bluuebunny/crossref_metadata_2025 huggingface dataset:
cAMP-Dependent Protein Kinase Mediates Activity-Regulated Synaptic Targeting of NMDA Receptors
Authors: Crump F. Thomas , Dillman Keith S. , Craig Ann Marie
Published: April 2018

Chronic activity blockade increases synaptic levels of NMDA receptor immunoreactivity in hippocampal neurons. We show here that blockade-induced synaptic NMDA receptors are functional and mediate enhanced excitotoxicity in response to synaptically released glutamate. Activity blockade increased the cell surface association of NMDA receptors. Blockade-induced synaptic targeting of NMDA receptors did not require protein synthesis but required phosphorylation and specifically cAMP-dependent protein kinase (PKA). Furthermore, activation of PKA was sufficient to induce synaptic targeting of NMDA receptors regardless of receptor activity status. These results implicate PKA activity downstream of receptor blockade as a mediator of enhanced synaptic transport or stabilization of NMDA receptors. Synaptic clustering of NR1-green fluorescent protein was observed in living neurons in response to NMDA receptor and cAMP phosphodiesterase antagonists and occurred gradually over the course of a day. This pathway represents a cellular mechanism for synaptic homeostasis and is likely to function in metaplasticity, long-term regulation of the ability of a synapse to undergo potentiation or depression.
The Role of Dopamine Receptors in Regulating the Size of Axonal Arbors
Authors: Parish C. L. , Finkelstein D. I. , Drago J. , Borrelli E. , Horne M. K.
Published: April 2018

Factors that regulate terminal arbor size of substantia nigra pars compacta (SNpc) neurons during development and after injury are not well understood. This study examined the role of dopamine receptors in regulating arbor size. Terminal arbors were examined in mice with targeted deletion of the D1 or D2 dopamine receptor [D1(−/−) and D2(−/−) mice, respectively]. Terminal trees were also examined after treatment with receptor blockers and after partial SNpc lesions. Immunohistochemistry was performed, and the number of SNpc neurons and dopaminergic terminals in the striatum was estimated. The number of dopaminergic SNpc neurons were reduced in D1(−/−) and D2(−/−) mice. Density of dopaminergic terminals was unchanged in D1(−/−) mice and increased in D2 (−/−) mice. Steady-state striatal DA and DOPAC levels revealed that dopamine activity was enhanced in D2(−/−) mice but reduced in D1(−/−) mice.

Two months after partial SNpc lesions, striatal terminal density was normal in both wild-type and D1(−/−) mice but reduced in D2(−/−) mice. Administration of DA receptor antagonists resulted in larger terminal arbors in D1(−/−) and wild-type mice, whereas D2(−/−) mice showed no change in terminal density.

Functional blockade of the D2R during development or in the adult brain results in increased axonal sprouting. Partial SNpc lesions resulted in compensatory sprouting, only in mice with functional D2R. These results suggest that individual dopaminergic axons in D2(−/−) mice have reached maximal arbor size. We conclude that the D2 receptor may play a role in modulating the extent of the terminal arbor of SNpc neurons.
Altered Respiratory Activity and Respiratory Regulations in Adult Monoamine Oxidase A-Deficient Mice
Authors: Burnet Henri , Bévengut Michelle , Chakri Fouad , Bou-Flores Céline , Coulon Patrice , Gaytán Susana , Pásaro Rosario , Hilaire Gérard
Published: April 2018

The abnormal metabolism of serotonin during the perinatal period alters respiratory network maturation at birth as revealed by comparing the monoamine oxidase A-deficient transgenic (Tg8) with the control (C3H) mice (Bou-Flores et al., 2000). To know whether these alterations occur only transiently or induce persistent respiratory dysfunction during adulthood, we studied the respiratory activity and regulations in adult C3H and Tg8 mice. First, plethysmographic and pneumotachographic analyses of breathing patterns revealed weaker tidal volumes and shorter inspiratory durations in Tg8 than in C3H mice. Second, electrophysiological studies showed that the firing activity of inspiratory medullary neurons and phrenic motoneurons is higher in Tg8 mice and that of the intercostal motoneurons in C3H mice. Third, histological studies indicated abnormally large cell bodies of Tg8 intercostal but not phrenic motoneurons. Finally, respiratory responses to hypoxia and lung inflation are weaker in Tg8 than in C3H mice.dl-p-chlorophenyl-alanine treatments applied to Tg8 mice depress the high serotonin level present during adulthood; the treated mice recover normal respiratory responses to both hypoxia and lung inflation, but their breathing parameters are not significantly affected. Therefore in Tg8 mice the high serotonin level occurring during the perinatal period alters respiratory network maturation and produces a permanent respiratory dysfunction, whereas the high serotonin level present in adults alters the respiratory regulatory processes. In conclusion, the metabolism of serotonin plays a crucial role in the maturation of the respiratory network and in both the respiratory activity and the respiratory regulations.
Inhibition of Neuropathic Pain by Selective Ablation of Brainstem Medullary Cells Expressing the μ-Opioid Receptor
Authors: Porreca Frank , Burgess Shannon E. , Gardell Luis R. , Vanderah Todd W. , Malan T. Philip , Ossipov Michael H. , Lappi Douglas A. , Lai Josephine
Published: April 2018

Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing μ-opioid receptors were targeted with a single microinjection of saporin conjugated to the μ-opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin–saporin, but not dermorphin or saporin, significantly decreased cells expressing μ-opioid receptor transcript. RVM dermorphin, saporin, or dermorphin–saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM dermorphin–saporin failed to elicit the expected increase in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin–saporin against SNL-induced pain was blocked by β-funaltrexamine, a selective μ-opioid receptor antagonist, indicating specific interaction of dermorphin–saporin with the μ-opioid receptor. RVM microinjection of dermorphin–saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM μ receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.
The Neuropeptide Y Y5 Receptor Mediates the Blockade of “Photic-Like” NMDA-Induced Phase Shifts in the Golden Hamster
Authors: Yannielli Paola C. , Harrington Mary E.
Published: April 2018

Circadian or daily rhythms generated from the mammalian suprachiasmatic nuclei (SCN) of the hypothalamus can be synchronized by light and nonphotic stimuli. Whereas glutamate mediates photic information, nonphotic information can in some cases be mediated by neuropeptide Y (NPY) or serotonin. NPY or serotonin can reduce the phase-resetting effect of light or glutamate; however, the mechanisms and level of interaction of these two kinds of stimuli are unknown. Here we investigate the effect of NPY on the NMDA-induced phase shift of the hamster SCN circadian neural activity rhythm by means of single-unit recording techniques.

NMDA (10–100 μm) applied in the early subjective night induced phase delays in the time of peak firing, whereas doses in the millimolar range disrupted firing patterns. The NMDA-induced phase delay was blocked by coapplication of NPY (0.02–200 μm). NPY Y1/Y5 and Y5 receptor agonists, but not the Y2 receptor agonist, blocked the NMDA-induced phase delay in a similar manner as NPY. The coapplication of a Y5 but not Y1 receptor antagonist eliminated NPY blockade of NMDA-induced phase delays, suggesting that the Y5 receptor is capable of mediating the inhibitory effect of NPY on photic responses. These results indicate that nonphotic and photic stimuli may interact at a level at or beyond NMDA receptor response and indicate that the Y5 receptor is involved in this interaction. Alteration of Y5 receptor function may therefore be expected to alter synchronization of circadian rhythms to light.
Chronic Intermittent Hypoxia Elicits Serotonin-Dependent Plasticity in the Central Neural Control of Breathing
Authors: Ling Liming , Fuller David D. , Bach Karen B. , Kinkead Richard , Olson E. Burdette , Mitchell Gordon S.
Published: April 2018

We tested the hypothesis that chronic intermittent hypoxia (CIH) elicits plasticity in the central neural control of breathingviaserotonin-dependent effects on the integration of carotid chemoafferent inputs. Adult rats were exposed to 1 week of nocturnal CIH (11–12% O2/air at 5 min intervals; 12 hr/night). CIH and untreated rats were then anesthetized, paralyzed, vagotomized, and artificially ventilated. Time-dependent hypoxic responses were assessed in the phrenic neurogram during and after three 5 min episodes of isocapnic hypoxia. Integrated phrenic amplitude (∫Phr) responses during hypoxia were greater after CIH at arterial oxygen pressures (PaO2) between 25 and 45 mmHg (p< 0.05), but not at higher PaO2levels. CIH did not affect hypoxic phrenic burst frequency responses, although the post-hypoxia frequency decline that is typical in rats was abolished. ∫Phr and frequency responses to electrical stimulation of the carotid sinus nerve were enhanced by CIH (p< 0.05). Serotonin-dependent long-term facilitation (LTF) of ∫Phr was enhanced after CIH at 15, 30, and 60 min after episodic hypoxia (p< 0.05). Pretreatment with the serotonin receptor antagonists methysergide (4 mg/kg, i.v.) and ketanserin (2 mg/kg, i.v.) reversed CIH-induced augmentation of the short-term hypoxic phrenic response and restored the post-hypoxia frequency decline in CIH rats. Whereas methysergide abolished CIH-enhanced phrenic LTF, the selective 5-HT2antagonist ketanserin only partially reversed this effect. The results suggest that CIH elicits unique forms of serotonin-dependent plasticity in the central neural control of breathing. Enhanced LTF after CIH may involve an upregulation of a non-5-HT2serotonin receptor subtype or subtypes.
Random Response Fluctuations Lead to Spurious Paired-Pulse Facilitation
Authors: Kim Jimok , Alger Bradley E.
Published: April 2018

We studied paired-pulse depression (PPD) of GABAAergic IPSCs under conditions of reduced transmitter release (caused by Cd2+, baclofen, or reduced stimulus intensity) with whole-cell voltage clamp in CA1 pyramidal cellsin vitro. The use-dependent model of paired-pulse responsiveness holds that a decrease in the probability of neurotransmitter release during the first stimulus will cause predictable changes in the paired-pulse ratio (PPR, the amplitude of the second IPSC divided by that of the first). However, the applicability of the use-dependent model to inhibitory synapses is controversial. Our results are inconsistent with this model, but are consistent with the hypothesis that random fluctuations in response size significantly influence PPR. PPR was sensitive to the extracellular stimulus intensity in all conditions. Changes in PPR were not correlated with changes in the first IPSC, but were correlated with changes in variability of the PPRs of individual traces. We show that spurious paired-pulse facilitation (PPF) can result from averaging randomly fluctuating PPRs because the method of calculating PPR as the mean of individual PPRs is biased in favor of high values of PPR. Spurious PPF can mask the intrinsic paired-pulse property of the synapses. Calculating PPR as the mean of the second response divided by the mean of the first avoids the error. We discuss a simple model that shows that spurious PPF depends on both the number of synapses recruited for release and the probability of release at each release site. The random factor can reconcile some conflicting published conclusions.
Loss of Neurofilaments Alters Axonal Growth Dynamics
Authors: Walker Kimberly L. , Yoo Hee Kwang , Undamatla Jayanthi , Szaro Ben G.
Published: April 2018

The highly regulated expression of neurofilament (NF) proteins during axon outgrowth suggests that NFs are important for axon development, but their contribution to axon growth is unclear. Previous experiments inXenopuslaevisembryos demonstrated that antibody-induced disruption of NFs stunts axonal growth but left unresolved how the loss of NFs affects the dynamics of axon growth. In the current study, dissociated cultures were made from the spinal cords of embryos injected at the two-cell stage with an antibody to the middle molecular mass NF protein (NF-M), and time-lapse videomicroscopy was used to study early neurite outgrowth in descendants of both the injected and uninjected blastomeres. The injected antibody altered the growth dynamics primarily in long neurites (>85 μm). These neurites were initiated just as early and terminated growth no sooner than did normal ones. Rather, they spent relatively smaller fractions of time actively extending than normal. When growth occurred, it did so at the same velocity. In very young neurites, which have NFs made exclusively of peripherin, NFs were unaffected, but in the shaft of older neurites, which have NFs that contain NF-M, NFs were disrupted. Thus growth was affected only after NFs were disrupted. In contrast, the distributions of α-tubulin and mitochondria were unaffected; thus organelles were still transported into neurites. However, mitochondrial staining was brighter in descendants of injected blastomeres, suggesting a greater demand for energy. Together, these results suggest a model in which intra-axonal NFs facilitate elongation of long axons by making it more efficient.
Visual Pathways Involved in Fear Conditioning Measured with Fear-Potentiated Startle: Behavioral and Anatomic Studies
Authors: Shi Changjun , Davis Michael
Published: April 2018

Visual pathways to the amygdala, a brain structure critical for classical fear conditioning, were investigated. Conditioned fear was measured in rats as increased acoustic startle amplitude in the presence versus absence of a light or an odor paired previously with foot shock (fear-potentiated startle). Post-training lesions of both the lateral geniculate body (LG) and lateral posterior nucleus (LP) of the thalamus together, but not lesions of LG or LP alone, completely blocked the expression of fear-potentiated startle to a visual conditioned stimulus (CS) but not to an olfactory CS. These lesions also did not block contextual fear conditioning using startle or freezing as measures. Local infusion of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f] quinoxaline-7-sulfonamide disodium, an AMPA antagonist, into the visual thalamus immediately before testing also blocked fear-potentiated startle to a visual CS, suggesting that the lesion effects were not attributable to damage of fibers of passage. Iontophoretic injections into the LP of the anterograde tracer biotinylated dextran amine resulted in heavy anterograde labeling in two amygdala–fugal cortical areas: area TE2 and dorsal perirhinal cortex (PR), and moderate labeling in the lateral amygdaloid nucleus (L). These results suggest that, during classical fear conditioning, a visual stimulus can be transmitted to the amygdala via either lemniscal (i.e., LG → V1, V2 → TE2/PR) or non-lemniscal (i.e., LP → V2, TE2/PR) thalamo-cortico-amygdala pathways, or direct thalamo-amygdala (i.e., LP → L) projections.
Exacerbation of Pain by Anxiety Is Associated with Activity in a Hippocampal Network
Authors: Ploghaus Alexander , Narain Charvy , Beckmann Christian F. , Clare Stuart , Bantick Susanna , Wise Richard , Matthews Paul M. , Rawlins J. Nicholas P. , Tracey Irene
Published: April 2018

It is common clinical experience that anxiety about pain can exacerbate the pain sensation. Using event-related functional magnetic resonance imaging (FMRI), we compared activation responses to noxious thermal stimulation while perceived pain intensity was manipulated by changes in either physical intensity or induced anxiety. One visual signal, which reliably predicted noxious stimulation of moderate intensity, came to evoke low anxiety about the impending pain. Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found that the entorhinal cortex of the hippocampal formation responded differentially to identical noxious stimuli, dependent on whether the perceived pain intensity was enhanced by pain-relevant anxiety. During this emotional pain modulation, entorhinal responses predicted activity in closely connected, affective (perigenual cingulate), and intensity coding (mid-insula) areas. Our finding suggests that accurate preparatory information during medical and dental procedures alleviates pain by disengaging the hippocampus. It supports the proposal that during anxiety, the hippocampal formation amplifies aversive events to prime behavioral responses that are adaptive to the worst possible outcome.
The NMDA Receptor M3 Segment Is a Conserved Transduction Element Coupling Ligand Binding to Channel Opening
Authors: Jones Kevin S. , VanDongen Hendrika M. A. , VanDongen Antonius M. J.
Published: April 2018

Ion channels alternate stochastically between two functional states, open and closed. This gating behavior is controlled by membrane potential or by the binding of neurotransmitters in voltage- and ligand-gated channels, respectively. Although much progress has been made in defining the structure and function of the ligand-binding cores and the voltage sensors, how these domains couple to channel opening remains poorly understood. Here we show that the M3 transmembrane segments of the NMDA receptor allosterically interact with both the ligand-binding cores and the channel gate. It is proposed that M3 functions as a transduction element whose conformational change couples ligand binding with channel opening. Furthermore, amino acid homology between glutamate receptor M3 segments and the equivalent S6 or TM2 segments in K+channels suggests that ion channel activation and gating are both structurally and functionally conserved.
Localization and Regulation of the Tissue Plasminogen Activator–Plasmin System in the Hippocampus
Authors: Sallés Fernando J. , Strickland Sidney
Published: April 2018

The extracellular protease cascade of tissue plasminogen activator (tPA) and plasminogen has been implicated in neuronal plasticity and degeneration. We show here that unstimulated expression of tPA in the mouse hippocampus is concentrated in the mossy fiber pathway, with little or no expression within the perforant path, the Schaffer collaterals, or neuronal cell bodies. tPA protein is also expressed in vascular endothelial cells throughout the brain parenchyma. Four hours after excitotoxic injury, tPA protein is transiently induced within CA1 pyramidal neurons. The induced CA1 tPA is localized to neurons that survive the injury and is enzymatically active. Within the mossy fiber pathway, injury resulted in decreased tPA protein. In contrast, mossy fiber tPA activity displayed a biphasic character: transient increase at 8 hr, then a decrease by 24 hr after injury. Analysis of plasminogen activator inhibitor-1 (PAI-1) expression showed that PAI-1 antigen is upregulated by 24 hr and could account for the tPA activity downregulation seen at this time point. Plasminogen immunohistochemistry suggested an increase within the mossy fiber pathway after injury. Finally, hippocampal tPA expression among various mammalian species was strikingly different. These results indicate a complex control of tPA protein and enzymatic activity in the hippocampus that may help regulate neuronal plasticity.
Selective Blockade of mGlu5 Metabotropic Glutamate Receptors Is Protective against Methamphetamine Neurotoxicity
Authors: Battaglia Giuseppe , Fornai Francesco , Busceti Carla L. , Aloisi Gabriella , Cerrito Franca , De Blasi Antonio , Melchiorri Daniela , Nicoletti Ferdinando
Published: April 2018

Methamphetamine (MA), a widely used drug of abuse, produces oxidative damage of nigrostriatal dopaminergic terminals. We examined the effect of subtype-selective ligands of metabotropic glutamate (mGlu) receptors on MA neurotoxicity in mice. MA (5 mg/kg, i.p.; injected three times, every 2 hr) induced, 5 d later, a substantial degeneration of striatal dopaminergic terminals associated with reactive gliosis. MA toxicity was primarily attenuated by the coinjection of the noncompetitive mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine and (E)-2-methyl-6-styrylpyridine both at 10 mg/kg, i.p.). In contrast, the mGlu1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (10 mg/kg, i.p.), and the mGlu2/3 receptor agonist (−)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (1 mg/kg, i.p.), failed to affect MA toxicity. mGlu5 receptor antagonists reduced the production of reactive oxygen species but did not reduce the acute stimulation of dopamine release induced by MA both in striatal synaptosomes and in the striatum of freely moving mice. We conclude that endogenous activation of mGlu5 receptors enables the development of MA neurotoxicity and that mGlu5 receptor antagonists are neuroprotective without interfering with the primary mechanism of action of MA.
Rapid Synaptic Remodeling by Protein Kinase C: Reciprocal Translocation of NMDA Receptors and Calcium/Calmodulin-Dependent Kinase II
Authors: Fong Dan K. , Rao Anuradha , Crump F. Thomas , Craig Ann Marie
Published: April 2018

In contrast to the rapid regulation of AMPA receptors, previous evidence has supported the idea that the synaptic density of NMDA-type glutamate receptors is fairly static, modulated only over a long time scale in a homeostatic manner. We report here that selective activation of protein kinase C (PKC) with phorbol esters induces a rapid dispersal of NMDA receptors from synaptic to extrasynaptic plasma membrane in cultured rat hippocampal neurons. PKC activation induced a simultaneous translocation of calcium/calmodulin-dependent kinase II (CaMKII) to synapses but no change in spine number, presynaptic terminal number, or the distribution of AMPA receptors or the synaptic scaffolding protein PSD-95. PKC-induced accumulation of CaMKII was dependent on filamentous actin, whereas dispersal of NMDA receptors occurred by a different mechanism independent of actin or CaMKII. Consistent with the decrease in synaptic density of NMDA receptors, phorbol ester pretreatment reduced excitotoxicity. These results reveal a surprisingly dynamic nature to the molecular composition and functional properties of glutamatergic postsynaptic specializations.
cAMP/Ca2+Response Element-Binding Protein Function Is Essential for Ocular Dominance Plasticity
Authors: Mower Amanda F. , Liao David S. , Nestler Eric J. , Neve Rachael L. , Ramoa Ary S.
Published: April 2018

The monocular deprivation model of amblyopia is characterized by a reduction in cortical responses to stimulation of the deprived eye. Although the effects of monocular deprivation on the primary visual cortex have been well characterized physiologically and anatomically, the molecular mechanisms underlying ocular dominance plasticity remain unknown. Previous studies have indicated that the transcription factor adenosine cAMP/Ca2+response element-binding protein (CREB) is activated during monocular deprivation. However, it remains unknown whether CREB function is required for the loss of cortical responses to the deprived eye. To address this issue, we used the herpes simplex virus (HSV) to express a dominant negative form of CREB (HSV-mCREB) containing a single point mutation that prevents its activation. Quantitative single-unit electrophysiology showed that cortical expression of this mutated form of CREB during monocular deprivation prevented the loss of responses to the deprived eye. This effect was specific and not related to viral toxicity, because overexpression of functional CREB or expression of β-galactosidase using HSV injections did not prevent the ocular dominance shift during monocular deprivation. Additional evidence for specificity was provided by the finding that blockade of ocular dominance plasticity was reversible; animals treated with HSV-mCREB recovered ocular dominance plasticity when mCREB expression declined. Moreover, this effect did not result from a suppression of sensory responses caused by the viral infection because neurons in infected cortex responded normally to visual stimulation. These findings demonstrate that CREB function is essential for ocular dominance plasticity.
Lack of the Cell-Cycle Inhibitor p27Kip1 Results in Selective Increase of Transit-Amplifying Cells for Adult Neurogenesis
Authors: Doetsch Fiona , Verdugo José Manuel-Garcia , Caille Isabelle , Alvarez-Buylla Arturo , Chao Moses V. , Casaccia-Bonnefil Patrizia
Published: April 2018

The subventricular zone (SVZ) is the largest germinal layer in the adult mammalian brain and comprises stem cells, transit-amplifying progenitors, and committed neuroblasts. Although the SVZ contains the highest concentration of dividing cells in the adult brain, the intracellular mechanisms controlling their proliferation have not been elucidated. We show here that loss of the cyclin-dependent kinase inhibitor p27Kip1 has very specific effects on a population of CNS progenitors responsible for adult neurogenesis. Using bromodeoxyuridine and [3H]thymidine incorporation to label cells in S phase and cell-specific markers and electron microscopy to identify distinct cell types, we compared the SVZ structure and proliferation characteristics of wild-type and p27Kip1-null mice. Loss of p27Kip1 had no effect on the number of stem cells but selectively increased the number of the transit-amplifying progenitors concomitantly with a reduction in the number of neuroblasts. We conclude that cell-cycle regulation of SVZ adult progenitors is remarkably cell-type specific, with p27Kip1 being a key regulator of the cell division of the transit-amplifying progenitors.
Elevated Fusiform Cell Activity in the Dorsal Cochlear Nucleus of Chinchillas with Psychophysical Evidence of Tinnitus
Authors: Brozoski T. J. , Bauer C. A. , Caspary D. M.
Published: April 2018

Chinchillas with psychophysical evidence of chronic tinnitus were shown to have significantly elevated spontaneous activity and stimulus-evoked responses in putative fusiform cells of the dorsal cochlear nuclei (DCN). Chinchillas were psychophysically trained and tested before and after exposure to a traumatic unilateral 80 dB (sound pressure level) 4 kHz tone. Before exposure, two groups were matched in terms of auditory discrimination performance (noise, and 1, 4, 6, and 10 kHz tones). After exposure, a single psychophysical difference emerged between groups. The exposed group displayed enhanced discrimination of 1 kHz tones (p= 0.00027). Postexposure discrimination of other stimuli was unaffected. It was hypothesized that exposed animals experienced a chronic subjective tone (i.e., tinnitus), resulting from their trauma, and that features of this subjective tone were similar enough to 1 kHz to affect discrimination of 1 kHz objective signals. After psychophysical testing, single-unit recordings were obtained from each animal's DCN fusiform cell layer. Putative fusiform cells of exposed animals showed significantly (p= 0.0136) elevated spontaneous activity, compared with cells of unexposed animals. Putative fusiform cells of exposed animals showed a greater stimulus-evoked response to tones at 1 kHz (p= 0.0000006) and at characteristic-frequency (p= 0.0000009). This increased activity was more pronounced on the exposed side. No increase in stimulus-evoked responses was observed to other frequencies or noise. These parallel psychophysical and electrophysiological results are consistent with the hypothesis that chronic tonal tinnitus is associated with, and may result from, trauma-induced elevation of activity of DCN fusiform cells.
Functional Interactions between Estrogen and Insulin-Like Growth Factor-I in the Regulation of α1B-Adrenoceptors and Female Reproductive Function
Authors: Quesada Arnulfo , Etgen Anne M.
Published: April 2018

The ovarian hormone estradiol (E2) and insulin-like growth factor-I (IGF-I) interact in the CNS to regulate neuroendocrine function and synaptic remodeling. Previously, our laboratory showed that 2 d E2treatment induces α1B-adrenoceptor expression and promotes IGF-I enhancement of α1-adrenoceptor potentiation of cAMP accumulation in the preoptic area (POA) and hypothalamus (HYP). This study examined the hypothesis that E2-dependent aspects of female reproductive function, including α1B-adrenoceptor expression and function in the POA and HYP, are mediated by brain IGF-I receptors (IGF-IRs) in female rats. Ovariohysterectomized rats were implanted with a guide cannula aimed at the third ventricle and treatedin vivowith vehicle or E2daily for 2 d before experimentation. Intracerebroventricular infusions of JB-1, a selective IGF-IR antagonist, were administered every 12 hr beginning 1 hr before the first E2injection. Administration of JB-1 during E2priming completely blocks hormone-induced luteinizing hormone release and partially inhibits hormone-dependent reproductive behavior. Reproductive behavior is restored by intracerebroventricular infusion of 8-bromo-cGMP, the second messenger implicated in α1-adrenergic facilitation of lordosis. In addition, blockade of IGF-IRs during E2priming prevents E2-induced increases in α1B-adenoceptor binding density and abolishes acute IGF-I enhancement of NE-stimulated cAMP accumulation in HYP and POA slices. These data document the existence of a novel mechanism by which IGF-I participates in the remodeling of noradrenergic receptor signaling in the HYP and POA after E2treatment. These events may help coordinate the timing of ovulation with the expression of sexual receptivity.
Rapid Neuromodulatory Actions of Integrin Ligands
Authors: Wildering Willem C. , Hermann Petra M. , Bulloch Andrew G. M.
Published: April 2018

Extracellular matrix (ECM) proteins and their receptors, the integrins, actively participate in the control of many fundamental cellular functions in the developing nervous system, including the regulation of cell migration, differentiation, and survival and the control of neurite outgrowth. ECM–integrin interactions in the mature nervous system are commonly considered to be more static in nature and of little importance in the regulation of neuronal function. In contrast, we demonstrate that integrins and their ligands are capable of rapid neuromodulatory actions. Specifically, we show that integrin ligands can alter neuronal pacemaker properties, intracellular free Ca2+levels, and voltage-gated Ca2+currents in a matter of minutes. These findings indicate that ECM–integrin interactions play a dynamic role in regulating the physiological status of mature neurons, a process that may contribute to synaptic plasticity, neural regeneration, and neuropathology.
Regulated Cationic Channel Function inXenopusOocytes ExpressingDrosophilaBig Brain
Authors: Yanochko Gina M. , Yool Andrea J.
Published: April 2018

Big brain(bib) is a neurogenic gene that when mutated causes defects in cell fate determination duringDrosophilaneurogenesis through an unknown mechanism. The protein Big Brain (BIB) has sequence identity with the major intrinsic protein family that includes the water- and ion-conducting aquaporin channels. We show here that BIB expressed heterologously inXenopusoocytes provides a voltage-insensitive, nonselective cation channel function with permeability to K+> Na+≫ tetraethylammonium. The conductance, activated in response to endogenous signaling pathways in BIB-expressing oocytes, is decreased after treatment with 20 μminsulin and is enhanced with 10 μmlavendustin A, a tyrosine kinase inhibitor. Western blot analysis confirms that BIB is tyrosine-phosphorylated. Both tyrosine phosphorylation and the potentiating effect of lavendustin A are removed by partial deletion of the C terminus (amino acids 317–700). Current activation is not observed in control oocytes or in oocytes expressing a nonfunctional mutant (BIB E71N) that appears to be expressed on the plasma membrane by confocal microscopy and Western blotting. These results indicate that BIB can participate in tyrosine kinase-regulated transmembrane signaling and may suggest a role for membrane depolarization in the neurogenic function of BIB in early development.
Localization of Activator Protein-1 Complex with DNA Binding Activity in Mitochondria of Murine Brain afterIn VivoTreatment with Kainate
Authors: Ogita Kiyokazu , Okuda Hiroaki , Kitano Masahiro , Fujinami Yoshiaki , Ozaki Kiyokazu , Yoneda Yukio
Published: April 2018

To elucidate mechanisms underlying mitochondrial dysfunctions induced by glutamate, we have examined the effects ofin vivotreatment with the ionotropic glutamate receptor agonist kainate on localization of the transcription factor activator protein-1 (AP-1) in mitochondria as well as nuclei of murine brain. A systemic administration of kainate dramatically enhanced AP-1 DNA binding in both mitochondrial and nuclear extracts of mouse cerebral cortex and hippocampus 1 hr to 3 d later. Unlabeled AP-1 probe selectively competed for AP-1 DNA binding in mitochondrial extracts of cortex and hippocampus obtained from mice injected with kainate. Supershift and immunoblotting analyses revealed participation of c-Fos, Fos-B, and Jun-B proteins in potentiation by kainate of mitochondrial AP-1 DNA binding in cortex and hippocampus. An immunohistochemical study demonstrated marked expression by kainate of c-Fos protein in the pyramidal and dentate granular layers, whereas an immunoelectron microscopic analysis showed localization of c-Fos protein within mitochondria, as well as nuclei, of the CA1 pyramidal and dentate granular cells in hippocampus obtained 2 hr after the administration of kainate. Mitochondrial AP-1 DNA binding was inhibited by particular unlabeled oligonucleotides containing sequences similar to the AP-1 site found in the noncoding region of mitochondrial DNA. Kainate markedly potentiated binding of radiolabeled oligonucleotide probes containing sequences effective in competing for AP-1 DNA binding in hippocampal mitochondrial extracts. These results suggest that kainate may facilitate expression of the AP-1 complex and subsequent translocation into mitochondria to participate in mechanisms associated with transcriptional regulation of mitochondrial DNA in murine hippocampus.
Metabotropic Glutamate Receptor 5 Upregulation in A-Fibers after Spinal Nerve Injury: 2-Methyl-6-(Phenylethynyl)-Pyridine (MPEP) Reverses the Induced Thermal Hyperalgesia
Authors: Hudson Lindsey J. , Bevan Stuart , McNair Kara , Gentry Clive , Fox Alyson , Kuhn Rainer , Winter Janet
Published: April 2018

Metabotropic glutamate receptor 5 (mGluR5) protein increased after sciatic nerve section in ipsilateral L4 and L5 DRG neuronal profiles, with most of the increase occurring in myelinated A-fiber somata. mGluR5 also increased in lamina II of the ipsilateral spinal cord and the proximal sciatic nerve stump in this model. After L5 spinal nerve ligation, mGluR5 immunoreactivity increased dramatically not only in damaged L5 but also in the neighboring undamaged L4. Interestingly, after partial sciatic nerve section, mGluR5 expression did not change in either L4 or L5 DRG neuronal profiles.

Both spinal nerve ligation and sciatic nerve partial section produced significant mechanical and thermal hyperalgesia and tactile allodynia. After partial sciatic nerve section, the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) had no effect on any of these behaviors. However, after L5 spinal nerve ligation, although MPEP failed to alter the induced tactile allodynia or mechanical hyperalgesia, it dose dependently reversed the developed thermal hyperalgesia.

Therefore, reversal of thermal hyperalgesia by MPEP correlates with increased mGluR5 in lumbar DRG A-fiber somata after nerve injury. Furthermore, A-fibers in the uninjured L4 DRG after L5 spinal nerve ligation that have increased mGluR5 are the same A-fibers that newly express vanilloid receptor 1 after such injury. Together, these results suggest that, after L5 spinal nerve injury, mGluR5 expression on A-fibers is essential to the development of thermal hyperalgesia. After partial nerve section, however, it is unlikely that thermal responses are mediated through mGluR5 because no such increase in mGluR5 is detected in this model and MPEP is ineffective.
Neural Correlates of Encoding Space from Route and Survey Perspectives
Authors: Shelton Amy L. , Gabrieli John D. E.
Published: April 2018

The neural mechanisms underlying ground-level spatial navigation have been investigated, but little is known about other kinds of spatial navigation. Functional magnetic resonance imaging was used to identify differences in brain activation for two types of spatial information, information from the ground-level perspective (route) and information from a global perspective (survey). Participants were scanned during the encoding of two different virtual reality environments, one from each perspective. Comparisons of brain activation during route and survey encoding suggested that both types of information recruited a common network of brain areas, but with important differences. Survey encoding recruited a subset of areas recruited by route encoding, but with greater activation in some areas, including inferior temporal cortex and posterior superior parietal cortex. Route encoding, in contrast, recruited regions that were not activated by survey encoding, including medial temporal lobe structures, anterior superior parietal cortex, and postcentral gyrus. These differences in brain activation are associated with differences in memory performance for the two types of spatial information and contribute to specification of brain components of spatial knowledge.
Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia
Authors: Middleton Frank A. , Mirnics Karoly , Pierri Joseph N. , Lewis David A. , Levitt Pat
Published: April 2018

Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.
Bimodal Interactions in the Superior Colliculus of the Behaving Cat
Authors: Populin Luis C. , Yin Tom C. T.
Published: April 2018

Bimodal enhancement, a form of nonlinear summation of physiological responses from two sensory modalities, has been demonstrated in the intermediate layers of the superior colliculus (SCi) and is thought to be a manifestation of a neural mechanism underlying behavioral facilitation to such stimuli. Most physiological studies, however, have been performed in anesthetized animals. We tested for bimodal enhancement in the SCi of behaving cats trained to orient to acoustic, visual, and bimodal stimuli. Surprisingly, we never observed the large enhanced responses reported in anesthetized animals, even when we varied the time between presentation of the visual and acoustic stimuli and/or decreased the level of the stimuli. Using three different behavioral paradigms, we found no support for enhanced interactions between auditory and visual modalities. Prominent depressive effects were seen, however, particularly when the cats were required to fixate a visual target during presentation of an acoustic stimulus.
α1b-Adrenergic Receptors Control Locomotor and Rewarding Effects of Psychostimulants and Opiates
Authors: Drouin Candice , Darracq Laurent , Trovero Fabrice , Blanc Gérard , Glowinski Jacques , Cotecchia Susanna , Tassin Jean-Pol
Published: April 2018

Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through α1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of α1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced byd-amphetamine (1–3 mg/kg), cocaine (5–20 mg/kg), or morphine (5–10 mg/kg) in mice lacking the α1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced byd-amphetamine (1–2 mg/kg), cocaine (5–15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm.

Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of α1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.
Completing the Corticofugal Loop: A Visual Role for the Corticogeniculate Type 1 Metabotropic Glutamate Receptor
Authors: Rivadulla Casto , Martı́nez Luis M. , Varela Carmen , Cudeiro Javier
Published: April 2018

The way in which the brain deals with sensory information relies not only on feedforward processing of signals from the periphery but also on feedback inputs. This is the case of the massive projection back from layer 6 in the visual cortex to the thalamus, for which, despite being the greatest single source of synaptic contacts, the functional role still remains unclear. In the cat lateral geniculate nucleus, part of this cortical feedback is mediated by type 1 metabotropic glutamate receptors (mGluR1s), which are exclusively located on distal segments of the relay-cell dendrites. Here we show that in adult cats the cortex uses a synaptic drive mediated by these receptors (mGluR1) specifically to enhance the excitatory center of the thalamic receptive field. Moreover the effect is maximum in response to those stimuli that effectively drive cortical cells, and importantly, it does not affect the spatiotemporal structure of the thalamic receptive field. Therefore, cortex, by closing this corticofugal “loop,” is able to increase the gain of its thalamic input within a focal spatial window, selecting key features of the incoming signal.
Activity Patterns in a Model for the Subthalamopallidal Network of the Basal Ganglia
Authors: Terman D. , Rubin J. E. , Yew A. C. , Wilson C. J.
Published: April 2018

Based on recent experimental data, we have developed a conductance-based computational network model of the subthalamic nucleus and the external segment of the globus pallidus in the indirect pathway of the basal ganglia. Computer simulations and analysis of this model illuminate the roles of the coupling architecture of the network, and associated synaptic conductances, in modulating the activity patterns displayed by this network. Depending on the relationships of these coupling parameters, the network can support three general classes of sustained firing patterns: clustering, propagating waves, and repetitive spiking that may show little regularity or correlation. Each activity pattern can occur continuously or in discrete episodes. We characterize the mechanisms underlying these rhythms, as well as the influence of parameters on details such as spiking frequency and wave speed. These results suggest that the subthalamopallidal circuit is capable both of correlated rhythmic activity and of irregular autonomous patterns of activity that block rhythmicity. Increased striatal input to, and weakened intrapallidal inhibition within, the indirect pathway can switch the behavior of the circuit from irregular to rhythmic. This may be sufficient to explain the emergence of correlated oscillatory activity in the subthalamopallidal circuit after destruction of dopaminergic neurons in Parkinson's disease and in animal models of parkinsonism.