DOCSLIB.ORG

Nucleus Accumbens Medium Spiny Neurons Target Non-Dopaminergic Neurons in the Ventral Tegmental Area

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nucleus Accumbens Medium Spiny Neurons Target Non-Dopaminergic Neurons in the Ventral Tegmental Area The Journal of Neuroscience, May 25, 2011 • 31(21):7811–7816 • 7811 Behavioral/Systems/Cognitive Nucleus Accumbens Medium Spiny Neurons Target Non-Dopaminergic Neurons in the Ventral Tegmental Area Yanfang Xia, Joseph R. Driscoll, Linda Wilbrecht, Elyssa B. Margolis, Howard L. Fields, and Gregory O. Hjelmstad Ernest Gallo Clinic and Research Center, Wheeler Center for the Neurobiology of Addiction, and Department of Neurology, University of California, San Francisco, Emeryville, California 94608 The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABAA or GABAB receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABAA receptors. Introduction neurons in a region with heterogeneous anatomical connectivity. In The ventral tegmental area (VTA) projection to the nucleus ac- this study, we used a viral vector to express channel rhodopsin-2 cumbens (NAc) is a critical element of circuits that mediate ap- (ChR2) in neurons of the NAc of rats and optically stimulated their petitive behaviors (Carr and Sesack, 2000a; Fields et al., 2007; axon terminals during ex vivo whole-cell recordings from VTA Humphries and Prescott, 2010). Although considerable focus has neurons in a midbrain slice. We found that NAc MSNs target been placed on the role of the dopamine projection from the VTA non-dopaminergic VTA neurons, including non-dopaminergic to the NAc, a significant number of VTA GABA neurons also neurons that project back to the NAc. Moreover, this connection ␮ project to the NAc (Van Bockstaele and Pickel, 1995; Carr and is mediated by GABAA receptors and is inhibited by -opioids, Sesack, 2000b; Margolis et al., 2006b). Moreover, a subset of NAc providing a potential mechanism for opioid reward. medium spiny neurons (MSNs) sends a reciprocal GABAergic Materials and Methods projection back to the VTA (Nauta et al., 1978; Heimer et al., Animals. Surgeries were performed on 27- to 29-d-old (70–80 g) male Sprague 1991; Kalivas et al., 1993; Lu et al., 1998; Usuda et al., 1998; Dawley rats. Animals were anesthetized with isoflurane. Adeno-associated virus Tripathi et al., 2010). This projection is thought to mediate a containing ChR2–tdtomato (AAV2/1 CAG::ChR2.tdtomato, a kind gift from “long-loop” inhibitory feedback to regulate dopamine neuron Karel Svoboda) was bilaterally injected (1 ␮l in each side) using a Hamilton activity (Einhorn et al., 1988; Rahman and McBride, 2000). How- syringe stereotaxically placed into the NAc shell (anteroposterior, ϩ1.5 mm ever, it is unresolved whether the axon terminals of the MSNs from bregma; mediolateral, Ϯ0.8 mm from bregma; ventral, Ϫ6.7 mm from synapse onto NAc-projecting dopamine neurons or a different skull surface). The injector was left in place for 5 min, raised 1 mm, and left class of VTA neuron. for an additional 5 min before being completely removed. Animals were The nature of the synaptic connection is also unknown. It has then returned to their home cages for 14–17 d before electrophysiologi- been proposed that the NAc projection to the VTA produces an cal experiments were performed. For retrograde tracer experiments, neuro-DiI (0.3 ␮l, 7% in ethanol; Biotium) was slowly injected (over 5 IPSC mediated exclusively by GABA receptors (Sugita et al., B min) into the NAc 2–3 h after the injection of the virus. Only data from 1992; Cameron and Williams, 1993). However, this model was rats in which the infection was confirmed were accepted. based on indirect evidence and, because of technical limitations, Slice preparation and electrophysiology. Coronal NAc slices (350 ␮m has never been directly tested. thick) or horizontal midbrain slices (150–200 ␮m thick) including the The recent development of optogenetic tools provides a novel VTA were prepared using a vibratome (Leica Instruments) in artificial method for isolating the action of specific afferent projections to CSF (ACSF) containing the following (in mM): 119 NaCl, 2.5 KCl, 1.3 MgSO4, 1.0 NaH2PO4, 2.5 CaCl2, 26.2 NaHCO3, and 11 glucose (satu- rated with 95% O2/5% CO2). Slices were submerged in ACSF and al- Received March 24, 2011; revised April 1, 2011; accepted April 6, 2011. lowed to recover for Ͼ1 h at room temperature. Author contributions: Y.X., L.W., E.B.M., H.L.F., and G.O.H. designed research; Y.X., J.R.D., and G.O.H. performed Individual slices were visualized under an upright microscope with research; Y.X., J.R.D., and G.O.H. analyzed data; Y.X., L.W., E.B.M., H.L.F., and G.O.H. wrote the paper. differential interference contrast optics and infrared and epifluorescent The authors declare no competing financial interests. illumination. Whole-cell recordings were made with 2.5–4 M⍀ pipettes This work was supported by the State of California for medical research on alcohol and substance abuse through containing the following (in mM): 123 K-gluconate, 10 HEPES, 0.2 the University of California, San Francisco and by the Wheeler Center for the Neurobiology of Addiction. We thank Kaidi He for technical assistance. EGTA, 8 NaCl, 2 MgATP, and 0.3 Na3GTP, pH 7.2 (osmolarity adjusted CorrespondenceshouldbeaddressedtoGregoryHjelmstad,ErnestGalloClinicandResearchCenter,5858Horton to 275 mOsm). In some experiments, 0.1% biocytin was included in the Street, Suite #200, Emeryville, CA 94608. E-mail: [email protected]. recording solution. Recordings were made using a Multiclamp 700A or DOI:10.1523/JNEUROSCI.1504-11.2011 Axopatch 1-D amplifier (Molecular Devices), filtered at 2 kHz, and col- Copyright © 2011 the authors 0270-6474/11/317811-06$15.00/0 lected at 5 kHz using procedures written for Igor Pro (Wavemetrics). 7812 • J. Neurosci., May 25, 2011 • 31(21):7811–7816 Xia et al. • Optogenetic Stimulation of NAc Efferents ChR2 was stimulated by flashing 470 nm A B C light (1–5 ms) through the light path of the microscope using a high-powered LED (XR-E XLamp LED; Cree) powered by an LED driver (Mightex Systems) under computer control. Electrically evoked GABAB IPSCs were isolated with picrotoxin (100 ␮M), DNQX (10 ␮M), sulpiride (10 ␮M), strychnine (1 ␮M), and D-AP-5 (10 ␮M) and were evoked with a train of seven pulses given once every 30 s through a bipolar stimulating electrode placed ϳ50 ␮m D E from the recorded neuron. Light-evoked IPSC amplitudes were calculated by comparing a 2 ms period at the peak of the response with a similar period just before light stimulation. The significance of drug effects was determined comparing the last 4 min of baseline with the last 4 min of drug application. Baclofen cur- rents were determined by measuringa1min average during the peak response compared with the baseline period. HCN currents (Ih) FG were recorded by voltage clamping cells at Ϫ60 mV and applying a series of steps from Ϫ40 to Ϫ 120 mV. The Ih magnitude was measured as the difference between the initial capacitative response to the voltage step and the final cur- rent. Series resistance was monitored online by measuring the peak of the capacitance tran- sient in response to a Ϫ4 mV voltage step ap- Figure 1. ChR2-expression in the NAc. A, Confocal image of ChR2–tdtomato expression (red) in NAc neurons. Scale bar, 50 ìm. plied at the onset of each sweep. All drugs were B, Diagram of experimental design: light stimulation (blue) of ChR2 expressing NAc MSN (red). C, Example recording from an MSN applied by bath perfusion. Stock solutions of showing responses to 1 ms pulses of light at three different intensities. D, MSNs can follow trains of light pulses up to 100 Hz. E, drugs are made and diluted (typically 1:1000) Averageprobabilityoffiringanactionpotential(AP)foreachstimulusinatrainforthreedifferentfrequencies(nϭ6).F,Example into ACSF immediately before application. recordingofalight-evokedIPSCinaneighboringuninfectedMSN(currentisinwardwhenholdingMSNatϪ75mV).ThisIPSCwas Statistical analyses were performed using the entirely blocked after the application of picrotoxin (PTX). G, IPSCs evoked in response to a 50 Hz train of light. ␹ 2 test, Student’s t test, or appropriate ANOVA as described in the text. Data are presented as in which higher intensities produced action potentials (Fig. 1C). Ϯ Ͻ mean SEM. Significance is defined as p 0.05. Trains of 1 ms light pulses reliably produced action potentials at Immunocytochemistry. For tyrosine hydroxylase (TH) immunoreac- frequencies up to 100 Hz (Fig. 1D,E). Trains with longer- tivity, immediately after recording, slices were fixed in 4% formaldehyde duration (5 ms) light pulses produced more erratic responses: for 2 h, then washed thoroughly, and stored at 4°C in PBS. Sections were double spikes early in the trains and less reliable spiking later in preblocked for 2 h in PBS plus 0.3% (v/v) Tween 20, 0.2% BSA, and 5% ϭ normal goat serum and then incubated for 48 h at 4°C with a rabbit the trains (n 5) (data not shown). In voltage-clamp recordings anti-tyrosine hydroxylase polyclonal antibody (1:100). The slices were from uninfected, neighboring MSNs, light evoked an inward cur- washed thoroughly in PBS with 0.3% Tween 20 before being agitated rent when the neuron was held at Ϫ75 mV that was blocked by ␮ overnight at 4°C with Cy5 anti-rabbit secondary antibody (1:100) and the GABAA receptor antagonist picrotoxin (100 M) (Fig.
Load more

Recommended publications
  • Nucleus Accumbens Medium Spiny Neurons Subtypes Signal Both Reward and Aversion
    Molecular Psychiatry https://doi.org/10.1038/s41380-019-0484-3 ARTICLE Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion 1,2 1,2,3,4 1,2 1,2 Carina Soares-Cunha ● Nivaldo A. P. de Vasconcelos ● Bárbara Coimbra ● Ana Verónica Domingues ● 1,2 1,2 1,2,5,6 1,2 1,2,7 Joana M. Silva ● Eduardo Loureiro-Campos ● Rita Gaspar ● Ioannis Sotiropoulos ● Nuno Sousa ● Ana João Rodrigues 1,2,7 Received: 25 June 2018 / Revised: 14 May 2019 / Accepted: 20 June 2019 © The Author(s) 2019. This article is published with open access Abstract Deficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1- expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2- MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their 1234567890();,: 1234567890();,: neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions.
    [Show full text]
  • TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms
    Neuropsychopharmacology (2016) 41, 2252–2262 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms 1 1 1 1,2 ,1 Kazunori Suzuki , Akina Harada , Hirobumi Suzuki , Maki Miyamoto and Haruhide Kimura* 1 2 CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan; Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D receptor agonist SKF82958 1 canceled antipsychotic-like effects of a dopamine D receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity 2 in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates.
    [Show full text]
  • Addiction Becomes Meeting Report a Brain Disease
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron, Vol. 26, 27±33, April, 2000, Copyright 2000 by Cell Press Addiction Becomes Meeting Report a Brain Disease Roy A. Wise* discriminative and executive functions of the medial pre- Intramural Research Program frontal cortex, the amygdala, and the hippocampus. A National Institute on Drug Abuse number of imaging studies suggested multiple cortical Baltimore, Maryland 21224 and subcortical structures that participate both in drug reward and in more natural motivational phenomena. For example, Hans Breiter (Massachusetts General Hos- At the end of the decade of the brain, the study of pital) showed functional magnetic resonance imaging neural mechanisms has come to dominate the study (fMRI) data implicating a generalized limbic and cortical of addiction. Whereas attention was once on somatic reward circuitry, stressing the nucleus accumbens and withdrawal symptoms and liver enzymes, it has turned sublenticular amygdala, in common aspects of drug (co- to reward circuitry in the brain and to neuroadaptations caine and morphine) reward and monetary rewards and in that circuitry that can change sensitivity to addictive in subjective probability assessment. These findings en- drugs and that, it is hoped, can explain the compulsive courage hypotheses about commonalities between the dimension of drug seeking in addicts. The focus on brain brain mechanisms of addiction and gambling. His data mechanisms of reward and addiction began with the implicate this circuitry in drug and nondrug reward ex- discoveries of brain reward circuitry in the 1950s and pectation as well as in drug and nondrug reward.
    [Show full text]
  • Structural Plasticity Associated with Exposure to Drugs of Abuse
    Neuropharmacology 47 (2004) 33–46 www.elsevier.com/locate/neuropharm Structural plasticity associatedwith exposure to drugsof abuse Terry E. Robinson a,Ã, Bryan Kolb b a Department of Psychology (Biopsychology) and Neuroscience Program, The University of Michigan, 525 E. University (East Hall), Ann Arbor, MI 48109, USA b Department of Psychology and Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Alta., Canada T1K 3M4 Received19 April 2004; receivedin revisedform 24 May 2004; accepted30 June 2004 Abstract Persistent changes in behavior andpsychological function that occur as a function of experience, such those associatedwith learning andmemory, are thought to be dueto the reorganization of synaptic connections (structural plasticity) in relevant brain circuits. Some of the most compelling examples of experience-dependent changes in behavior and psychological function, changes that can last a lifetime, are those that accrue with the development of addictions. However, until recently, there has been almost no research on whether potentially addictive drugs produce forms of structural plasticity similar to those associated with other forms of experience-dependent plasticity. In this paper we summarize evidence that, indeed, exposure to amphetamine, cocaine, nicotine or morphine produces persistent changes in the structure of dendrites and dendritic spines on cells in brain regions involvedin incentive motivation andreward(such as the nucleus accumbens), andjudgmentandthe inhibitory control of beha- vior (such as the prefrontal cortex). It is suggestedthat structural plasticity associatedwith exposure to drugsof abuse reflects a reorganization of patterns of synaptic connectivity in these neural systems, a reorganization that alters their operation, thus con- tributing to some of the persistent sequela associated with drug use—including addiction.
    [Show full text]
  • Egr-1 Induces DARPP-32 Expression in Striatal Medium Spiny Neurons Via a Conserved Intragenic Element
    Thomas Jefferson University Jefferson Digital Commons Farber Institute for Neurosciences Faculty Papers Farber Institute for Neurosciences 5-16-2012 Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element. Serene Keilani Departments of Neurology and Pediatrics, Mount Sinai School of Medicine, New York Samira Chandwani Departments of Neurology and Pediatrics, Mount Sinai School of Medicine, New York Georgia Dolios Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York Alexey Bogush Weinberg Unit for ALS Research, Department of Neuroscience, Farber Institute for Neuroscience, Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/farberneursofp Heike Beck Walter Par Brt ofendel the NeurCenterology of Experimental Commons Medicine, Ludwig Maximilians University Let us know how access to this document benefits ouy See next page for additional authors Recommended Citation Keilani, Serene; Chandwani, Samira; Dolios, Georgia; Bogush, Alexey; Beck, Heike; Hatzopoulos, Antonis K; Rao, Gadiparthi N; Thomas, Elizabeth A; Wang, Rong; and Ehrlich, Michelle E, "Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element." (2012). Farber Institute for Neurosciences Faculty Papers. Paper 16. https://jdc.jefferson.edu/farberneursofp/16 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship.
    [Show full text]
  • In Vivo Imaging Identifies Temporal Signature of D1 and D2 Medium Spiny Neurons in Cocaine Reward
    In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward Erin S. Caliparia, Rosemary C. Bagota, Immanuel Purushothamana, Thomas J. Davidsonb, Jordan T. Yorgasonc, Catherine J. Peñaa, Deena M. Walkera, Stephen T. Pirpiniasa, Kevin G. Guisea, Charu Ramakrishnanb, Karl Deisserothb,d,e, and Eric J. Nestlera,1 aFishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; bDepartment of Bioengineering, Stanford University, Stanford, CA 94305; cVollum Institute, Oregon Health and Science University, Portland, OR 97239; dHoward Hughes Medical Institute, Stanford University, Stanford, CA 94305; and eDepartment of Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA 94305 Edited by Susan G. Amara, National Institutes of Health, Bethesda, MD, and approved January 8, 2016 (received for review October 27, 2015) The reinforcing and rewarding properties of cocaine are attributed largely nonoverlapping populations of medium spiny neurons to its ability to increase dopaminergic transmission in nucleus (MSNs) (13). These two subtypes of MSNs exert opposite effects accumbens (NAc). This action reinforces drug taking and seeking on behavior, with optogenetic activation of D1-type neurons pro- and leads to potent and long-lasting associations between the moting positive reinforcement and increasing the formation of – rewarding effects of the drug and the cues associated with its cocaine reward context associations and activation of D2-type availability. The inability to extinguish these associations is a key factor neurons being aversive and decreasing cocaine reward (14, 15); contributing to relapse. Dopamine produces these effects by control- related differences in behavioral responses are seen in response to ling the activity of two subpopulations of NAc medium spiny neurons D1 vs.
    [Show full text]
  • Neuronal Circuits: Deciphering Striatal Innervation
    RESEARCH HIGHLIGHTS IN BRIEF NEUROTRANSMITTER RECEPTORS Splicing up synaptic strength Neurexins, which are presynaptic cell adhesion molecules, have multiple alternatively spliced forms, but why this splicing is needed is unclear. Aoto et al. created mice that constitutively expressed a variant of neurexin 3 that includes alternatively spliced sequence 4 (NRX3SS4+) and in which SS4 could be excised by Cre recombination. NRX3SS4+ expression decreased postsynaptic AMPA receptor levels in neurons and impaired long-term potentiation in hippocampal slices. SS4 excision rescued these effects, suggesting that NRX3 alternative splicing may trans-synaptically regulate AMPA receptor trafficking and synaptic strength. ORIGINAL RESEARCH PAPER Aoto, J. et al. Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell 154, 75–88 (2013) SENSORY PROCESSING Parallel paths In the standard view of sensory processing, information is conveyed from the thalamus to cortical layer 4 (L4), L2/3 and then L5/6. In a new study in rats, barrel cortex whole-cell recordings showed that postsynaptic potentials with similar latencies occurred in L4 and many L5/6 neurons after whisker stimulation, and paired in vivo recordings revealed that thalamocortical neurons may directly synapse onto L5 neurons. Moreover, lidocaine-induced suppression of L4 activity did not affect L5/6 sensory-evoked activity. Thus, in sensory processing, the thalamus may activate parallel cortical pathways. ORIGINAL RESEARCH PAPER Constantinople, C. M. & Bruno, R. M. Deep cortical layers are activated directly by thalamus. Science 340, 1591–1594 (2013) BEHAVIOURAL NEUROSCIENCE Promoting the interspecies divide Interspecies mating is rare even in closely related species, but how this is prevented is unclear.
    [Show full text]
  • Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible
    cells Article Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible 1, 1, 1,2,3,4, Victoria Sofie Witzig y , Daniel Komnig y and Björn H. Falkenburger * 1 Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany; [email protected] (V.S.W.); [email protected] (D.K.) 2 JARA-Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, 52074 Aachen, Germany 3 Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany 4 Deutsches Zentrum für Neurodegenerative Erkrankungen, 01307 Dresden, Germany * Correspondence: [email protected] or [email protected]; Tel.: +49-351-458-2532; Fax: +49-351-458-4365 These authors contributed equally to this work. y Received: 20 October 2020; Accepted: 6 November 2020; Published: 9 November 2020 Abstract: The classical motor symptoms of Parkinson’s disease (PD) are caused by degeneration of dopaminergic neurons in the substantia nigra, which is followed by secondary dendritic pruning and spine loss at striatal medium spiny neurons (MSN). We hypothesize that these morphological changes at MSN underlie at least in part long-term motor complications in PD patients. In order to define the potential benefits and limitations of dopamine substitution, we tested in a mouse model whether dendritic pruning and spine loss can be reversible when dopaminergic axon terminals regenerate. In order to induce degeneration of nigrostriatal dopaminergic neurons we used the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice; 30 mg/kg MPTP was applied i.p. on five consecutive days.
    [Show full text]
  • D2 Dopamine Receptors in Striatal Medium Spiny Neurons Reduce L
    The Journal of Neuroscience, December 15, 2000, 20(24):8987–8995 D2 Dopamine Receptors in Striatal Medium Spiny Neurons Reduce ␤ 2؉ L-Type Ca Currents and Excitability via a Novel PLC 1–IP3– Calcineurin-Signaling Cascade Salvador Herna´ ndez-Lo´ pez,1 Tatiana Tkatch,1 Enrique Perez-Garci,2 Elvira Galarraga,2 Jose´ Bargas,2 Heidi Hamm,3 and D. James Surmeier1,3 1Department of Physiology and 3Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611, and 2Instituto de Fisiologia Celular, UNAM Apartado Postal 70-253, Mexico DF 4510 In spite of the recognition that striatal D2 receptors are critical calcium-dependent phosphatase calcineurin. In addition to pro- determinants in a variety of psychomotor disorders, the cellular viding a unifying mechanism to explain the apparently divergent mechanisms by which these receptors shape neuronal activity effects of D2 receptors in striatal medium spiny neurons, this have remained a mystery. The studies presented here reveal that novel signaling linkage provides a foundation for understanding D2 receptor stimulation in enkephalin-expressing medium spiny how this pivotal receptor shapes striatal excitability and gene neurons suppresses transmembrane Ca 2ϩ currents through expression. L-type Ca 2ϩ channels, resulting in diminished excitability. This Key words: neostriatum; patch clamp; dopamine; neuromodu- modulation is mediated by G␤␥ activation of phospholipase C, lation; medium spiny neuron; basal ganglia; electrophysiology; mobilization of intracellular Ca 2ϩ stores, and activation of the single-cell RT-PCR; ion channel; calcium ϩ Disruptions in striatal dopaminergic signaling are thought to un- rather than decreases, activity and intracellular Ca 2 levels in derlie a variety of psychomotor disorders including drug abuse, striatal medium spiny neurons.
    [Show full text]
  • ACNP 59Th Annual Meeting: Poster Session I
    www.nature.com/npp ABSTRACTS COLLECTION ACNP 59th Annual Meeting: Poster Session I Neuropsychopharmacology (2020) 45:68–169; https://doi.org/10.1038/s41386-020-00890-7 Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Presenting author disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting. M1. Juvenile Social Isolation of Rats Induces Lost of Jessica Jessica Deslauriers*, Jose Figueroa, Cindy Napan, Corticotropin Releasing Factor-Receptor 1 Antagonist Effect in Yanilka Soto-Muniz, Victoria Risbrough the Nucleus Accumbens Université Laval, Québec, Canada Katia Gysling*, Juan Zegers, Javier Novoa, Hector Yarur Background: Post-traumatic stress disorder (PTSD) is a common Pontificia Universidad Catolica de Chile, Santiago, Chile psychiatric condition that is defined by its paradigmatic symptoms including but not limited to anxiety, avoidance, and increased arousal Background: Social isolation is a model of chronic stress widely by environmental cues due to a severely traumatic event. Recent used to study early life adversity. It is well known that early life studies show that this condition is correlated with both peripheral 1234567890();,: adversity may lead to the development of psychiatric disorders in and central immune dysfunction, but the relationship between adulthood. Juvenile rats exposed to social isolation showed inflammation and PTSD remains unclear. In a mouse model of PTSD, increased anxiety-like behavior and significant changes in Nucleus we found increased plasma levels of the pro-inflammatory cytokine Accumbens (Nac) dopamine (DA) activity in adulthood (Lukkes interleukin-1β (IL-1β) after exposure to trauma. A major component in et al.
    [Show full text]
  • Article-P1339.Pdf
    LABORATORY INVESTIGATION J Neurosurg 126:1339–1350, 2017 Intermittent bilateral deep brain stimulation of the nucleus accumbens shell reduces intravenous methamphetamine intake and seeking in Wistar rats Vinita Batra, PhD,1 Thanh Lam N. Tran, BS,2 Jessica Caputo, BS,2 Glenn F. Guerin, BS,2 Nicholas E. Goeders, PhD,2 and Jessica Wilden, MD1 1Department of Neurosurgery and 2Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana OBJECTIVE There is increasing interest in neuromodulation for addiction. Methamphetamine abuse is a global health epidemic with no proven treatment. The objective of this study was to examine the effects of intermittent nucleus accum- bens shell (AcbSh) deep brain stimulation (DBS) on operant methamphetamine intake and on methamphetamine seek- ing when stimulation is delivered in an environment different from that of drug use. METHODS Eighteen rats were implanted with intravenous (IV) catheters and bilateral AcbSh electrodes and subse- quently underwent daily sessions in 2-lever (active/methamphetamine and inactive/no reward) operant chambers to establish IV methamphetamine self-administration. After stable responding was achieved, 3 hours of DBS or sham treat- ment was administered (sham: 0 µA, n = 8; active: 200 µA, n = 10) in a separate nondrug environment prior to the daily operant sessions for 5 consecutive days. Immediately following each DBS/sham treatment, rats were placed in the oper- ant chambers to examine the effects of remote stimulation on methamphetamine intake. After the 5 days of therapy were finished, rats reestablished a posttreatment baseline, followed by extinction training, abstinence, and 1 day of relapse testing to assess methamphetamine-seeking behavior.
    [Show full text]
  • Striatal Vulnerability in Huntington's Disease: Neuroprotection Versus
    brain sciences Review Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity Ryoma Morigaki 1,2,3 and Satoshi Goto 1,2,* 1 Parkinson’s Disease and Dystonia Research Center, Tokushima University Hospital, Tokushima University, Tokushima 770-8503, Japan; [email protected] 2 Department of Neurodegenerative Disorders Research, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima University, Tokushima 770-8503, Japan 3 Department of Neurosurgery, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima University, Tokushima 770-8503, Japan * Correspondence: [email protected]; Tel.: +81-88-633-7206; Fax: +81-88-633-7208 Academic Editor: Edamakanti Chandrakanth Reddy Received: 2 May 2017; Accepted: 3 June 2017; Published: 7 June 2017 Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal
    [Show full text]