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Psychiatric Disease Eric Burguire (ICM Institute, Paris) - PowerPoint PPT Presentation

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2018 UE Neural Network Master2 BIP Optogenetic and the Circuit Dynamics of Psychiatric Disease Eric Burguire (ICM Institute, Paris) http://bebgteam.net/team/eric-burguiere/ Psychiatric Diseases Symptoms Quantitative Behaviors Animal

  1. 2018 UE Neural Network – Master2 BIP Optogenetic and the Circuit Dynamics of Psychiatric Disease Eric Burguière (ICM Institute, Paris) http://bebgteam.net/team/eric-burguiere/

  2. Psychiatric Diseases Symptoms Quantitative Behaviors Animal Models

  3. Psychiatric Diseases Obsessive Compulsive Disorders Symptoms Obsessions + Compulsions Quantitative Behaviors Compulsive Behaviors Mouse model of OCD Animal Models (SAPAP3-KO)

  4. Methodological Approaches Behaviors

  5. Methodological Approaches Behaviors Electrophysiology ?

  6. Methodological Approaches Behaviors Electrophysiology Optogenetic K+ Opsine Na+ Cl-

  7. Translational Approach Behavior Electrophysiology Therapy

  8. What is the optogenetic technology?

  9. Chlamydomonas reinhardtii

  10. Channelrhodopsin (ChR2) Activation du cycle cellulaire

  11. Virus

  16. https://www.youtube.com/watch?v=v7uRFVR9BPU

  17. 1st part: Optogenetic: Basic concepts and methodology

  18. Optogenetic approach allows to manipulate neural activity with great: 1) Spatial and cellular specificity 2) Temporal specificity

  19. 3 pillars for spatial specificity: - Expression pattern of the opsin - Location of light delivery - Optical power

  20. Genetic expression specificity (Aravanis et al, J Neural Eng , 2007)

  21. Promoter specificity approach

  22. Cre-Lox System Deniz Atasoy et al. J. Neurosci. 2008;28:7025-7030

  23. Transgenic Mouse Lines

  26. Injection of AAV-CamKII-Chr2 in OFC Striatum OFC OFC Striatum

  27. (Tay K and Deisseroth K, Nature Reviews , 2012)

  28. Light diffusion in brain tissue (Welch et al., Nature , 2007)

  29. Local activation by laser stimulation (Burguiere et al., Science , 2013)

  30. 3 pillars for timing specificity: - Type of Opsins - Nature of the Light Source - Shutters

  31. (Yizhar al., Nature , 2007)

  33. Diode-pumped Solid-State (DPSS) Laser Plus: High power (interesting for compensating for poor coupling, doing beam splitting etc...) Minus: Price, Space occupancy, Temporal characteristics

  34. Diode-pumped Solid-State (DPSS) Laser Problems: Not steady state before warming period Not reliable with TTL pulse

  35. An alternative: Mechanical shutters …but noisy, specially at high frequency

  36. Light-emitting diode (LED) Plus: Nearly linear electrical current to optical power output, Cheap, Easy to handle Minus: Power

  37. Conventional LED architecture… ...but could be wireless (Iwai et al., Neurosci Res 2011 )

  38. 2 nd part: Deconstructing the circuitry of compulsive behaviors with an optogenetic approach

  39. Psychiatric Diseases Obsessive Compulsive Disorders Symptoms Obsessions + Compulsions Quantitative Behaviors Compulsive Behaviors Mouse model of OCD Animal Models (SAPAP3-KO)

  40. Mouse model of OCD SAPAP3-KO mice: Over-grooming behaviors Higher anxiety Postsynaptic scalfolding protein that participates to the neurotransmission of cortical inputs Welch et al., Nature , 2007

  41. Methodological Approaches Behaviors Working Hypothesis Learning theories of human compulsive behavior suggest that repetitive behaviors can result from malfunction of a learning process leading to loss of the ability to repress sensorimotor associations.

  42. X 50

  43. Behaviour Burguière E, Monteiro P, Feng G, Graybiel, , Science, 2013

  44. Which circuitry could be affected in this behavioural deficit? Dorso- Medial Striatum - Lateral OFC and Dorso-Medial Striatum lesions studies showed emergence of impulsive behaviors ( Eagle et al. 2008; Rogers et al., 2001; Winstanley et al., 2004 ) - Lateral OFC projects to Dorso-Medial Striatum ( Schilman et al., 2008)

  45. Methodological Approaches Behaviors Electrophysiology ?

  46. Extracellular Recording Setup

  47. Hyperactivity in the striatum but not in the OFC

  48. Methodological Approaches Behaviors Electrophysiology Optogenetic K+ Opsine Na+ Cl-

  49. Optogenetic Stimulation of the OFC-Striatal Pathway - Injection of AAV-CamKII-Chr2 virus in lateral OFC - 3 weeks minimum of expression LFPs in OFC and Striatum OFC Striatum

  50. Optogenetic Stimulation of the OFC-Striatal Pathway - Injection of AAV-CamKII-Chr2 virus in lateral OFC - 3 weeks minimum of expression LFPs in OFC and Striatum OFC Striatum

  51. Optogenetic Stimulation of the OFC-Striatal Pathway - Injection of AAV-CamKII-Chr2 virus in lateral OFC - 3 weeks minimum of expression LFPs in OFC and Striatum OFC Striatum

  52. Optogenetic Modulation of the striatal activity (Burguière et al. , Science, 2013)

  53. PV-interneurons are reduced in SAPAP3-KO mouse MSN PV+ MSN PV+ MSN PV+ PV+ PV+ PV+ PV+ SAPAP3-KO Silberberg and Bolam, Curr Op Neurobio 2015 Burguière E, Monteiro P, Feng G, Graybiel, Science, 2013

  54. Behavioral effects of OFC-striatal optogenetic stimulation

  55. Behavioral effects of OFC-striatal optogenetic stimulation Laser Stimulation (5Hz, 5ms pulse, 5mW) in homecage 3min ON/3min OFF during 30 min

  56. Repetitive Behaviors Burguière E, Monteiro P, Feng G and Graybiel, Curr Opin Neurobiol, 2015

  57. Current questions  Are the striatal PV-interneurons sufficient to reduce compulsive grooming ?  Can we optimize temporal specificity for preventing compulsive events?

  58. Practical example

  59. Current questions  Are the striatal PV-interneurons sufficient to reduce compulsive grooming ?

  60. Creation of a new line of mice

  61. Current questions  Are the striatal PV-interneurons sufficient to reduce compulsive grooming ?  Can we optimize temporal specificity for preventing compulsive events?

  62. Lizbeth Mondragon Frequency (Hz) 250 Frequency (Hz) 250 60 60 15 15 4 4 1 1 Frequency (Hz) 250 Frequency (Hz) 250 60 60 15 15 4 4 1 1 Frequency (Hz) 250 Frequency (Hz) 250 60 60 15 15 4 4 1 1

  64. Closed-loop stimulation BaseLine Closed- Yoked 2 min/bloc = 36 min Session: Loop x 4 times Prediction N predictions = N random stimulations Grooming time (in s) - @10mW 5ms 20 HZ 45,00 40,00 35,00 29,97 30,00 25,00 21,6 20,00 15,00 11,70 10,00 5,00 0,00 % Time grooming Baseline CL-On Joked (Error bars represent SEM, n=2, 6 Sessions, 36 min each)

  65. Pathophysiology of Compulsive Disorders Subthalamic Nucleus

  66. Pathophysiology of Compulsive Disorders  What are the effects of Subthalamic electrical stimulation on the Nucleus neuronal circuitry?

  68.  What optogenetic approach could we use to mimic these 3 scenarii?

  69. Inhibitory Opsine Excitatory Opsine

  70. Some weblinks: Methodological and very informative http://www.openoptogenetics.org/index.php?title=Main_Page Optogenetic ressource centers (virus construct, opsins, etc.): http://web.stanford.edu/group/dlab/optogenetics/ http://www.syntheticneurobiology.org/protocols Nice tool to calculate irradiance of the light in the tissue: http://web.stanford.edu/group/dlab/cgi-bin/graph/chart.php

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