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Peter Attia MDPeter Attia MD

191 - Revolutionizing our understanding of mental illness with optogenetics

Sign up to receive Peter's email newsletter: https://bit.ly/4c602k2 View show notes for this episode: https://bit.ly/3nxroak Karl Deisseroth is a world-renowned clinical psychiatrist, neuroscientist, and author of Projections: A Story of Human Emotions. In the episode, Karl explains his unique career path that led to the development of optogenetics—a revolutionary technique that uses specialized light-sensitive ion channels to precisely control the activity of select populations of neurons. Karl provides a concise overview of how optogenetics works and how it can be used to better understand mental illness, to identify the neurons responsible for specific behaviors, and to guide development of new treatments. Karl uses his experience as a practicing psychiatrist to provide deep insights into depression, anxiety, autism, and personality disorders and explains the role of optogenetics in mapping out brain regions responsible for common mental health afflictions. We discuss: 00:00:00 - Intro 00:00:10 - Karl’s journey through medical school and interest in the brain 00:14:51 - A profound medical school experience that changed Karl’s career path to psychiatry 00:25:07 - Karl’s commitment to research and challenges overcome early in his career 00:32:43 - The state of psychiatry and mental health therapies when Karl started his lab in 2004 00:38:13 - Neuroscience 101: fundamentals of neuroanatomy and neurophysiology 00:48:05 - Traditional techniques for identifying the brain regions involved in specific behaviors 00:52:30 - Intro to optogenetics and how to get a gene into a neuron 01:04:50 - How viruses helped make optogenetics possible 01:19:41 - How optogenetics was used to investigate the effects of dopamine neurons 01:27:02 - Appreciating the power of optogenetics 01:32:42 - Investigating and treating anxiety with optogenetics 01:45:12 - Autism and autism-related anxiety, and the potential of optogenetics in treating autism 01:52:41 - Optogenetics as a powerful tool for the discovery and creation of medical treatments 01:55:59 - Karl’s inspiration to write his book, Projections 02:01:44 - Mania and bipolar disorder: evolutionary basis, symptoms, and the high prevalence in North America 02:13:50 - Depression: evolutionary basis and insights from optogenetics 02:31:03 - The effects of trauma early in life -------- About: The Peter Attia Drive is a weekly, ultra-deep-dive podcast focusing on maximizing health, longevity, critical thinking…and a few other things. With over 35 million episodes downloaded, it features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more. Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (delay the onset of chronic disease), while simultaneously improving healthspan (quality of life). Learn more: https://bit.ly/3nxroak Subscribe to receive exclusive subscriber-only content: https://bit.ly/3rkeCwS Sign up to receive Peter's email newsletter: https://bit.ly/3A8PltK Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Podcasts: http://bit.ly/TheDriveGoogle

Peter AttiahostKarl Deisserothguest
Jan 17, 20222h 42mWatch on YouTube ↗

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At a glance

WHAT IT’S REALLY ABOUT

Karl Deisseroth traces optogenetics from psychiatry ward to mental illness insights

  1. Deisseroth describes switching from planned neurosurgery to psychiatry after a transformative rotation on a locked VA unit, then combining a research-track residency with a postdoc in Rob Malenka's lab while raising his son.
  2. He explains that psychiatry in 2004 lacked cell-specific tools, since ECT, vagus nerve stimulation, TMS and medications all act non-specifically and their mechanisms remain unclear.
  3. He details how optogenetics works, using light-activated microbial opsins, viral gene delivery, promoter-based cell targeting and the brain's immune privilege, with the approach solved by 2009.
  4. He recounts findings that complex states like anxiety, parenting, social interaction and depression break into separable features controlled by distinct cell types, and says optogenetics is chiefly a discovery tool that could guide future treatments.
  5. The conversation closes with the evolutionary logic of mania, depression and emotional tears from his book Projections, plus the lasting effects of early trauma.

IDEAS WORTH REMEMBERING

5 ideas

A locked-ward rotation redirected Deisseroth's career

Meeting a patient with schizoaffective disorder, whose reality differed completely from his own, showed him that the mystery of emotion in the brain was why he went to medical school, and he dropped neurosurgery.

Psychiatric treatments were unmoored from mechanism

Deisseroth says ECT, VNS, TMS and medications all act without cell-type specificity, so the field had effective but poorly understood tools and no precise causal handle.

Delivery and specificity were the hard part of optogenetics

The opsin proteins had been known for decades. The breakthroughs were viral gene delivery with many copies per cell, promoters borrowed from genes like tyrosine hydroxylase to target cell types, and the brain's immune privilege.

Complex mental states decompose into separate cell-based features

Optogenetics showed distinct cells control anxiety's breathing changes, avoidance behavior and negative feeling, and mice could show avoidance without negative valence. Similar separations appeared in parenting and social interaction.

Optogenetics is mainly a discovery tool, not a therapy

Deisseroth sees its main value as identifying which cells cause or relieve symptoms so medications and stimulation can be designed, though he cites Botond Roska conferring some sight on a blind person as a direct use.

WORDS WORTH SAVING

5 quotes

Viruses are professional introducers of genetic material into cells. They are extremely good at that. They are evolved for that.

— Karl Deisseroth

Optogenetics in my view is, is by far the most important aspect of it is it's a discovery and understanding tool.

— Karl Deisseroth

Depressed person thinks nothing's possible.

— Karl Deisseroth

It's a truth channel. It, it, it's not so easily gameable.

— Karl Deisseroth

We have to value the whole spectrum and understand the whole spectrum as part of who we are as, as the human family.

— Karl Deisseroth

Path from neurosurgery to psychiatryLimits of ECT, VNS, TMS and medicationsHow optogenetics and viral delivery workDopamine neurons and place preference experimentsAnxiety broken into separable componentsAutism, anxiety and social interaction circuitsEvolutionary basis of mania, depression and tears

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