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

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

Nov 28, 2023 31 likes •746 views

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

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Optogenetic and the Circuit Dynamics of Psychiatric Disease

Eric Burguière (ICM Institute, Paris) http://bebgteam.net/team/eric-burguiere/ 2018 UE Neural Network – Master2 BIP

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Psychiatric Diseases Symptoms Quantitative Behaviors Animal Models

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Psychiatric Diseases Symptoms Quantitative Behaviors Animal Models Compulsive Behaviors Obsessive Compulsive Disorders

Mouse model of OCD (SAPAP3-KO)

Obsessions + Compulsions

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Behaviors

Methodological Approaches

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Behaviors Electrophysiology ?

Methodological Approaches

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Behaviors

Methodological Approaches

Electrophysiology Optogenetic

Opsine

Cl- K+ Na+

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Therapy Electrophysiology Behavior

Translational Approach

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What is the optogenetic technology?

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Chlamydomonas reinhardtii

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Activation du cycle cellulaire Channelrhodopsin (ChR2)

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Virus

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

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1st part: Optogenetic: Basic concepts and methodology

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

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3 pillars for spatial specificity:

  • Expression pattern of the opsin
  • Location of light delivery
  • Optical power
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(Aravanis et al, J Neural Eng, 2007)

Genetic expression specificity

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Promoter specificity approach

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

Cre-Lox System

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Transgenic Mouse Lines

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Injection of AAV-CamKII-Chr2 in OFC

OFC Striatum

OFC Striatum

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

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(Welch et al., Nature, 2007)

Light diffusion in brain tissue

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Local activation by laser stimulation

(Burguiere et al., Science, 2013)

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3 pillars for timing specificity:

  • Type of Opsins
  • Nature of the Light Source
  • Shutters
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(Yizhar al., Nature, 2007)

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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

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Problems: Not steady state before warming period Not reliable with TTL pulse

Diode-pumped Solid-State (DPSS) Laser

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An alternative: Mechanical shutters

…but noisy, specially at high frequency

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Light-emitting diode (LED)

Plus: Nearly linear electrical current to optical power output, Cheap, Easy to handle Minus: Power

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(Iwai et al., Neurosci Res 2011) ...but could be wireless

Conventional LED architecture…

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

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Psychiatric Diseases Symptoms Quantitative Behaviors Animal Models Compulsive Behaviors Obsessive Compulsive Disorders

Mouse model of OCD (SAPAP3-KO)

Obsessions + Compulsions

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Welch et al., Nature, 2007

SAPAP3-KO mice: Over-grooming behaviors Higher anxiety

Mouse model of OCD

Postsynaptic scalfolding protein that participates to the neurotransmission of cortical inputs

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Behaviors

Methodological Approaches

Working Hypothesis

Learning theories of human compulsive behavior suggest that repetitive behaviors can result from malfunction of a learning process leading to loss

  • f the ability to repress sensorimotor associations.
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X 50

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

Behaviour

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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)
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Behaviors Electrophysiology ?

Methodological Approaches

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Extracellular Recording Setup

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Hyperactivity in the striatum but not in the OFC

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Behaviors

Methodological Approaches

Electrophysiology Optogenetic

Opsine

Cl- K+ Na+

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Optogenetic Stimulation of the OFC-Striatal Pathway

OFC Striatum LFPs in OFC and Striatum

  • Injection of AAV-CamKII-Chr2 virus in lateral OFC
  • 3 weeks minimum of expression
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OFC Striatum LFPs in OFC and Striatum

  • Injection of AAV-CamKII-Chr2 virus in lateral OFC
  • 3 weeks minimum of expression

Optogenetic Stimulation of the OFC-Striatal Pathway

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OFC Striatum LFPs in OFC and Striatum

  • Injection of AAV-CamKII-Chr2 virus in lateral OFC
  • 3 weeks minimum of expression

Optogenetic Stimulation of the OFC-Striatal Pathway

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Optogenetic Modulation of the striatal activity

(Burguière et al., Science, 2013)

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PV-interneurons are reduced in SAPAP3-KO mouse

Silberberg and Bolam, Curr Op Neurobio 2015 Burguière E, Monteiro P, Feng G, Graybiel, Science, 2013

PV+ PV+ PV+ PV+ PV+ PV+ PV+ MSN MSN MSN

SAPAP3-KO

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Behavioral effects of OFC-striatal

  • ptogenetic stimulation
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Laser Stimulation (5Hz, 5ms pulse, 5mW) in homecage 3min ON/3min OFF during 30 min

Behavioral effects of OFC-striatal

  • ptogenetic stimulation
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Repetitive Behaviors

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

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Current questions

  • Are

the striatal PV-interneurons sufficient to reduce compulsive grooming ?

  • Can

we

  • ptimize

temporal specificity for preventing compulsive events?

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Practical example

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Current questions

  • Are

the striatal PV-interneurons sufficient to reduce compulsive grooming ?

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Creation of a new line of mice

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Current questions

  • Are

the striatal PV-interneurons sufficient to reduce compulsive grooming ?

  • Can

we

  • ptimize

temporal specificity for preventing compulsive events?

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Lizbeth Mondragon

250 60 15 4 1 Frequency (Hz) 250 60 15 4 1 Frequency (Hz) 250 60 15 4 1 Frequency (Hz) 250 60 15 4 1 Frequency (Hz) 250 60 15 4 1 Frequency (Hz) 250 60 15 4 1 Frequency (Hz)

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BaseLine Closed- Loop Prediction Yoked 2 min/bloc x 4 times = 36 min

Session:

29,97 11,70 21,6 0,00 5,00 10,00 15,00 20,00 25,00 30,00 35,00 40,00 45,00 % Time grooming

Grooming time (in s) - @10mW 5ms 20 HZ

Baseline CL-On Joked

(Error bars represent SEM, n=2, 6 Sessions, 36 min each)

N predictions = N random stimulations

Closed-loop stimulation

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Pathophysiology of Compulsive Disorders

Subthalamic Nucleus

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Subthalamic Nucleus

  • What are the effects of

electrical stimulation on the neuronal circuitry?

Pathophysiology of Compulsive Disorders

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  • What optogenetic approach could we use to mimic these 3

scenarii?

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Inhibitory Opsine Excitatory Opsine

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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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