, we assessed the number of RGCs 14 d after ON transection under a combined treatment strategy of IGF-I and WM. As expected, WM significantly reduced the neuroprotective effects of IGF-I. In summary, we show for the first timein vivothat IGF is neuroprotective via PI3-K-dependent Akt phosphorylation and by inhibition of caspase-3.
Odors Elicit Three Different Oscillations in the Turtle Olfactory Bulb
Authors: Lam Ying-Wan , Cohen Lawrence B. , Wachowiak Matt , Zochowski Michal R.
Published: April 2018

We measured the spatiotemporal aspects of the odor-induced population response in the turtle olfactory bulb using a voltage-sensitive dye, RH414, and a 464-element photodiode array. In contrast with previous studies of population activity using local field potential recordings, we distinguished four signals in the response. The one called DC covered almost the entire area of the olfactory bulb; in addition, three oscillations, named rostral, middle, and caudal according to their locations, occurred over broad regions of the bulb. In a typical odor-induced response, the DC signal appeared almost immediately after the start of the stimulus, followed by the middle oscillation, the rostral oscillation, and last, the caudal oscillation. The initial frequencies of the three oscillations were 14.1, 13.0, and 6.6 Hz, respectively. When the rostral and caudal oscillations occurred together, their frequencies differed by a factor of 1.99 ± 0.01.

The following evidence suggests that the four signals are functionally independent: (1) in different animals some signals could be easily detected whereas others were undetectable; (2) the four signals had different latencies and frequencies; (3) the signals occurred in different locations and propagated in different directions; (4) the signals responded differently to changes in odor concentration; (5) the signals had different shapes; and (6) the rostral and caudal signals added in a simple, linear manner in regions where the location of the two signals overlapped. However, the finding that the frequency of the rostral oscillation is precisely two times that of the caudal oscillation suggests a significant relationship between the two.

The location of the caudal oscillation in the bulb changed from cycle to cycle, implying that different groups of neurons are active in different cycles. This result is consistent with the earlier findings in the olfactory system of the locust (Wehr and Laurent, 1996).

Our results suggest an additional complexity of parallel processing of olfactory input by multiple functional population domains.
The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons
Authors: Weiss Craig , Preston Alison R. , Oh M. Matthew , Schwarz Roy D. , Welty Devin , Disterhoft John F.
Published: April 2018

The M1 muscarinic agonist CI-1017 was administered intravenously to aging rabbits on a daily basis before and during hippocampally dependent trace eyeblink conditioning sessions. Circulating levels of CI-1017 were significantly related to the drug dose. The drug was found to significantly increase the rate and amount of learning in a dose-dependent manner with no significant effects on the amplitude, area, or latency of conditioned responses. There was no evidence of pseudoconditioning at the highest drug concentration, and the minimally effective dose produced only mild and temporary hypersalivation as a side effect. CI-1017 (10 μm) was also found to increase the excitability of CA1 pyramidal neurons recorded from hippocampal slices from young and aging naive rabbits as measured by changes in spike-frequency adaptation and the postburst afterhyperpolarization. These biophysical changes were reversed with either atropine (1 μm) or pirenzepine (1 μm). These results suggest that M1 agonists ameliorate age-related learning and memory impairments at least in part by reducing the afterhyperpolarization and spike-frequency adaptation of hippocampal pyramidal neurons and that M1 agonists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease.