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

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/

Psychiatric Diseases Symptoms Quantitative Behaviors Animal Models

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

Methodological Approaches Behaviors

Methodological Approaches Behaviors Electrophysiology ?

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

Translational Approach Behavior Electrophysiology Therapy

What is the optogenetic technology?

Chlamydomonas reinhardtii

Channelrhodopsin (ChR2) Activation du cycle cellulaire

Virus

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

1st part: Optogenetic: Basic concepts and methodology

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

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

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

Promoter specificity approach

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

Transgenic Mouse Lines

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

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

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

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

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

(Yizhar al., Nature , 2007)

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

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

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

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

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

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

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

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

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.

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

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)

Methodological Approaches Behaviors Electrophysiology ?

Extracellular Recording Setup

Hyperactivity in the striatum but not in the OFC

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

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

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

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

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

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

Behavioral effects of OFC-striatal optogenetic stimulation

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

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

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

Practical example

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

Creation of a new line of mice

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

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

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)

Pathophysiology of Compulsive Disorders Subthalamic Nucleus

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

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

Inhibitory Opsine Excitatory Opsine

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