24 results on '"Good CH"'
Search Results
2. An implantable device for wireless monitoring of diverse physio-behavioral characteristics in freely behaving small animals and interacting groups.
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Ouyang W, Kilner KJ, Xavier RMP, Liu Y, Lu Y, Feller SM, Pitts KM, Wu M, Ausra J, Jones I, Wu Y, Luan H, Trueb J, Higbee-Dempsey EM, Stepien I, Ghoreishi-Haack N, Haney CR, Li H, Kozorovitskiy Y, Heshmati M, Banks AR, Golden SA, Good CH, and Rogers JA
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- Animals, Mice, Heart Rate physiology, Male, Prostheses and Implants, Respiratory Rate physiology, Monitoring, Physiologic methods, Monitoring, Physiologic instrumentation, Algorithms, Wireless Technology, Behavior, Animal physiology, Optogenetics methods
- Abstract
Comprehensive, continuous quantitative monitoring of intricately orchestrated physiological processes and behavioral states in living organisms can yield essential data for elucidating the function of neural circuits under healthy and diseased conditions, for defining the effects of potential drugs and treatments, and for tracking disease progression and recovery. Here, we report a wireless, battery-free implantable device and a set of associated algorithms that enable continuous, multiparametric physio-behavioral monitoring in freely behaving small animals and interacting groups. Through advanced analytics approaches applied to mechano-acoustic signals of diverse body processes, the device yields heart rate, respiratory rate, physical activity, temperature, and behavioral states. Demonstrations in pharmacological, locomotor, and acute and social stress tests and in optogenetic studies offer unique insights into the coordination of physio-behavioral characteristics associated with healthy and perturbed states. This technology has broad utility in neuroscience, physiology, behavior, and other areas that rely on studies of freely moving, small animal models., Competing Interests: Declaration of interests J.A.R. and A.R.B. are co-founders of a company, NeuroLux Inc., that has potential commercial interest in this technology. C.H.G., K.J.K., R.M.P.X., S.M.F., J.A., and I.J. are employees of NeuroLux Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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3. An integrated microfluidic and fluorescence platform for probing in vivo neuropharmacology.
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Piantadosi SC, Lee MK, Wu M, Huynh H, Avila R, Pizzano C, Zamorano CA, Wu Y, Xavier R, Stanslaski M, Kang J, Thai S, Kim Y, Zhang J, Huang Y, Kozorovitskiy Y, Good CH, Banks AR, Rogers JA, and Bruchas MR
- Abstract
Neurotechnologies and genetic tools for dissecting neural circuit functions have advanced rapidly over the past decade, although the development of complementary pharmacological method-ologies has comparatively lagged. Understanding the precise pharmacological mechanisms of neuroactive compounds is critical for advancing basic neurobiology and neuropharmacology, as well as for developing more effective treatments for neurological and neuropsychiatric disorders. However, integrating modern tools for assessing neural activity in large-scale neural networks with spatially localized drug delivery remains a major challenge. Here, we present a dual microfluidic-photometry platform that enables simultaneous intracranial drug delivery with neural dynamics monitoring in the rodent brain. The integrated platform combines a wireless, battery-free, miniaturized fluidic microsystem with optical probes, allowing for spatially and temporally specific drug delivery while recording activity-dependent fluorescence using genetically encoded calcium indicators (GECIs), neurotransmitter sensors GRAB
NE and GRABDA , and neuropeptide sensors. We demonstrate the performance this platform for investigating neuropharmacological mechanisms in vivo and characterize its efficacy in probing precise mechanistic actions of neuroactive compounds across several rapidly evolving neuroscience domains.- Published
- 2024
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4. A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.
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Ouyang W, Lu W, Zhang Y, Liu Y, Kim JU, Shen H, Wu Y, Luan H, Kilner K, Lee SP, Lu Y, Yang Y, Wang J, Yu Y, Wegener AJ, Moreno JA, Xie Z, Wu Y, Won SM, Kwon K, Wu C, Bai W, Guo H, Liu TL, Bai H, Monti G, Zhu J, Madhvapathy SR, Trueb J, Stanslaski M, Higbee-Dempsey EM, Stepien I, Ghoreishi-Haack N, Haney CR, Kim TI, Huang Y, Ghaffari R, Banks AR, Jhou TC, Good CH, and Rogers JA
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- Animals, Optogenetics methods, Optogenetics instrumentation, Body Temperature physiology, Male, Electric Power Supplies, Sleep physiology, Wakefulness physiology, Rats, Epilepsy therapy, Prostheses and Implants, Wireless Technology instrumentation, Electroencephalography instrumentation, Electroencephalography methods, Electromyography methods
- Abstract
Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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5. A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.
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Murphy KR, Farrell JS, Gomez JL, Stedman QG, Li N, Leung SA, Good CH, Qiu Z, Firouzi K, Butts Pauly K, Khuri-Yakub BPT, Michaelides M, Soltesz I, and de Lecea L
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- Animals, Brain diagnostic imaging, Brain physiology, Ultrasonography, Hippocampus diagnostic imaging, Epilepsy therapy, Epilepsy, Temporal Lobe
- Abstract
Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.
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- 2022
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6. Author Correction: Wireless multilateral devices for optogenetic studies of individual and social behaviors.
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Yang Y, Wu M, Vázquez-Guardado A, Wegener AJ, Grajales-Reyes JG, Deng Y, Wang T, Avila R, Moreno JA, Minkowicz S, Dumrongprechachan V, Lee J, Zhang S, Legaria AA, Ma Y, Mehta S, Franklin D, Hartman L, Bai W, Han M, Zhao H, Lu W, Yu Y, Sheng X, Banks A, Yu X, Donaldson ZR, Gereau RW 4th, Good CH, Xie Z, Huang Y, Kozorovitskiy Y, and Rogers JA
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- 2022
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7. Preparation and use of wireless reprogrammable multilateral optogenetic devices for behavioral neuroscience.
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Yang Y, Wu M, Wegener AJ, Vázquez-Guardado A, Efimov AI, Lie F, Wang T, Ma Y, Banks A, Li Z, Xie Z, Huang Y, Good CH, Kozorovitskiy Y, and Rogers JA
- Subjects
- Animals, Mice, Wireless Technology, Neurosciences, Optogenetics methods
- Abstract
Wireless battery-free optogenetic devices enable behavioral neuroscience studies in groups of animals with minimal interference to natural behavior. Real-time independent control of optogenetic stimulation through near-field communication dramatically expands the realm of applications of these devices in broad contexts of neuroscience research. Dissemination of these tools with advanced functionalities to the neuroscience community requires protocols for device manufacturing and experimental implementation. This protocol describes detailed procedures for fabrication, encapsulation and implantation of recently developed advanced wireless devices in head- and back-mounted forms. In addition, procedures for standard implementation of experimental systems in mice are provided. This protocol aims to facilitate the application of wireless optogenetic devices in advanced optogenetic experiments involving groups of freely moving rodents and complex environmental designs. The entire protocol lasts ~3-5 weeks., (© 2022. Springer Nature Limited.)
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- 2022
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8. Altered sleep during spontaneous cannabinoid withdrawal in male mice.
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Missig G, Mehta N, Robbins JO, Good CH, Iliopoulos-Tsoutsouvas C, Makriyannis A, Nikas SP, Bergman J, Carlezon WA Jr, and Paronis CA
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- Animals, Cannabinoid Receptor Agonists pharmacology, Electroencephalography, Male, Mice, Orexins, Sleep, Sleep, REM physiology, Cannabinoids pharmacology
- Abstract
Cessation of cannabinoid use in humans often leads to a withdrawal state that includes sleep disruption. Despite important health implications, little is known about how cannabinoid abstention affects sleep architecture, in part because spontaneous cannabinoid withdrawal is difficult to model in animals. In concurrent work we report that repeated administration of the high-efficacy cannabinoid 1 (CB1) receptor agonist AM2389 to mice for 5 days led to heightened locomotor activity and paw tremor following treatment discontinuation, potentially indicative of spontaneous cannabinoid withdrawal. Here, we performed parallel studies to examine effects on sleep. Using implantable electroencephalography (EEG) and electromyography (EMG) telemetry we examined sleep and neurophysiological measures before, during, and after 5 days of twice-daily AM2389 injections. We report that AM2389 produces decreases in locomotor activity that wane with repeated treatment, whereas discontinuation produces rebound increases in activity that persist for several days. Likewise, AM2389 initially produces profound increases in slow-wave sleep (SWS) and decreases in rapid eye movement (REM) sleep, as well as consolidation of sleep. By the third AM2389 treatment, this pattern transitions to decreases in SWS and total time sleeping. This pattern persists following AM2389 discontinuation and is accompanied by emergence of sleep fragmentation. Double-labeling immunohistochemistry for hypocretin/orexin (a sleep-regulating peptide) and c-Fos (a neuronal activity marker) in lateral hypothalamus revealed decreases in c-Fos/orexin+ cells following acute AM2389 and increases following discontinuation, aligning with the sleep changes. These findings indicate that AM2389 profoundly alters sleep in mice and suggest that sleep disruption following treatment cessation reflects spontaneous cannabinoid withdrawal., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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9. Wireless multilateral devices for optogenetic studies of individual and social behaviors.
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Yang Y, Wu M, Vázquez-Guardado A, Wegener AJ, Grajales-Reyes JG, Deng Y, Wang T, Avila R, Moreno JA, Minkowicz S, Dumrongprechachan V, Lee J, Zhang S, Legaria AA, Ma Y, Mehta S, Franklin D, Hartman L, Bai W, Han M, Zhao H, Lu W, Yu Y, Sheng X, Banks A, Yu X, Donaldson ZR, Gereau RW 4th, Good CH, Xie Z, Huang Y, Kozorovitskiy Y, and Rogers JA
- Subjects
- Animals, Mice, Optogenetics instrumentation, Social Behavior, Wireless Technology instrumentation
- Abstract
Advanced technologies for controlled delivery of light to targeted locations in biological tissues are essential to neuroscience research that applies optogenetics in animal models. Fully implantable, miniaturized devices with wireless control and power-harvesting strategies offer an appealing set of attributes in this context, particularly for studies that are incompatible with conventional fiber-optic approaches or battery-powered head stages. Limited programmable control and narrow options in illumination profiles constrain the use of existing devices. The results reported here overcome these drawbacks via two platforms, both with real-time user programmability over multiple independent light sources, in head-mounted and back-mounted designs. Engineering studies of the optoelectronic and thermal properties of these systems define their capabilities and key design considerations. Neuroscience applications demonstrate that induction of interbrain neuronal synchrony in the medial prefrontal cortex shapes social interaction within groups of mice, highlighting the power of real-time subject-specific programmability of the wireless optogenetic platforms introduced here.
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- 2021
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10. Improved Testing and Design of Intubation Boxes During the COVID-19 Pandemic.
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Turer DM, Good CH, Schilling BK, Turer RW, Karlowsky NR, Dvoracek LA, Ban H, Chang JS, and Rubin JP
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- Aerosols, COVID-19 transmission, Cross Infection prevention & control, Equipment Design, Filtration instrumentation, Humans, Infectious Disease Transmission, Patient-to-Professional prevention & control, Manikins, Pandemics, Pneumonia, Viral transmission, Pneumonia, Viral virology, SARS-CoV-2, Vacuum, COVID-19 prevention & control, Infection Control instrumentation, Intubation, Intratracheal instrumentation, Pneumonia, Viral prevention & control
- Abstract
Study Objective: Throughout the coronavirus disease 2019 pandemic, many emergency departments have been using passive protective enclosures ("intubation boxes") during intubation. The effectiveness of these enclosures remains uncertain. We sought to quantify their ability to contain aerosols using industry standard test protocols., Methods: We tested a commercially available passive protective enclosure representing the most common design and compared this with a modified enclosure that incorporated a vacuum system for active air filtration during simulated intubations and negative-pressure isolation. We evaluated the enclosures by using the same 3 tests air filtration experts use to certify class I biosafety cabinets: visual smoke pattern analysis using neutrally buoyant smoke, aerosol leak testing using a test aerosol that mimics the size of virus-containing particulates, and air velocity measurements., Results: Qualitative evaluation revealed smoke escaping from all passive enclosure openings. Aerosol leak testing demonstrated elevated particle concentrations outside the enclosure during simulated intubations. In contrast, vacuum-filter-equipped enclosures fully contained the visible smoke and test aerosol to standards consistent with class I biosafety cabinet certification., Conclusion: Passive enclosures for intubation failed to contain aerosols, but the addition of a vacuum and active air filtration reduced aerosol spread during simulated intubation and patient isolation., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2021
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11. Sleep in the United States Military.
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Good CH, Brager AJ, Capaldi VF, and Mysliwiec V
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- Animals, Humans, Sleep Disorders, Circadian Rhythm epidemiology, Sleep Wake Disorders epidemiology, Sleep Wake Disorders physiopathology, Sleep Wake Disorders psychology, Stress Disorders, Post-Traumatic epidemiology, Stress Disorders, Post-Traumatic physiopathology, Stress Disorders, Post-Traumatic psychology, United States epidemiology, Military Personnel psychology, Sleep physiology, Sleep Disorders, Circadian Rhythm physiopathology, Sleep Disorders, Circadian Rhythm psychology
- Abstract
The military lifestyle often includes continuous operations whether in training or deployed environments. These stressful environments present unique challenges for service members attempting to achieve consolidated, restorative sleep. The significant mental and physical derangements caused by degraded metabolic, cardiovascular, skeletomuscular, and cognitive health often result from insufficient sleep and/or circadian misalignment. Insufficient sleep and resulting fatigue compromises personal safety, mission success, and even national security. In the long-term, chronic insufficient sleep and circadian rhythm disorders have been associated with other sleep disorders (e.g., insomnia, obstructive sleep apnea, and parasomnias). Other physiologic and psychologic diagnoses such as post-traumatic stress disorder, cardiovascular disease, and dementia have also been associated with chronic, insufficient sleep. Increased co-morbidity and mortality are compounded by traumatic brain injury resulting from blunt trauma, blast exposure, and highly physically demanding tasks under load. We present the current state of science in human and animal models specific to service members during- and post-military career. We focus on mission requirements of night shift work, sustained operations, and rapid re-entrainment to time zones. We then propose targeted pharmacological and non-pharmacological countermeasures to optimize performance that are mission- and symptom-specific. We recognize a critical gap in research involving service members, but provide tailored interventions for military health care providers based on the large body of research in health care and public service workers.
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- 2020
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12. Gene expression and neurochemical characterization of the rostromedial tegmental nucleus (RMTg) in rats and mice.
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Smith RJ, Vento PJ, Chao YS, Good CH, and Jhou TC
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- Animals, Behavior, Animal, Forkhead Transcription Factors genetics, Gene Expression Regulation, Male, Mice, Transgenic, Motor Activity, Neural Pathways metabolism, Optogenetics, Protein Precursors genetics, Proto-Oncogene Proteins c-fos metabolism, Rats, Sprague-Dawley, Receptors, Opioid genetics, Repressor Proteins genetics, Time Factors, Ventral Tegmental Area cytology, Forkhead Transcription Factors metabolism, Neurons metabolism, Protein Precursors metabolism, Receptors, Opioid metabolism, Repressor Proteins metabolism, Ventral Tegmental Area metabolism
- Abstract
The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic structure identified in 2009 that receives strong inputs from the lateral habenula and other sources, sends dense inhibitory projections to midbrain dopamine (DA) neurons, and plays increasingly recognized roles in aversive learning, addiction, and other motivated behaviors. In general, little is known about the genetic identity of these neurons. However, recent work has identified the transcription factor FoxP1 as enhanced in the mouse RMTg (Lahti et al. in Development 143(3):516-529, 2016). Hence, in the current study, we used RNA sequencing to identify genes significantly enhanced in the rat RMTg as compared to adjacent VTA, and then examined the detailed distribution of two genes in particular, prepronociceptin (Pnoc) and FoxP1. In rats and mice, both Pnoc and FoxP1 were expressed at high levels in the RMTg and colocalized strongly with previously established RMTg markers. FoxP1 was particularly selective for RMTg neurons, as it was absent in most adjacent brain regions. We used these gene expression patterns to refine the anatomic characterization of RMTg in rats, extend this characterization to mice, and show that optogenetic manipulation of RMTg in mice bidirectionally modulates real-time place preference. Hence, RMTg neurons in both rats and mice exhibit distinct genetic profiles that correlate with their distinct connectivity and function.
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- 2019
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13. Norepinephrine activates dopamine D4 receptors in the rat lateral habenula.
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Root DH, Hoffman AF, Good CH, Zhang S, Gigante E, Lupica CR, and Morales M
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- Animals, Dopamine metabolism, Dopamine pharmacology, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Dopamine Plasma Membrane Transport Proteins antagonists & inhibitors, Dopaminergic Neurons metabolism, Dopaminergic Neurons physiology, Habenula cytology, Habenula physiology, Isoxazoles pharmacology, Male, Norepinephrine metabolism, Piperazines pharmacology, Piperidines pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D4 antagonists & inhibitors, Ventral Tegmental Area cytology, Ventral Tegmental Area metabolism, Ventral Tegmental Area physiology, Vesicular Monoamine Transport Proteins genetics, Vesicular Monoamine Transport Proteins metabolism, Habenula metabolism, Norepinephrine pharmacology, Receptors, Dopamine D4 metabolism
- Abstract
The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function., (Copyright © 2015 the authors 0270-6474/15/353460-10$15.00/0.)
- Published
- 2015
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14. Dopamine D4 receptor excitation of lateral habenula neurons via multiple cellular mechanisms.
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Good CH, Wang H, Chen YH, Mejias-Aponte CA, Hoffman AF, and Lupica CR
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- Amphetamine pharmacology, Animals, Cesium pharmacology, Cocaine pharmacology, Dopamine pharmacology, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Dopamine Uptake Inhibitors pharmacology, Feedback, Physiological, Glutamic Acid metabolism, Habenula cytology, Habenula metabolism, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels antagonists & inhibitors, Male, Neurons drug effects, Neurons metabolism, Pedunculopontine Tegmental Nucleus cytology, Pedunculopontine Tegmental Nucleus physiology, Piperazines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D4 agonists, Receptors, Dopamine D4 antagonists & inhibitors, Synaptic Transmission, Ventral Tegmental Area cytology, Ventral Tegmental Area physiology, gamma-Aminobutyric Acid metabolism, Action Potentials, Habenula physiology, Neurons physiology, Receptors, Dopamine D4 metabolism
- Abstract
Glutamatergic lateral habenula (LHb) output communicates negative motivational valence to ventral tegmental area (VTA) dopamine (DA) neurons via activation of the rostromedial tegmental nucleus (RMTg). However, the LHb also receives a poorly understood DA input from the VTA, which we hypothesized constitutes an important feedback loop regulating DA responses to stimuli. Using whole-cell electrophysiology in rat brain slices, we find that DA initiates a depolarizing inward current (I(DAi)) and increases spontaneous firing in 32% of LHb neurons. I(DAi) was also observed upon application of amphetamine or the DA uptake blockers cocaine or GBR12935, indicating involvement of endogenous DA. I(DAi) was blocked by D4 receptor (D4R) antagonists (L745,870 or L741,742), and mimicked by a selective D4R agonist (A412997). I(DAi) was associated with increased whole-cell conductance and was blocked by Cs+ or a selective blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, ZD7288. I(DAi) was also associated with a depolarizing shift in half-activation voltage for the hyperpolarization-activated cation current (Ih) mediated by HCN channels. Recordings from LHb neurons containing fluorescent retrograde tracers revealed that I(DAi) was observed only in cells projecting to the RMTg and not the VTA. In parallel with direct depolarization, DA also strongly increased synaptic glutamate release and reduced synaptic GABA release onto LHb cells. These results demonstrate that DA can excite glutamatergic LHb output to RMTg via multiple cellular mechanisms. Since the RMTg strongly inhibits midbrain DA neurons, activation of LHb output to RMTg by DA represents a negative feedback loop that may dampen DA neuron output following activation.
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- 2013
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15. Cocaine drives aversive conditioning via delayed activation of dopamine-responsive habenular and midbrain pathways.
- Author
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Jhou TC, Good CH, Rowley CS, Xu SP, Wang H, Burnham NW, Hoffman AF, Lupica CR, and Ikemoto S
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- Animals, Avoidance Learning physiology, Conditioning, Operant physiology, Habenula physiology, Injections, Intravenous, Male, Mesencephalon physiology, Neural Pathways drug effects, Neural Pathways physiology, Rats, Rats, Sprague-Dawley, Rats, Wistar, Avoidance Learning drug effects, Cocaine administration & dosage, Conditioning, Operant drug effects, Dopamine physiology, Habenula drug effects, Mesencephalon drug effects
- Abstract
Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons.
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- 2013
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16. Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease.
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Good CH, Hoffman AF, Hoffer BJ, Chefer VI, Shippenberg TS, Bäckman CM, Larsson NG, Olson L, Gellhaar S, Galter D, and Lupica CR
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- Animals, Corpus Striatum, Disease Models, Animal, Dopamine metabolism, Female, Male, Mice, Mice, Inbred C57BL, Neurons metabolism, Parkinson Disease genetics, Substantia Nigra, Cyclic Nucleotide-Gated Cation Channels physiology, DNA-Binding Proteins genetics, Mitochondrial Proteins genetics, Neurons physiology, Parkinson Disease physiopathology, Transcription Factors genetics
- Abstract
Parkinson's disease (PD) involves progressive loss of nigrostriatal dopamine (DA) neurons over an extended period of time. Mitochondrial damage may lead to PD, and neurotoxins affecting mitochondria are widely used to produce degeneration of the nigrostriatal circuitry. Deletion of the mitochondrial transcription factor A gene (Tfam) in C57BL6 mouse DA neurons leads to a slowly progressing parkinsonian phenotype in which motor impairment is first observed at ~12 wk of age. L-DOPA treatment improves motor dysfunction in these "MitoPark" mice, but this declines when DA neuron loss is more complete. To investigate early neurobiological events potentially contributing to PD, we compared the neurochemical and electrophysiological properties of the nigrostriatal circuit in behaviorally asymptomatic 6- to 8-wk-old MitoPark mice and age-matched control littermates. Release, but not uptake of DA, was impaired in MitoPark mouse striatal brain slices, and nigral DA neurons lacked characteristic pacemaker activity compared with control mice. Also, hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel function was reduced in MitoPark DA neurons, although HCN messenger RNA was unchanged. This study demonstrates altered nigrostriatal function that precedes behavioral parkinsonian symptoms in this genetic PD model. A full understanding of these presymptomatic cellular properties may lead to more effective early treatments of PD.
- Published
- 2011
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17. NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization.
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Luo Y, Good CH, Diaz-Ruiz O, Zhang Y, Hoffman AF, Shan L, Kuang SY, Malik N, Chefer VI, Tomac AC, Lupica CR, and Bäckman CM
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- Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Conditioning, Psychological physiology, Dopamine Plasma Membrane Transport Proteins metabolism, Gene Knockout Techniques, Glutamic Acid metabolism, Integrases metabolism, Mice, Motor Activity drug effects, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Olfactory Bulb drug effects, Olfactory Bulb metabolism, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate deficiency, Receptors, N-Methyl-D-Aspartate genetics, Recombination, Genetic genetics, Signal Transduction drug effects, Synapses drug effects, Synapses metabolism, Ventral Tegmental Area physiology, Cocaine pharmacology, Dopamine metabolism, Neurons drug effects, Neurons metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Ventral Tegmental Area cytology
- Abstract
Background: The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA) DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre) mice)., Methodology and Principal Findings: Using an additional NR1(DATCre) mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre) mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre) mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine., Conclusions/significance: These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre) mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.
- Published
- 2010
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18. Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus.
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Laaris N, Good CH, and Lupica CR
- Subjects
- Animals, Axons drug effects, Axons metabolism, Dose-Response Relationship, Drug, Dronabinol administration & dosage, Hippocampus metabolism, In Vitro Techniques, Inhibitory Postsynaptic Potentials drug effects, Inhibitory Postsynaptic Potentials physiology, Membrane Potentials drug effects, Membrane Potentials physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons metabolism, Psychotropic Drugs administration & dosage, Receptor, Cannabinoid, CB1 genetics, Receptor, Cannabinoid, CB1 metabolism, Receptors, GABA-A metabolism, Dronabinol pharmacology, Hippocampus drug effects, Neurons drug effects, Psychotropic Drugs pharmacology, Receptor, Cannabinoid, CB1 agonists, gamma-Aminobutyric Acid metabolism
- Abstract
Marijuana impairs learning and memory through actions of its psychoactive constituent, delta-9-tetrahydrocannabinol (Delta(9)-THC), in the hippocampus, through activation of cannabinoid CB1 receptors (CB1R). CB1Rs are found on glutamate and GABA neuron axon terminals in the hippocampus where they control neurotransmitter release. Previous studies suggest that Delta(9)-THC is a partial agonist of CB1Rs on glutamate axon terminals in the hippocampus, whereas its effects on GABA terminals have not been described. Using whole-cell electrophysiology in brain slices from C57BL6/J mice, we examined Delta(9)-THC effects on synaptic GABA IPSCs and postsynaptic GABA currents elicited by laser-induced photo-uncaging (photolysis) of alpha-carboxy-2-nitrobenzyl (CNB) caged GABA. Despite robust inhibition of synaptic IPSCs in wildtype mice by the full synthetic agonist WIN55,212-2, using a Tween-80 and DMSO vehicle, Delta(9)-THC had no effects on IPSCs in this, or in a low concentration of another vehicle, randomly-methylated beta-cyclodextrin (RAMEB, 0.023%). However, IPSCs were inhibited by Delta(9)-THC in 0.1% RAMEB, but not in neurons from CB1R knockout mice. Whereas Delta(9)-THC did not affect photolysis-evoked GABA currents, these responses were prolonged by a GABA uptake inhibitor. Concentration-response curves revealed that the maximal effects of Delta(9)-THC and WIN55,212-2 were similar, indicating that Delta(9)-THC is a full agonist at CB1Rs on GABA axon terminals. These results suggest that Delta(9)-THC inhibits GABA release, but does not directly alter GABA(A) receptors or GABA uptake in the hippocampus. Furthermore, full agonist effects of Delta(9)-THC on IPSCs likely result from a much higher expression of CB1Rs on GABA versus glutamate axon terminals in the hippocampus., (Published by Elsevier Ltd.)
- Published
- 2010
- Full Text
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19. Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs.
- Author
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Good CH and Lupica CR
- Subjects
- Animals, Dopamine Uptake Inhibitors pharmacology, Excitatory Postsynaptic Potentials drug effects, Illicit Drugs pharmacology, Immunohistochemistry, Injections, Intraperitoneal, Long-Term Synaptic Depression drug effects, Male, Mesencephalon cytology, Mesencephalon drug effects, Neurons, Afferent drug effects, Neurons, Afferent metabolism, Organ Culture Techniques, Pedunculopontine Tegmental Nucleus metabolism, Rats, Rats, Sprague-Dawley, Synapses drug effects, Ventral Tegmental Area metabolism, Cocaine pharmacology, Dopamine metabolism, Dronabinol pharmacology, Mesencephalon metabolism, Neuronal Plasticity drug effects, Psychotropic Drugs pharmacology, Receptors, AMPA metabolism, Synapses metabolism
- Abstract
Ventral tegmental area (VTA) dopamine (DA) neurons play a pivotal role in processing reward-related information and are involved in drug addiction and mental illness in humans. Information is conveyed to the VTA in large part by glutamatergic afferents that arise in various brain nuclei, including the pedunculopontine nucleus (PPN). Using a unique rat brain slice preparation, we found that PPN stimulation activates afferents targeting GluR2-containing AMPA receptors (AMPAR) on VTA DA neurons, and these afferents did not exhibit long-term depression (LTD). In contrast, activation of glutamate afferents onto the same DA neurons via stimulation within the VTA evoked EPSCs mediated by GluR2-lacking AMPARs that demonstrated LTD or EPSCs mediated by GluR2-containing AMPA receptors that did not express LTD. Twenty-four hours after single cocaine injections to rats, GluR2-lacking AMPARs were increased at both PPN and local VTA projections, and this permitted LTD expression in both pathways. Single injections with the main psychoactive ingredient of marijuana, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), increased GluR2-lacking AMPA receptors and permitted LTD in only the PPN pathway, and these effects were prevented by in vivo pretreatment with the cannabinoid CB1 receptor antagonist AM251. These results demonstrate that cocaine more globally increases GluR2-lacking AMPA receptors at all glutamate synapses on VTA dopamine neurons, whereas Delta(9)-THC selectively increased GluR2-lacking AMPA receptors at subcortical PPN synapses. This suggests that different abused drugs may exert influence over distinct sets of glutamatergic afferents to VTA DA neurons which may be associated with different reinforcing or addictive properties of these drugs.
- Published
- 2010
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20. Properties of distinct ventral tegmental area synapses activated via pedunculopontine or ventral tegmental area stimulation in vitro.
- Author
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Good CH and Lupica CR
- Subjects
- Aconitine analogs & derivatives, Aconitine pharmacology, Afferent Pathways drug effects, Animals, Bicuculline pharmacology, Dihydro-beta-Erythroidine pharmacology, Electric Stimulation, Excitatory Amino Acid Antagonists pharmacology, GABA Antagonists pharmacology, In Vitro Techniques, Nicotine pharmacology, Nicotinic Antagonists pharmacology, Patch-Clamp Techniques, Pedunculopontine Tegmental Nucleus drug effects, Picrotoxin pharmacology, Quinoxalines pharmacology, Rats, Rats, Sprague-Dawley, Reaction Time drug effects, Reaction Time physiology, Receptors, Nicotinic physiology, Strontium pharmacology, Synapses drug effects, Synaptic Transmission drug effects, Ventral Tegmental Area drug effects, alpha7 Nicotinic Acetylcholine Receptor, Afferent Pathways physiology, Pedunculopontine Tegmental Nucleus physiology, Synapses physiology, Synaptic Transmission physiology, Ventral Tegmental Area physiology
- Abstract
Anatomical studies indicate that synaptic inputs from many cortical and subcortical structures converge on neurons of the ventral tegmental area (VTA). Although in vitro electrophysiological studies have examined synaptic inputs to dopamine (DA) and non-DA neurons in the VTA, they have largely relied upon local electrical stimulation to activate these synapses. This provides little information regarding the distinct properties of synapses originating from different brain areas. Using whole-cell recordings in parasagittal rat brain slices that preserved subcortical axons from the pedunculopontine nucleus (PPN) to the VTA, we compared these synapses with those activated by intra-VTA stimulation. PPN-evoked currents demonstrated longer latencies than intra-VTA-evoked currents, and both VTA and PPN responses were mediated by GABA(A) and AMPA receptors. However, unlike VTA-evoked currents, PPN currents were exclusively mediated by glutamate in 25-40% of the VTA neurons. Consistent with a cholinergic projection from the PPN to the VTA, nicotinic acetylcholine receptors (nAChR) were activated by endogenous acetylcholine released during PPN, but not VTA, stimulation. This was seen as a reduction of PPN-evoked, and not VTA-evoked, synaptic currents by the alpha7-nAChR antagonist methyllycaconitine (MLA) and the agonist nicotine. The beta2-nAChR subunit antagonist dihydro-beta-erythroidine had no effect on VTA- or PPN-evoked synaptic currents. The effects of MLA on PPN-evoked currents were unchanged by the GABA(A) receptor blocker picrotoxin, indicating that alpha7-nAChRs presynaptically modulated glutamate and not GABA release. These differences in physiological and pharmacological properties demonstrate that ascending PPN and presumed descending inputs to VTA utilize distinct mechanisms to differentially modulate neuronal activity and encode cortical and subcortical information.
- Published
- 2009
- Full Text
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21. Muscarinic and nicotinic responses in the developing pedunculopontine nucleus (PPN).
- Author
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Good CH, Bay KD, Buchanan R, Skinner RD, and Garcia-Rill E
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Aging physiology, Animals, Animals, Newborn, Cell Differentiation physiology, Muscarinic Agonists pharmacology, Muscarinic Antagonists pharmacology, Neurons drug effects, Nicotinic Agonists pharmacology, Nicotinic Antagonists pharmacology, Organ Culture Techniques, Pedunculopontine Tegmental Nucleus drug effects, Rats, Rats, Sprague-Dawley, Receptors, Muscarinic drug effects, Receptors, Nicotinic drug effects, Sleep, REM physiology, Sodium Channel Blockers pharmacology, Synaptic Transmission drug effects, Synaptic Transmission physiology, Acetylcholine metabolism, Neurons metabolism, Pedunculopontine Tegmental Nucleus growth & development, Pedunculopontine Tegmental Nucleus metabolism, Receptors, Muscarinic metabolism, Receptors, Nicotinic metabolism
- Abstract
The pedunculopontine nucleus (PPN), the cholinergic arm of the reticular activating system (RAS), is known to modulate waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, with the majority occurring between 12 and 21 days. We investigated the possibility that changes in the cholinergic, muscarinic and/or nicotinic, input to PPN neurons could explain at least part of the developmental decrease in REM sleep. We recorded intracellularly from PPN neurons in 12-21 day rat brainstem slices maintained in artificial cerebrospinal fluid (aCSF) and found that application of the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) depolarized PPN neurons early in development, then hyperpolarized PPN neurons by day 21. Most of the effects of DMPP persisted following application of the sodium channel blocker tetrodotoxin (TTX), and in the presence of glutamatergic, serotonergic, noradrenergic and GABAergic antagonists, but were blocked by the nicotinic antagonist mecamylamine (MEC). The mixed muscarinic agonist carbachol (CAR) hyperpolarized all type II (A current) PPN cells and depolarized all type I (low threshold spike-LTS current) and type III (A+LTS current) PPN cells, but did not change effects during the period known for the developmental decrease in REM sleep. The effects of CAR persisted in the presence of TTX but were mostly blocked by the muscarinic antagonist atropine (ATR), and the remainder by MEC. We conclude that, while the nicotinic inputs to the PPN may help modulate the developmental decrease in REM sleep, the muscarinic inputs appear to modulate different types of cells differentially.
- Published
- 2007
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22. Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells.
- Author
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Good CH
- Subjects
- Action Potentials physiology, Cannabinoid Receptor Modulators metabolism, Endocannabinoids, Feedback physiology, Homeostasis physiology, Neural Inhibition physiology, Purkinje Cells physiology, Synaptic Transmission physiology
- Published
- 2007
- Full Text
- View/download PDF
23. Alpha-2 adrenergic regulation of pedunculopontine nucleus neurons during development.
- Author
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Bay KD, Mamiya K, Good CH, Skinner RD, and Garcia-Rill E
- Subjects
- Acetylcholine pharmacology, Action Potentials drug effects, Action Potentials physiology, Action Potentials radiation effects, Adrenergic alpha-Antagonists pharmacology, Analysis of Variance, Anesthetics, Local pharmacology, Animals, Animals, Newborn, Biotin analogs & derivatives, Biotin metabolism, Electric Stimulation methods, Female, In Vitro Techniques, Male, NADP metabolism, Neurons classification, Neurons physiology, Neurons radiation effects, Pedunculopontine Tegmental Nucleus growth & development, Pregnancy, Pyrimidines pharmacology, Rats, Rats, Sprague-Dawley, Tetrodotoxin pharmacology, Yohimbine pharmacology, Adrenergic alpha-Agonists pharmacology, Clonidine pharmacology, Neurons drug effects, Pedunculopontine Tegmental Nucleus cytology
- Abstract
Rapid eye movement sleep decreases between 10 and 30 days postnatally in the rat. The pedunculopontine nucleus is known to modulate waking and rapid eye movement sleep, and pedunculopontine nucleus neurons are thought to be hyperpolarized by noradrenergic input from the locus coeruleus. The goal of the study was to investigate the possibility that a change in alpha-2 adrenergic inhibition of pedunculopontine nucleus cells during this period could explain at least part of the developmental decrease in rapid eye movement sleep. We, therefore, recorded intracellularly in 12-21 day rat brainstem slices maintained in oxygenated artificial cerebrospinal fluid. Putative cholinergic vs. non-cholinergic pedunculopontine nucleus neurons were identified using nicotinamide adenine dinucleotide phosphate diaphorase histochemistry and intracellular injection of neurobiotin (Texas Red immunocytochemistry). Pedunculopontine nucleus neurons also were identified by intrinsic membrane properties, type I (low threshold spike), type II (A) and type III (A+low threshold spike), as previously described. Clonidine (20 microM) hyperpolarized most cholinergic and non-cholinergic pedunculopontine nucleus cells. This hyperpolarization decreased significantly in amplitude (mean+/-S.E.) from -6.8+/-1.0 mV at 12-13 days, to -3.0+/-0.7 mV at 20-21 days. However, much of these early effects (12-15 days) were indirect such that direct effects (tested following sodium channel blockade with tetrodotoxin (0.3 microM)) resulted in hyperpolarization averaging -3.4+/-0.5 mV, similar to that evident at 16-21 days. Non-cholinergic cells were less hyperpolarized than cholinergic cells at 12-13 days (-1.6+/-0.3 mV), but equally hyperpolarized at 20-21 days (-3.3+/-1.3 mV). In those cells tested, hyperpolarization was blocked by yohimbine, an alpha-2 adrenergic receptor antagonist (1.5 microM). These results suggest that the alpha-2 adrenergic receptor on cholinergic pedunculopontine nucleus neurons activated by clonidine may play only a modest role, if any, in the developmental decrease in rapid eye movement sleep. Clonidine blocked or reduced the hyperpolarization-activated inward cation conductance, so that its effects on the firing rate of a specific population of pedunculopontine nucleus neurons could be significant. In conclusion, the alpha-2 adrenergic input to pedunculopontine nucleus neurons appears to consistently modulate the firing rate of cholinergic and non-cholinergic pedunculopontine nucleus neurons, with important effects on the regulation of sleep-wake states.
- Published
- 2006
- Full Text
- View/download PDF
24. Prenatal exposure to cigarette smoke affects the physiology of pedunculopontine nucleus (PPN) neurons in development.
- Author
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Good CH, Bay KD, Buchanan RA, McKeon KA, Skinner RD, and Garcia-Rill E
- Subjects
- Animals, Animals, Newborn, Body Weight drug effects, Carbon Monoxide blood, Cardiovascular Agents pharmacology, Dose-Response Relationship, Drug, Electric Stimulation methods, Electrophysiology methods, Female, Fetal Viability drug effects, Gas Chromatography-Mass Spectrometry methods, Male, Membrane Potentials drug effects, Membrane Potentials physiology, Neurons physiology, Nicotine blood, Pregnancy, Pregnancy Rate, Pyrimidines pharmacology, Rats, Time Factors, Neurons drug effects, Nicotine pharmacology, Pedunculopontine Tegmental Nucleus drug effects, Pedunculopontine Tegmental Nucleus growth & development, Pedunculopontine Tegmental Nucleus pathology, Prenatal Exposure Delayed Effects, Smoking
- Abstract
Prenatal exposure to cigarette smoke is known to produce lasting arousal, attentional and cognitive deficits in humans. The pedunculopontine nucleus (PPN), as the cholinergic arm of the reticular activating system (RAS), is known to modulate arousal, waking and rapid eye movement (REM) sleep. REM sleep decreases between 10 and 30 days postnatally in the rat, especially at 12-21 days. Pregnant dams were exposed to 350 ml of cigarette smoke for 15 min, 3 times per day, from day E14 until birth, and the pups allowed to mature. Intracellularly recorded PPN neurons in 12-21 day rat brainstem slices were tested for intrinsic membrane properties, including the hyperpolarization-activated cation current Ih, which is known to drive oscillatory activity. Type II (A-current) PPN cells from 12-16 day old offspring of treated animals had a 1/2max Ih amplitude of (mean +/- SE) 4.1 +/- 0.9 mV, while 17-21 day cells had a higher 1/2max Ih of 9.9 +/- 1.1 mV (p < 0.0001). Cells from 12-16 day old control brainstems had a 1/2max Ih of 1.3 +/- 0.1 mV, which was lower (p < 0.05) than in cells from prenatally treated offspring; while 17-21 day old cells from controls had a 1/2max Ih of 3.3 +/- 0.3 mV, which was also lower (p < 0.01) than in cells from prenatally treated offspring. In addition, changes in resting membrane potential [control -65. +/- 0.9 mV (n=32); exposed -55.0 +/- 1.4 mV (n = 27) (p < 0.0001)], and action potential (AP) threshold [control -56.5 +/- 0.7 mV (n = 32), exposed -47.0 +/- 1.4 mV (n = 27) (p < 0.0001)], suggest that prenatal exposure to cigarette smoke induced marked changes in cells in the cholinergic arm of the RAS, rendering them more excitable. Such data could partially explain the differences seen in individuals whose parents smoked during pregnancy, especially in terms of their hypervigilance and increased propensity for attentional deficits and cognitive/behavioral disorders.
- Published
- 2006
- Full Text
- View/download PDF
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