112 results on '"Metherate R"'
Search Results
2. THE ROLE OF SYNAPTIC ZINC IN ACTIVITY-DEPENDENT Aß OLIGOMER FORMATION AND ACCUMULATION AT EXCITATORY SYNAPSES.: OP03-04
- Author
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Busciglio, J., Deshpande, A., Glabe, C., Metherate, R., Kawai, H., and Vogler, E.
- Published
- 2009
3. Cholinergic Modulation of Neuronal Excitability in Cat Somatosensory Cortex
- Author
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Dykes, R. W., Metherate, R., Tremblay, N., Avoli, Massimo, editor, Reader, Tomás A., editor, Dykes, Robert W., editor, and Gloor, Pierre, editor
- Published
- 1988
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4. Bicuculline-induced alterations of response properties in functionally identified ventroposterior thalamic neurones
- Author
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Hicks, T. P., Metherate, R., Landry, P., and Dykes, R. W.
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- 1986
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5. Heightened Nicotinic Regulation of Auditory Cortex during Adolescence
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Kawai, H. D., primary, Kang, H.-A., additional, and Metherate, R., additional
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- 2011
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6. A Role for Synaptic Zinc in Activity-Dependent A Oligomer Formation and Accumulation at Excitatory Synapses
- Author
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Deshpande, A., primary, Kawai, H., additional, Metherate, R., additional, Glabe, C. G., additional, and Busciglio, J., additional
- Published
- 2009
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7. Spectral integration in primary auditory cortex: Laminar processing of afferent input, in vivo and in vitro
- Author
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Kaur, S., primary, Rose, H.J., additional, Lazar, R., additional, Liang, K., additional, and Metherate, R., additional
- Published
- 2005
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8. Thalamic stimulation largely elicits orthodromic, rather than antidromic, cortical activation in an auditory thalamocortical slice
- Author
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Rose, H.J, primary and Metherate, R, additional
- Published
- 2001
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9. Parvalbumin and calbindin are differentially distributed within primary and secondary subregions of the mouse auditory forebrain
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Cruikshank, S.J, primary, Killackey, H.P, additional, and Metherate, R, additional
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- 2001
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10. Facilitation of an NMDA receptor-mediated EPSP by paired-pulse stimulation in rat neocortex via depression of GABAergic IPSPs.
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Metherate, R, primary and Ashe, J H, additional
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- 1994
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11. Ionic flux contributions to neocortical slow waves and nucleus basalis- mediated activation: whole-cell recordings in vivo
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Metherate, R, primary and Ashe, JH, additional
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- 1993
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12. Cellular bases of neocortical activation: modulation of neural oscillations by the nucleus basalis and endogenous acetylcholine
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Metherate, R, primary, Cox, CL, additional, and Ashe, JH, additional
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- 1992
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13. Amino acids as transmitters of synaptic excitation in neocortical sensory processes
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Hicks, T. P., primary, Kaneko, T., additional, Metherate, R., additional, Oka, J.-I., additional, and Stark, C. A., additional
- Published
- 1991
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14. Transient and prolonged effects of acetylcholine on responsiveness of cat somatosensory cortical neurons
- Author
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Dykes, R., primary, Metherate, R., additional, and Tremblay, N., additional
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- 1990
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15. A thalamic terminus of the lateral cervical nucleus: the lateral division of the posterior nuclear group.
- Author
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Metherate, R. S., da Costa, D. C., Herron, P., and Dykes, R. W.
- Published
- 1986
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16. Functional Role of GABA in Cat Primary Somatosensory Cortex: Shaping Receptive Fields of Cortical Neurons.
- Author
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DYKES, R. W., LANDRY, P., METHERATE, R., and HICKS, T. P.
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- 1984
- Full Text
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17. Differential modulation of auditory thalamocortical and intracortical synaptic transmission by cholinergic agonist
- Author
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Hsieh, C. Y., Cruikshank, S. J., and Metherate, R.
- Published
- 2000
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18. Intrinsic electrophysiology of neurons in thalamorecipient layers of developing rat auditory cortex
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Metherate, R. and Aramakis, V.B.
- Published
- 1999
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19. Transient and prolonged effects of acetylcholine on responsiveness of cat somatosensory cortical neurons.
- Author
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Metherate, R, Tremblay, N, and Dykes, R W
- Abstract
1. Two-hundred and seven neurons were examined for changes in their responsiveness during the iontophoretic administration of acetylcholine (ACh) in barbiturate-anesthetized cats. 2. The laminar locations of 78 cells were determined. Cholinoceptive neurons were found in all cortical layers and ranged from 50% of the cells tested in layer I to 78% in layer VI. 3. When the responsiveness of a neuron was measured by the magnitude of the discharge generated by a fixed dose of glutamate, 30 of 47 cases (64%) were potentiated, and 4 (8%) were depressed when ACh was administered during glutamate-induced excitation. 4. ACh administered during glutamate excitation was significantly more effective in altering neuronal responsiveness than was ACh administered alone (P less than 0.001). 5. When the responsiveness of a neuron was measured by the magnitude of the discharge generated by a standard somatic stimulus applied to the receptive field, 42 of 52 cases (81%) were potentiated during ACh application. This was again different from ACh treatment alone where only 4 of 27 tests (15%) resulted in subsequent enhancement of the response to somatic stimuli. 6. ACh generally increased the responsiveness of neurons with peripheral receptive fields and caused the appearance of a receptive field in some cells lacking one. 7. In many cases the changes in excitability, as measured by responses either to glutamate or to somatic stimulation, remained for prolonged time periods. When glutamate was used to test excitability, 34% (16 of 47) of the enhancements lasted more than 5 min. When somatic stimuli were used 29% (15 of 52) lasted more than 5 min. With both measures some neurons still displayed enhanced responses more than 1 h after the treatment with ACh. 8. ACh appears to act as a permissive agent that allows modification of the effectiveness with which previously existing afferent inputs drive somatosensory cortical neurons. 9. This mechanism to alter neuronal responsiveness has many of the characteristics necessary to account for the reorganization observed in somatosensory cortex following alterations in its afferent drive and may be related to some forms of learning and memory.
- Published
- 1988
20. The effects of acetylcholine on response properties of cat somatosensory cortical neurons.
- Author
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Metherate, R, Tremblay, N, and Dykes, R W
- Abstract
1. Two-hundred thirty-three single neurons were isolated and studied in somatosensory cortex of cats anesthetized with pentobarbital sodium or urethane. Two-hundred and three were studied during iontophoretic administration of acetylcholine (ACh), 173 during administration of glutamate, and 24 during administration of atropine. 2. Fifty-six percent of the 218 neurons tested responded to somatic stimuli. Another 21% did so during glutamate administration. In 11 cases ACh iontophoresis uncovered a receptive field in a previously unresponsive cell. 3. Forty-six percent of the 160 cells tested responded to thalamic stimulation. Another 17% did so in the presence of glutamate, but 19 cells responded to neither cutaneous nor thalamic stimuli. 4. Sixteen percent of the 203 cells tested were overtly excited by ACh and the responses to somatic stimulation of 29% were modulated by administration of ACh. Cells displaying overt excitation and/or modulation of responses were said to be cholinoceptive and made up 39% of the sample. These cells were located in all cortical layers. 5. Cholinoceptive neurons were more likely than noncholinoceptive cells to be driven by thalamic stimulation. 6. The changes observed during ACh administration tended to be facilitatory: an enhanced responsiveness to somatic stimuli, an increased firing rate, or an increased receptive-field size. However, in 10 of the 203 cases tested one or more of these variables decreased. 7. The enhanced responsiveness during ACh administration was a robust phenomenon; responses were often increased by as much as 200% and the discharge pattern was altered so that bursts of impulses following stimulation were more common. 8. ACh tended to enhance one attribute of a cell selectively rather than to act as a general excitant. 9. ACh is a powerful neuromodulatory agent in somatosensory cortex that, when released in specific behavioral states, should enhance the responsiveness of cortical neurons.
- Published
- 1988
21. Excitatory amino acids as transmitters in thalamo-cortical systems of the cat's somatosensory pathways
- Author
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Hicks, T., Kaneko, T., Metherate, R., Oka, J., Stark, C., Cavalheiro, E., Lehmann, J., and Turski, L.
- Published
- 1988
22. Functional properties of neurons mediated by GABA in cat somatosensory cortex under barbiturate and urethane anesthesia
- Author
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Hicks, T., Landry, Peter, Metherate, R., Dykes, R., Rowe, M., and Willis, W.
- Published
- 1985
23. Specificity of connections in the ventroposterior nuclei of the thalamus
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Dykes, R., Landry, Peter, Hicks, T., Diadori, P., and Metherate, R.
- Published
- 1988
24. Convergence and specificity of function in single neurons of the ventroposterior thalamic nuclei
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Dykes, R., Hicks, T., Metherate, R., Landry, Peter, Bentivoglio, M., and Spreafico, R.
- Published
- 1988
25. Excitatory amino acid antagonists and synaptic transmission in the cat's intact thalamocortical somatosensory pathway
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Oka, J., Metherate, R., Hicks, T., Hicks, T., Lodge, D., and McLennan, H.
- Published
- 1987
26. Simultaneous recordings from pairs of cat somatosensory cortical neurons with overlapping peripheral receptive fields
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Metherate, R., primary and Dykes, R.W., additional
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- 1985
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27. Gel route preparation of low fusing dental porcelain frit
- Author
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Mabie, C. P., primary, Menis, D. L., additional, Whitenton, E. P., additional, Trout, R. L., additional, Metherate, R. S., additional, and Ferry, C. H., additional
- Published
- 1983
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28. Specificity of connections in the ventroposterior nuclei of the thalamus
- Author
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DYKES, R, primary, LANDRY, P, additional, HICKS, T, additional, DIADORI, P, additional, and METHERATE, R, additional
- Published
- 1988
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29. Acetylcholine permits long-term enhancement of neuronal responsiveness in cat primary somatosensory cortex
- Author
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Metherate, R., primary, Tremblay, N., additional, and Dykes, R.W., additional
- Published
- 1987
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30. Task-dependent effects of nicotine treatment on auditory performance in young-adult and elderly human nonsmokers.
- Author
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Sun S, Kapolowicz MR, Richardson M, Metherate R, and Zeng FG
- Subjects
- Affect drug effects, Aged, Aged, 80 and over, Cross-Over Studies, Discrimination, Psychological drug effects, Female, Humans, Male, Middle Aged, Nicotine administration & dosage, Nicotine Chewing Gum, Oxygen blood, Pitch Perception drug effects, Psychomotor Performance, Receptors, Nicotinic drug effects, Receptors, Nicotinic physiology, Research Design, Signal-To-Noise Ratio, Single-Blind Method, Young Adult, Aging physiology, Auditory Perception drug effects, Nicotine pharmacology, Non-Smokers psychology
- Abstract
Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19-23 years old) normal-hearing nonsmokers and elderly (61-80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.
- Published
- 2021
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31. Nicotine Enhances Amplitude and Consistency of Timing of Responses to Acoustic Trains in A1.
- Author
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Intskirveli I and Metherate R
- Subjects
- Acoustic Stimulation methods, Acoustics, Animals, Auditory Cortex physiology, Evoked Potentials, Auditory physiology, Evoked Potentials, Auditory, Brain Stem physiology, Male, Mice, Time Factors, Auditory Cortex drug effects, Evoked Potentials, Auditory drug effects, Evoked Potentials, Auditory, Brain Stem drug effects, Nicotine pharmacology
- Abstract
Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2-40 Hz; each train repeated 25 times). CSD recordings were obtained using a 16-channel multiprobe inserted in A1 of urethane/xylazine-anesthetized mice, and analysis focused on two current sinks in the middle (layer 4) and deep (layers 5/6) layers. CF trains produced adaptation of the layer 4 response that was weak at 2 Hz, stronger at 5-10 Hz and complete at 20-40 Hz. In contrast, the layer 5/6 current sink exhibited less adaptation at 2-10 Hz, and simultaneously recorded auditory brainstem responses (ABRs) showed no adaptation even at 40 Hz. Systemic nicotine (2.1 mg/kg) enhanced layer 4 responses throughout the one-second stimulus train at rates ≤10 Hz. Nicotine enhanced both response amplitude within each train and the consistency of response timing across 25 trials. Nicotine did not alter the degree of adaptation over one-second trials, but its effect to increase amplitudes revealed a novel, slower form of adaptation that developed over multiple trials. Nicotine did not affect responses that were fully adapted (20-40 Hz trains), nor did nicotine affect any aspect of the layer 5/6 current sink or ABRs. The overall effect of nicotine in layer 4 was to enhance all responses within each train, to emphasize earlier trials across multiple trials, and to improve the consistency of timing across all trials. These effects may improve processing of complex acoustic streams, including speech, that contain information in the 2-10 Hz range., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Intskirveli and Metherate.)
- Published
- 2021
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32. Nicotine enhances auditory processing in healthy and normal-hearing young adult nonsmokers.
- Author
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Pham CQ, Kapolowicz MR, Metherate R, and Zeng FG
- Subjects
- Acoustic Stimulation methods, Acoustic Stimulation psychology, Adolescent, Adult, Attention drug effects, Attention physiology, Auditory Perception physiology, Cross-Over Studies, Female, Healthy Volunteers, Hearing physiology, Humans, Male, Oximetry methods, Single-Blind Method, Young Adult, Auditory Perception drug effects, Hearing drug effects, Nicotine administration & dosage, Nicotine Chewing Gum, Non-Smokers psychology
- Abstract
Rationale: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans., Objectives: The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individual's baseline performance., Methods: Young (18-27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance., Results: Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = - 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement., Conclusions: Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.
- Published
- 2020
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33. Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex.
- Author
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Askew CE, Lopez AJ, Wood MA, and Metherate R
- Subjects
- Animals, Auditory Cortex physiology, Female, Inhibitory Postsynaptic Potentials drug effects, Interneurons metabolism, Male, Mice, Nicotinic Agonists pharmacology, Pyramidal Cells physiology, Vasoactive Intestinal Peptide metabolism, Auditory Cortex drug effects, Interneurons drug effects, Nicotine pharmacology, Pyramidal Cells drug effects
- Abstract
Nicotine activates nicotinic acetylcholine receptors and improves cognitive and sensory function, in part by its actions in cortical regions. Physiological studies show that nicotine amplifies stimulus-evoked responses in sensory cortex, potentially contributing to enhancement of sensory processing. However, the role of specific cell types and circuits in the nicotinic modulation of sensory cortex remains unclear. Here, we performed whole-cell recordings from pyramidal (Pyr) neurons and inhibitory interneurons expressing parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) in mouse auditory cortex, in vitro. Bath application of nicotine strongly depolarized and excited VIP neurons, weakly depolarized Pyr neurons, and had no effect on the membrane potential of SOM or PV neurons. The use of receptor antagonists showed that nicotine's effects on VIP and Pyr neurons were direct and indirect, respectively. Nicotine also enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Pyr, VIP, and SOM, but not PV, cells. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we show that chemogenetic inhibition of VIP neurons prevents nicotine's effects on Pyr neurons. Since VIP cells preferentially contact other inhibitory interneurons, we suggest that nicotine drives VIP cell firing to disinhibit Pyr cell somata, potentially making Pyr cells more responsive to auditory stimuli. In parallel, activation of VIP cells also directly inhibits Pyr neurons, likely altering integration of other synaptic inputs. These cellular and synaptic mechanisms likely contribute to nicotine's beneficial effects on cognitive and sensory function., (© 2019 The Authors. Synapse Published by Wiley Periodicals, Inc.)
- Published
- 2019
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34. Enhanced Sensory-Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors.
- Author
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Gil SM and Metherate R
- Subjects
- Animals, Cognition Disorders metabolism, Cognition Disorders pathology, Humans, Sensation Disorders metabolism, Sensation Disorders pathology, Cognition drug effects, Cognition Disorders prevention & control, Nicotinic Agonists therapeutic use, Receptors, Nicotinic metabolism, Sensation Disorders prevention & control
- Abstract
Activation of nicotinic acetylcholine receptors (nAChRs) enhances sensory-cognitive function in human subjects and animal models, yet the neural mechanisms are not fully understood. This review summarizes recent studies on nicotinic regulation of neural processing in the cerebral cortex that point to potential mechanisms underlying enhanced cognitive function. Studies from our laboratory focus on nicotinic regulation of auditory cortex and implications for auditory-cognitive processing, but relevant emerging insights from multiple brain regions are discussed. Although the major contributions of the predominant nAChRs containing α7 (homomeric receptors) or α4 and β2 (heteromeric) subunits are well recognized, recent results point to additional, potentially critical contributions from α2 subunits that are relatively sparse in cortex. Ongoing studies aim to elucidate the specific contributions to cognitive and cortical function of diverse nAChRs., Implications: This review highlights the therapeutic potential of activating nAChRs in the cerebral cortex to enhance cognitive function. Future work also must determine the contributions of relatively rare but important nAChR subtypes, potentially to develop more selective treatments for cognitive deficits., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
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35. Development of fluorescence imaging probes for nicotinic acetylcholine α4β2 ∗ receptors.
- Author
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Samra GK, Intskirveli I, Govind AP, Liang C, Lazar R, Green WN, Metherate R, and Mukherjee J
- Subjects
- Animals, Binding Sites, Brain metabolism, Dose-Response Relationship, Drug, Fluorescent Dyes chemical synthesis, Fluorescent Dyes pharmacokinetics, HEK293 Cells, Humans, Mice, Molecular Structure, Positron-Emission Tomography, Structure-Activity Relationship, Tissue Distribution, Fluorescent Dyes chemistry, Optical Imaging, Receptors, Nicotinic analysis
- Abstract
Nicotinic acetylcholine α4β2
∗ receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2∗ nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [18 F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2∗ nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the α4β2∗ nAChRs in [3 H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in α4β2∗ nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface α4β2∗ nAChRs, labeled with antibodies specific for a β2 subunit extracellular epitope indicating that nifrofam labels α4β2∗ nAChR high-affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of α4β2∗ nAChRs in brain regions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2018
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36. Human brain imaging of nicotinic acetylcholine α4β2* receptors using [ 18 F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways.
- Author
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Mukherjee J, Lao PJ, Betthauser TJ, Samra GK, Pan ML, Patel IH, Liang C, Metherate R, and Christian BT
- Subjects
- Adult, Aged, Animals, Dose-Response Relationship, Drug, Female, Humans, Macaca mulatta, Male, Mice, Middle Aged, Nicotine pharmacology, Nicotinic Agonists pharmacology, Positron-Emission Tomography, Protein Binding drug effects, Rats, Rats, Sprague-Dawley, Young Adult, Aging physiology, Brain diagnostic imaging, Brain drug effects, Brain metabolism, Pyridines pharmacokinetics, Pyrroles pharmacokinetics, Receptors, Nicotinic metabolism, Sex Characteristics
- Abstract
Nicotinic acetylcholinergic receptors (nAChR's) have been implicated in several brain disorders, including addiction, Parkinson's disease, Alzheimer's disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [
18 F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.34 nM), hα3β2 (0.80 nM) and hα4β2 (0.83 nM) nAChR but weaker (27-219 nM) for hβ4 nAChR subtypes and 169 nM for hα7 nAChR. In functional assays, Nifene (100 μM) exhibited 14% agonist and >50% antagonist characteristics. In 14-day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 μg/kg/day (278 μg/m2 /day). In human PET studies, [18 F]Nifene (185 MBq; <0.10 μg) was well tolerated with no adverse effects. Distribution volume ratios (DVR) of [18 F]Nifene in white matter thalamic radiations were ∼1.6 (anterior) and ∼1.5 (superior longitudinal fasciculus). Habenula known to contain α3β2 nAChR exhibited low levels of [18 F]Nifene binding while the red nucleus with α2β2 nAChR had DVR ∼1.6-1.7. Females had higher [18 F]Nifene binding in all brain regions, with thalamus showing >15% than males. No significant aging effect was observed in [18 F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18 F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18 F]Nifene PET may be used to study α4β2* nAChRs in various CNS disorders and for translational research., (© 2017 Wiley Periodicals, Inc.)- Published
- 2018
- Full Text
- View/download PDF
37. Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions.
- Author
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Askew C, Intskirveli I, and Metherate R
- Subjects
- Acoustic Stimulation, Analysis of Variance, Animals, Auditory Cortex physiology, Auditory Pathways drug effects, Auditory Pathways physiology, Auditory Perception physiology, Evoked Potentials, Auditory drug effects, GABA-A Receptor Agonists pharmacology, Male, Mice, Microinjections, Muscimol pharmacology, Oxadiazoles pharmacology, Pyridines pharmacology, Receptors, Nicotinic metabolism, Auditory Cortex drug effects, Auditory Perception drug effects, Nicotine pharmacology, Nicotinic Agonists pharmacology
- Abstract
Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli. TINN stimuli consist of a tone at the characteristic frequency (CF) of the recording site embedded within a white noise stimulus filtered to create a spectral "notch" of variable width centered on CF. Systemic nicotine (2.1 mg/kg) enhanced responses to the CF tone and to narrow-notch stimuli, yet reduced the response to wider-notch stimuli, indicating increased response gain within a narrowed RF. Subsequent manipulations showed that modulation of cortical RFs by systemic nicotine reflected effects at several levels in the auditory pathway: nicotine suppressed responses in the auditory midbrain and thalamus, with suppression increasing with spectral distance from CF so that RFs became narrower, and facilitated responses in the thalamocortical pathway, while nicotinic actions within A1 further contributed to both suppression and facilitation. Thus, multiple effects of systemic nicotine integrate along the ascending auditory pathway. These actions at nAChRs in cortical and subcortical circuits, which mimic effects of auditory attention, likely contribute to nicotinic enhancement of sensory and cognitive processing.
- Published
- 2017
- Full Text
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38. Spectral breadth and laminar distribution of thalamocortical inputs to A1.
- Author
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Intskirveli I, Joshi A, Vizcarra-Chacón BJ, and Metherate R
- Subjects
- Action Potentials, Animals, Cerebral Cortex cytology, Cerebral Cortex physiology, GABA-A Receptor Agonists pharmacology, Male, Mice, Muscimol pharmacology, Neural Pathways cytology, Neural Pathways drug effects, Neural Pathways physiology, Neurons physiology, Thalamus cytology, Thalamus physiology, Cerebral Cortex drug effects, Neurons drug effects, Thalamus drug effects
- Abstract
The GABAergic agonist muscimol is used to inactivate brain regions in order to reveal afferent inputs in isolation. However, muscimol's use in primary auditory cortex (A1) has been questioned on the grounds that it may unintentionally suppress thalamocortical inputs. We tested whether muscimol can preferentially suppress cortical, but not thalamocortical, circuits in urethane-anesthetized mice. We recorded tone-evoked current source density profiles to determine frequency receptive fields (RFs) for three current sinks: the "layer 4" sink (fastest onset, middle-layer sink) and current sinks 100 μm above ("layer 2/3") and 300 μm below ("layer 5/6") the main input. We first determined effects of muscimol dose (0.01-1 mM) on the characteristic frequency (CF) tone-evoked layer 4 sink. An "ideal" dose (100 μM) had no effect on CF-evoked sink onset latency or initial response but reduced peak amplitude by >80%, implying inhibition of intracortical, but not thalamocortical, activity. We extended the analysis to current sinks in layers 2/3 and 5/6 and for all three sinks determined RF breadth (quarter-octave steps, 20 dB above CF threshold). Muscimol reduced RF breadth 42% in layer 2/3 (from 2.4 ± 0.14 to 1.4 ± 0.11 octaves), 14% in layer 4 (2.2 ± 0.12 to 1.9 ± 0.10 octaves), and not at all in layer 5/6 (1.8 ± 0.10 to 1.7 ± 0.12 octaves). The results provide an estimate of the laminar and spectral extent of thalamocortical projections and support the hypothesis that intracortical pathways contribute to spectral integration in A1., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
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39. Synaptic interactions and inhibitory regulation in auditory cortex.
- Author
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Askew CE and Metherate R
- Subjects
- Animals, GABA Agents metabolism, Humans, Interneurons physiology, Mice, Rats, Receptors, GABA-B metabolism, Receptors, Glutamate metabolism, Schizophrenia physiopathology, Auditory Cortex physiology, Electrical Synapses physiology, Evoked Potentials, Auditory physiology, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
This Special Issue focuses on the auditory-evoked mismatch negativity (MMN), an electrophysiological index of change, and its reduction in schizophrenia. The following brief review is an attempt to complement the behavioral and clinical contributions to the Special Issue by providing basic information on synaptic interactions and processing in auditory cortex. A key observation in previous studies is that the MMN involves activation of cortical N-methyl-D-aspartate (NMDA) receptors. Yet, NMDA receptor activation is regulated by a number of synaptic events, which also may contribute to the MMN reduction in schizophrenia. Accordingly, this review will focus on synaptic interactions, notably inhibitory regulation of NMDA receptor-mediated activity, in auditory cortex., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2016
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40. Convergence of nicotine-induced and auditory-evoked neural activity activates ERK in auditory cortex.
- Author
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Kawai HD, La M, Kang HA, Hashimoto Y, Liang K, Lazar R, and Metherate R
- Subjects
- Acoustic Stimulation, Animals, Auditory Cortex cytology, Auditory Cortex metabolism, Calbindins, Dihydro-beta-Erythroidine pharmacology, Extracellular Signal-Regulated MAP Kinases genetics, Mice, Neurons drug effects, Neurons metabolism, Neurons physiology, Phosphorylation, Protein Subunits metabolism, Receptors, Nicotinic metabolism, S100 Calcium Binding Protein G genetics, S100 Calcium Binding Protein G metabolism, Thalamus cytology, Thalamus metabolism, Auditory Cortex physiology, Evoked Potentials, Auditory, Extracellular Signal-Regulated MAP Kinases metabolism, Nicotine pharmacology
- Abstract
Enhancement of sound-evoked responses in auditory cortex (ACx) following administration of systemic nicotine is known to depend on activation of extracellular-signaling regulated kinase (ERK), but the nature of this enhancement is not clear. Here, we show that systemic nicotine increases the density of cells immunolabeled for phosphorylated (activated) ERK (P-ERK) in mouse primary ACx (A1). Cortical injection of dihydro-β-erythroidine reduced nicotine-induced P-ERK immunolabel, suggesting a role for nicotinic acetylcholine receptors located in A1 and containing α4 and β2 subunits. P-ERK expressing cells were distributed mainly in layers 2/3 and more sparsely in lower layers, with many cells exhibiting immunolabel within pyramidal-shaped somata and proximal apical dendrites. About one-third of P-ERK positive cells also expressed calbindin. In the thalamus, P-ERK immunopositive cells were found in the nonlemniscal medial geniculate (MG) and adjacent nuclei, but were absent in the lemniscal MG. Pairing broad spectrum acoustic stimulation (white noise) with systemic nicotine increased P-ERK immunopositive cell density in ACx as well as the total amount of P-ERK protein, particularly the phosphorylated form of ERK2. However, narrow spectrum (tone) stimulation paired with nicotine increased P-ERK immunolabel preferentially at a site within A1 where the paired frequency was characteristic frequency (CF), relative to a second site with a spectrally distant CF (two octaves above or below the paired frequency). Together, these results suggest that ERK is activated optimally where nicotinic signaling and sound-evoked neural activity converge., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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41. Tone-detection training enhances spectral integration mediated by intracortical pathways in primary auditory cortex.
- Author
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Guo F, Intskirveli I, Blake DT, and Metherate R
- Subjects
- Acoustic Stimulation, Animals, Male, Neuronal Plasticity physiology, Rats, Rats, Sprague-Dawley, Auditory Cortex physiology, Conditioning, Operant physiology, Evoked Potentials, Auditory physiology
- Abstract
Auditory-cued behavioral training can alter neural circuits in primary auditory cortex (A1), but the mechanisms and consequences of experience-dependent cortical plasticity are not fully understood. To address this issue, we trained adult rats to detect a 5 kHz target in order to receive a food reward. After 14 days training we identified three locations within A1: (i) the region representing the characteristic frequency (CF) 5 kHz, (ii) a nearby region with CF ∼10 kHz, and (iii) a more distant region with CF ∼20 kHz. In order to compare functional connectivity in A1 near to, vs. far from, the representation of the target frequency, we placed a 16-channel multiprobe in middle- (∼10 kHz) and high- (∼20 kHz) CF regions and obtained current-source density (CSD) profiles evoked by a range of tone stimuli (CF±1-3 octaves in quarter-octave steps). Our aim was to construct "CSD receptive fields" (CSD RFs) in order to determine the laminar and spectral profile of tone-evoked current sinks, and infer changes to thalamocortical and intracortical inputs. Behavioral training altered CSD RFs at the 10 kHz, but not 20 kHz, site relative to CSD RFs in untrained control animals. At the 10 kHz site, current sinks evoked by the target frequency were enhanced in layer 2/3, but the initial current sink in layer 4 was not altered. The results imply training-induced plasticity along intracortical pathways connecting the target representation with nearby cortical regions. Finally, we related behavioral performance (sensitivity index, d') to CSD responses in individual animals, and found a significant correlation between the development of d' over training and the amplitude of the target-evoked current sink in layer 2/3. The results suggest that plasticity along intracortical pathways is important for auditory learning., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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42. Nicotinic filtering of sensory processing in auditory cortex.
- Author
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Metherate R, Intskirveli I, and Kawai HD
- Abstract
Although it has been known for decades that the drug nicotine can improve cognitive function, the nature of its effects and the underlying mechanisms are not well understood. Nicotine activates nicotinic acetylcholine (ACh) receptors (nAChRs) that normally are activated by endogenous ACh, presumably "hijacking" the cholinergic contribution to multiple cognitive functions, notably attention. Thus, studying nicotine's effects helps to better understand a commonly used drug as well as functions of nAChRs. Moreover, nicotinic agonists are being developed to treat a variety of disorders that involve attention-related or age-related cognitive dysfunction. Studies have shown that nicotine can enhance processing of attended stimuli and/or reduce processing of distracters; that is, nicotine enhances attentional filtering. To examine potential mechanisms within sensory cortex that may contribute to cognitive functions, here we describe nicotinic actions in primary auditory cortex, where well-characterized neural "filters"-frequency receptive fields-can be exploited to examine nicotinic regulation of cortical processing. Using tone-evoked current-source density (CSD) profiles, we show that nicotine produces complex, layer-dependent effects on spectral and temporal processing that, broadly speaking, enhance responses to characteristic frequency (optimal) stimuli while simultaneously suppressing responses to spectrally distant stimuli. That is, nicotine appears to narrow receptive fields and enhances processing within the narrowed receptive field. Since basic cortical circuitry and nAChR distributions are similar across neocortex, these findings may generalize to neural processing in other sensory regions, and to non-sensory regions where afferent inputs are more difficult to manipulate experimentally. Similar effects across sensory and non-sensory cortical circuits could contribute to nicotinic enhancement of cognitive functions.
- Published
- 2012
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43. Nicotinic neuromodulation in auditory cortex requires MAPK activation in thalamocortical and intracortical circuits.
- Author
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Intskirveli I and Metherate R
- Subjects
- Acoustic Stimulation, Animals, Auditory Cortex metabolism, Butadienes pharmacology, Enzyme Inhibitors pharmacology, Evoked Potentials, Auditory drug effects, Evoked Potentials, Auditory physiology, MAP Kinase Kinase Kinase 1 antagonists & inhibitors, Male, Mice, Neural Pathways metabolism, Neurons drug effects, Neurons metabolism, Nitriles pharmacology, Synaptic Transmission drug effects, Synaptic Transmission physiology, Thalamus metabolism, Auditory Cortex drug effects, Neural Pathways drug effects, Nicotine pharmacology, Receptors, Nicotinic metabolism, Thalamus drug effects
- Abstract
Activation of nicotinic acetylcholine receptors (nAChRs) by systemic nicotine enhances sensory-cognitive function and sensory-evoked cortical responses. Although nAChRs mediate fast neurotransmission at many synapses in the nervous system, nicotinic regulation of cortical processing is neuromodulatory. To explore potential mechanisms of nicotinic neuromodulation, we examined whether intracellular signal transduction involving mitogen-activated protein kinase (MAPK) contributes to regulation of tone-evoked responses in primary auditory cortex (A1) in the mouse. Systemic nicotine enhanced characteristic frequency (CF) tone-evoked current-source density (CSD) profiles in A1, including the shortest-latency (presumed thalamocortical) current sink in layer 4 and longer-latency (presumed intracortical) sinks in layers 2-4, by increasing response amplitudes and decreasing response latencies. Microinjection of the MAPK kinase (MEK) inhibitor U0126 into the thalamus, targeting the auditory thalamocortical pathway, blocked the effect of nicotine on the initial (thalamocortical) CSD component but did not block enhancement of longer-latency (intracortical) responses. Conversely, microinjection of U0126 into supragranular layers of A1 blocked nicotine's effect on intracortical, but not thalamocortical, CSD components. Simultaneously with enhancement of CF-evoked responses, responses to spectrally distant (nonCF) stimuli were reduced, implying nicotinic "sharpening" of frequency receptive fields, an effect also blocked by MEK inhibition. Consistent with these physiological results, acoustic stimulation with nicotine produced immunolabel for activated MAPK in A1, primarily in layer 2/3 cell bodies. Immunolabel was blocked by intracortical microinjection of the nAChR antagonist dihydro-β-erythroidine, but not methyllycaconitine, implicating α4β2*, but not α7, nAChRs. Thus activation of MAPK in functionally distinct forebrain circuits--thalamocortical, local intracortical, and long-range intracortical--underlies nicotinic neuromodulation of A1.
- Published
- 2012
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44. Nicotinic acetylcholine receptors in rat forebrain that bind ¹⁸F-nifene: relating PET imaging, autoradiography, and behavior.
- Author
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Bieszczad KM, Kant R, Constantinescu CC, Pandey SK, Kawai HD, Metherate R, Weinberger NM, and Mukherjee J
- Subjects
- Animals, Autoradiography, Cerebellum diagnostic imaging, Cerebellum metabolism, Corpus Striatum diagnostic imaging, Corpus Striatum metabolism, Frontal Lobe diagnostic imaging, Frontal Lobe metabolism, Hippocampus diagnostic imaging, Hippocampus metabolism, Mice, Mice, Knockout, Nerve Fibers, Myelinated diagnostic imaging, Nerve Fibers, Myelinated metabolism, Positron-Emission Tomography, Prosencephalon diagnostic imaging, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Thalamus diagnostic imaging, Thalamus metabolism, Avoidance Learning physiology, Fluorine Radioisotopes pharmacokinetics, Prosencephalon metabolism, Pyridines pharmacokinetics, Pyrroles pharmacokinetics, Receptors, Nicotinic metabolism
- Abstract
Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound ¹⁸F-nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory-cognitive task. We first show negligible binding of ¹⁸F-nifene in mice lacking the β2 nAChR subunit, consistent with previous findings that ¹⁸F-nifene binds to α4β2* nAChRs. We then examined the distribution of ¹⁸F-nifene in rat using three methods: in vivo PET, ex vivo PET and autoradiography. Generally, ¹⁸F-nifene labeled forebrain regions known to contain nAChRs, and the three methods produced similar relative binding among regions. Importantly, ¹⁸F-nifene also labeled some white matter (myelinated axon) tracts, most prominently in the temporal subcortical region that contains the auditory thalamocortical pathway. Finally, we related ¹⁸F-nifene binding in several forebrain regions to each animal's performance on an auditory-cued, active avoidance task. The strongest correlations with performance after 14 days training were found for ¹⁸F-nifene binding in the temporal subcortical white matter, subiculum, and medial frontal cortex (correlation coefficients, r > 0.8); there was no correlation with binding in the auditory thalamus or auditory cortex. These findings suggest that individual performance is linked to nicotinic functions in specific brain regions, and further support a role for nAChRs in sensory-cognitive function., (Copyright © 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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- View/download PDF
45. Functional connectivity and cholinergic modulation in auditory cortex.
- Author
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Metherate R
- Subjects
- Animals, Auditory Cortex drug effects, Cholinergic Agonists pharmacology, Cholinergic Antagonists pharmacology, Humans, Models, Neurological, Thalamus drug effects, Auditory Cortex physiology, Auditory Pathways physiology, Cholinergic Neurons physiology, Thalamus physiology
- Abstract
Although it is known that primary auditory cortex (A1) contributes to the processing and perception of sound, its precise functions and the underlying mechanisms are not well understood. Recent studies point to a remarkably broad spectral range of largely subthreshold inputs to individual neurons in A1--seemingly encompassing, in some cases, the entire audible spectrum--as evidence for potential, and potentially unique, cortical functions. We have proposed a general mechanism for spectral integration by which information converges on neurons in A1 via a combination of thalamocortical pathways and intracortical long-distance, "horizontal", pathways. Here, this proposal is briefly reviewed and updated with results from multiple laboratories. Since spectral integration in A1 is dynamically regulated, we also show how one regulatory mechanism--modulation by the neurotransmitter acetylcholine (ACh)--could act within the hypothesized framework to alter integration in single neurons. The results of these studies promote a cellular understanding of information processing in A1., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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46. Null mutations in EphB receptors decrease sharpness of frequency tuning in primary auditory cortex.
- Author
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Intskirveli I, Metherate R, and Cramer KS
- Subjects
- Animals, Auditory Pathways physiology, Evoked Potentials, Auditory, Male, Mice, Receptors, Eph Family metabolism, Auditory Cortex physiology, Auditory Threshold physiology, Mutation genetics, Receptors, Eph Family genetics
- Abstract
Primary auditory cortex (A1) exhibits a tonotopic representation of characteristic frequency (CF). The receptive field properties of A1 neurons emerge from a combination of thalamic inputs and intracortical connections. However, the mechanisms that guide growth of these inputs during development and shape receptive field properties remain largely unknown. We previously showed that Eph family proteins help establish tonotopy in the auditory brainstem. Moreover, other studies have shown that these proteins shape topography in visual and somatosensory cortices. Here, we examined the contribution of Eph proteins to cortical organization of CF, response thresholds and sharpness of frequency tuning. We examined mice with null mutations in EphB2 and EphB3, as these mice show significant changes in auditory brainstem connectivity. We mapped A1 using local field potential recordings in adult EphB2(-/-);EphB3(-/-) and EphB3(-/-) mice, and in a central A1 location inserted a 16-channel probe to measure tone-evoked current-source density (CSD) profiles. Based on the shortest-latency current sink in the middle layers, which reflects putative thalamocortical input, we determined frequency receptive fields and sharpness of tuning (Q(20)) for each recording site. While both mutant mouse lines demonstrated increasing CF values from posterior to anterior A1 similar to wild type mice, we found that the double mutant mice had significantly lower Q(20) values than either EphB3(-/-) mice or wild type mice, indicating broader tuning. In addition, we found that the double mutants had significantly higher CF thresholds and longer onset latency at threshold than mice with wild type EphB2. These results demonstrate that EphB receptors influence auditory cortical responses, and suggest that EphB signaling has multiple functions in auditory system development.
- Published
- 2011
- Full Text
- View/download PDF
47. Nicotinic modulation of tone-evoked responses in auditory cortex reflects the strength of prior auditory learning.
- Author
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Liang K, Poytress BS, Weinberger NM, and Metherate R
- Subjects
- Acetylcholine physiology, Acoustic Stimulation, Animals, Auditory Cortex drug effects, Avoidance Learning drug effects, Behavior, Animal drug effects, Behavior, Animal physiology, Evoked Potentials, Auditory drug effects, Evoked Potentials, Auditory physiology, Male, Rats, Rats, Sprague-Dawley, Auditory Cortex physiology, Avoidance Learning physiology, Nicotine pharmacology, Nicotinic Agonists pharmacology, Receptors, Nicotinic physiology
- Abstract
Nicotinic acetylcholine receptors (nAChRs) contribute to sensory-cognitive function, as demonstrated by evidence that nAChR activation enhances, and nAChR blockade impairs, neural processing of sensory stimuli and sensory-cognitive behavior. To better understand the relationship between nAChR function and behavior, here we compare the strength of nAChR-mediated physiology in individual animals to their prior auditory behavioral performance. Adult rats were trained on an auditory-cued, active avoidance task over 4 days and classified as "good," "intermediate" or "poor" performers based on their initial rate of learning and eventual level of performance. Animals were then anesthetized, and tone-evoked local field potentials (LFPs) recorded in layer 4 of auditory cortex (ACx) before and after a test dose of nicotine (0.7mg/kg, s.c.) or saline. In "good" performers, nicotine enhanced LFP amplitude and decreased response threshold to characteristic frequency (CF) stimuli, yet had opposite effects (decreased amplitude, increased threshold) on responses to spectrally distant stimuli; i.e., cortical receptive fields became more selective for CF stimuli. In contrast, nicotine had little effect on LFP amplitude in "intermediate" or "poor" performing animals. Nicotine did, however, reduce LFP onset latency in all three groups, indicating that all received an effective dose of the drug. Our findings suggest that nicotinic regulation of cortical receptive fields may be a distinguishing feature of the best-performing animals, and may facilitate sensory-related learning by enhancing receptive field selectivity.
- Published
- 2008
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48. Nicotinic control of axon excitability regulates thalamocortical transmission.
- Author
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Kawai H, Lazar R, and Metherate R
- Subjects
- Acoustic Stimulation methods, Action Potentials drug effects, Action Potentials physiology, Action Potentials radiation effects, Analysis of Variance, Animals, Axons drug effects, Cerebral Cortex cytology, Dihydro-beta-Erythroidine pharmacology, Dose-Response Relationship, Radiation, Electric Stimulation methods, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Excitatory Postsynaptic Potentials radiation effects, In Vitro Techniques, Mice, Neural Pathways physiology, Neurons drug effects, Nicotine pharmacology, Nicotinic Agonists pharmacology, Patch-Clamp Techniques methods, Reaction Time drug effects, Reaction Time physiology, Reaction Time radiation effects, Synaptic Transmission drug effects, Synaptic Transmission radiation effects, Thalamus cytology, Axons physiology, Cerebral Cortex physiology, Neurons cytology, Receptors, Nicotinic physiology, Synaptic Transmission physiology, Thalamus physiology
- Abstract
The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability. Exogenous nicotine enhanced the probability and synchrony of evoked action potential discharges along thalamocortical axons in vitro, but had little effect on synaptic release mechanisms. In vivo, the blockade of nAChRs in the thalamocortical pathway reduced sound-evoked cortical responses, especially those evoked by sounds near the acoustic threshold. These data indicate that endogenous acetylcholine activates nAChRs in the thalamocortical pathway to lower the threshold for thalamocortical transmission and to increase the magnitude of sensory-evoked cortical responses. Our results show that a neurotransmitter can modulate sensory processing by regulating conduction along myelinated thalamocortical axons.
- Published
- 2007
- Full Text
- View/download PDF
49. Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats.
- Author
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Liang K, Poytress BS, Chen Y, Leslie FM, Weinberger NM, and Metherate R
- Subjects
- Animals, Animals, Newborn, Auditory Cortex drug effects, Auditory Cortex growth & development, Auditory Cortex physiopathology, Auditory Pathways drug effects, Auditory Pathways growth & development, Auditory Pathways physiopathology, Avoidance Learning drug effects, Avoidance Learning physiology, Cognition Disorders chemically induced, Cognition Disorders physiopathology, Disease Models, Animal, Female, Geniculate Bodies drug effects, Geniculate Bodies growth & development, Geniculate Bodies physiopathology, Language Development Disorders physiopathology, Learning Disabilities physiopathology, Male, Nicotinic Agonists adverse effects, Nicotinic Antagonists pharmacology, Pregnancy, Rats, Rats, Sprague-Dawley, Receptors, Nicotinic metabolism, Smoking adverse effects, Acetylcholine metabolism, Language Development Disorders chemically induced, Learning Disabilities chemically induced, Nicotine adverse effects, Prenatal Exposure Delayed Effects physiopathology, Receptors, Nicotinic drug effects
- Abstract
Children of women who smoke cigarettes during pregnancy display cognitive deficits in the auditory-verbal domain. Clinical studies have implicated developmental exposure to nicotine, the main psychoactive ingredient of tobacco, as a probable cause of subsequent auditory deficits. To test for a causal link, we have developed an animal model to determine how neonatal nicotine exposure affects adult auditory function. In adult control rats, nicotine administered systemically (0.7 mg/kg, s.c.) enhanced the sensitivity to sound of neural responses recorded in primary auditory cortex. The effect was strongest in cortical layers 3 and 4, where there is a dense concentration of nicotinic acetylcholine receptors (nAChRs) that has been hypothesized to regulate thalamocortical inputs. In support of the hypothesis, microinjection into layer 4 of the nonspecific nAChR antagonist mecamylamine (10 microM) strongly reduced sound-evoked responses. In contrast to the effects of acute nicotine and mecamylamine in adult control animals, neither drug was as effective in adult animals that had been treated with 5 days of chronic nicotine exposure (CNE) shortly after birth. Neonatal CNE also impaired performance on an auditory-cued active avoidance task, while having little effect on basic auditory or motor functions. Thus, neonatal CNE impairs nicotinic regulation of cortical function, and auditory learning, in the adult. Our results provide evidence that developmental nicotine exposure is responsible for auditory-cognitive deficits in the offspring of women who smoke during pregnancy, and suggest a potential underlying mechanism, namely diminished function of cortical nAChRs.
- Published
- 2006
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50. Auditory thalamocortical transmission is reliable and temporally precise.
- Author
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Rose HJ and Metherate R
- Subjects
- 2-Amino-5-phosphonovalerate pharmacology, Animals, Dose-Response Relationship, Radiation, Electric Stimulation methods, Excitatory Amino Acid Antagonists pharmacology, Excitatory Postsynaptic Potentials physiology, Geniculate Bodies physiology, In Vitro Techniques, Mice, Neural Pathways radiation effects, Patch-Clamp Techniques methods, Reaction Time physiology, Synapses physiology, Synapses radiation effects, Auditory Cortex cytology, Neural Pathways physiology, Neurons physiology, Thalamus physiology
- Abstract
We have used the auditory thalamocortical slice to characterize thalamocortical transmission in primary auditory cortex (ACx) of the juvenile mouse. "Minimal" stimulation was used to activate medial geniculate neurons during whole cell recordings from regular-spiking (RS cells; mostly pyramidal) and fast-spiking (FS, putative inhibitory) neurons in ACx layers 3 and 4. Excitatory postsynaptic potentials (EPSPs) were considered monosynaptic (thalamocortical) if they met three criteria: low onset latency variability (jitter), little change in latency with increased stimulus intensity, and little change in latency during a high-frequency tetanus. Thalamocortical EPSPs were reliable (probability of postsynaptic responses to stimulation was approximately 1.0) as well as temporally precise (low jitter). Both RS and FS neurons received thalamocortical input, but EPSPs in FS cells had faster rise times, shorter latencies to peak amplitude, and shorter durations than EPSPs in RS cells. Thalamocortical EPSPs depressed during repetitive stimulation at rates (2-300 Hz) consistent with thalamic spike rates in vivo, but at stimulation rates > or = 40 Hz, EPSPs also summed to activate N-methyl-D-aspartate receptors and trigger long-lasting polysynaptic activity. We conclude that thalamic inputs to excitatory and inhibitory neurons in ACx activate reliable and temporally precise monosynaptic EPSPs that in vivo may contribute to the precise timing of acoustic-evoked responses.
- Published
- 2005
- Full Text
- View/download PDF
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