By playing, you agree to uListen's Terms and Privacy Policy and YouTube's Terms of Service.
Peter Attia MD191 - Revolutionizing our understanding of mental illness with optogenetics
Summaries, chapters, transcripts, and FAQs on this page are made by uListen, not YouTube.
CHAPTERS
- 0:02 – 6:41
From Harvard Biochemistry to the MSTP and a Neurosurgery Plan
Peter Attia and Karl Deisseroth reconnect as Stanford med school classmates. Karl explains his undergraduate path, his early interest in the brain, his choice of the MD-PhD program, and why he aimed for neurosurgery.
- •Karl concentrated in biochemical sciences at Harvard, surrounded by theoretical physicist friends
- •He wanted to unite cells and biology with words, emotion and literature, and saw medicine as the route to the human brain
- •The MSTP let him keep both clinical and research threads alive
- •He picked neurosurgery as his first clinical rotation because neurosurgeons seemed to have the most direct access to the brain
- 6:41 – 14:18
Neurosurgery Rotations and the Pull of the Brain
Peter and Karl compare their early rotation experiences. Karl describes a thalamic neglect patient who drew half a clock, the awe of seeing exposed dura, and his observation that neurosurgery residents grew less able to philosophize over time.
- •Peter's pediatrics rotation went poorly, while general surgery clicked for him
- •Karl worked with a patient with neglect syndrome who drew only half a clock
- •He felt a spirituality in seeing the exposed brain
- •He noticed neurosurgery residents had less freedom to think deeply as training progressed
- •Peter recalled watching an awake brain procedure as an intern
- 14:18 – 25:07
The Locked Psychiatric Ward That Changed Karl's Path
Karl went into the required psychiatry rotation with a get-me-through-it attitude, but a locked VA unit transformed him. Meeting a patient with schizoaffective disorder, he saw suffering and mystery that connected to his question of what an emotion is physically, and he switched from neurosurgery to psychiatry.
- •Psychiatry still has no biomarker to define a patient's state
- •The locked unit showed severe disorders in a pure, acute form
- •Karl met a patient with schizoaffective disorder who inhabited a completely different reality
- •Peter contrasted the lack of tools in psychiatry with fixing a gunshot wound
- •Karl's scientific training made the mystery attractive, though his father was disappointed
- 25:07 – 33:14
Combining Psychiatry Residency, Lab Work, and Single Fatherhood
Karl describes the challenge of keeping a research career alive during residency. He did a research-track residency at Stanford alongside a postdoc in Rob Malenka's lab while raising his young son.
- •Stepping away from research for even a year makes it hard to catch up
- •He chose a research-track residency and worked nights and weekends in the lab
- •Rob Malenka, a psychiatrist and neuroscientist, understood his schedule
- •He sometimes took call from the lab while patch clamping
- •His son, born in 1996, gave him perspective and is now an MSTP student
- 33:14 – 38:14
The State of Psychiatric Treatment in 2004
As he started his lab in 2004, Karl saw that psychiatric treatments like ECT, vagus nerve stimulation, TMS and medications were effective only to a degree and were not understood or cell-type specific. This gap motivated the need for precise causal tools.
- •ECT is highly effective for treatment-resistant depression but often needs maintenance and its mechanism is unknown
- •Vagus nerve stimulation and TMS had small, inconsistent effects at the population level
- •Medications act throughout the brain without cell type specificity
- •The field was unmoored from scientific understanding
- 38:14 – 48:05
Neuroscience 101: Neurons, Synapses, and Brain Evolution
At Peter's request, Karl lays out neuroanatomy and neurophysiology. He covers neurons, axons, dendrites and synapses, the cortex versus deep ancestral structures across vertebrates, and neurons that release multiple neurotransmitters.
- •The brain has about 90 billion neurons communicating electrically and chemically across synapses
- •Deep structures like the hypothalamus and brain stem are conserved across vertebrates
- •Human cortex is a thin six-layer rind, and mice have a similar cortex
- •Dopamine neurons can also release glutamate or GABA
- 48:05 – 52:30
Limits of Electrodes and the Need for Cell-Type Specificity
Karl explains how electrodes could record and stimulate but affect every nearby cell and axon. Researchers could test sufficiency crudely but had no good way to turn cells off, so it was unclear which cells mattered for behavior.
- •Electrodes affect every electrical element near them, including passing axons
- •Rodents press levers thousands of times for stimulation near dopamine neurons, but the responsible cells were uncertain
- •Adding activity tests sufficiency, while removing it tests necessity
- •Inhibiting cells was crude and not cell-type specific
- 52:30 – 57:18
Microbial Opsins and the Idea Behind Optogenetics
Karl introduces channelrhodopsins, light-activated proteins from microbes that were known for decades. He explains why putting them into neurons only became plausible once genes could be delivered into neurons, and how Francis Crick had called for light-based control.
- •Microbial opsins receive a photon and move ions across the cell membrane
- •They were discovered in 1971 and taught in Stryer's biochemistry textbook
- •Delivering genes into neurons was the main obstacle until the late 1990s
- •Crick suggested in 1999 that light might control specific cell types
- 57:18 – 1:08:36
Using Viruses to Deliver Genes into Neurons
Karl explains DNA, RNA and viruses as professional gene deliverers, and how modified safe viruses carried opsin genes into neurons. He also covers the race with other labs, why high copy numbers were needed because opsin currents are tiny, and how dose affects expression.
- •Viruses are evolved to introduce genetic material into cells
- •Engineered viruses cannot propagate, so dose determines cell coverage and copies per cell
- •Opsins generate tiny currents, requiring roughly 100,000 to a million per cell to reach hundreds of picoamps
- •Karl's lab published first in 2005, with other labs submitting soon after
- 1:08:36 – 1:20:45
Targeting Specific Cell Types with Promoters and Avoiding Immune Attack
Focal viral injection gives spatial specificity, but cell-type specificity came from borrowing promoters, such as that of the dopamine-related tyrosine hydroxylase gene, to drive opsin expression. Karl also explains that the brain's immune privilege helps opsin-expressing cells avoid immune destruction.
- •Injecting a virus into a spot targets cell bodies rather than passing axons
- •Capsid engineering was plausible but not generalizable
- •Promoters and enhancers from cell-defining genes restrict opsin production to the target cell type
- •Solving generalizable targeting took until about 2009
- •The brain's immune privilege protects expression, while peripheral optogenetics loses expression over months
- 1:20:45 – 1:32:54
First Experiment: Dopamine Neurons and Place Preference
Karl describes the 2009 experiment activating VTA dopamine neurons with light in a two-room test. Mice preferred the room paired with stimulation and would press levers thousands of times, and Karl discusses the field's quick uptake and the funding.
- •Conditioned place preference showed mice preferred the room where dopamine neurons were light-activated
- •The test can show positive or negative valence
- •Animals will work extremely hard for light stimulation of dopamine neurons
- •Psychiatrists recognized the value immediately, and the DNA clones were sent to thousands of labs
- •Early funding was hard but then came from NIMH, NIDA, DARPA, NSF, and private donors
- 1:32:54 – 1:52:42
Dissecting Anxiety, Parenting, and Social Behavior
Karl explains that anxiety has separable physiological, behavioral, and negative-valence components, and that optogenetics in 2013 showed distinct cell sets control each. Similar work by Catherine Dulac broke parenting into parts, and this leads into anxiety in autism and the prospects for treatment.
- •Psychiatric disorders require impaired social or occupational functioning
- •Different cells control breathing changes, avoidance behavior, and the negative feeling of anxiety
- •Mice could be made to avoid open spaces without the negative valence
- •Catherine Dulac's lab separated retrieving young from grooming them
- •Anxiety in autism relates to information overload in social interaction, and optogenetics identified cells that improve social interaction in mice
- 1:52:42 – 2:01:43
Optogenetics as a Discovery Tool and the Book Projections
Karl says optogenetics matters most as a tool for understanding which cells cause symptoms, which then opens the door to medications and targeted stimulation. He mentions Botond Roska's work restoring some sight, then Peter praises Karl's book Projections and Karl describes how he wrote it.
- •Understanding causal cells opens the door to every kind of treatment
- •Botond Roska conferred a form of sight on a blind person using optogenetics
- •Karl wanted readers to feel altered states, adapting the writing style to each story
- •He wrote the bulk of the book from 2017 to 2020 in blocked-out time around a busy family life
- 2:01:43 – 2:14:24
Mania, Bipolar Disorder, and Evolutionary Perspectives
Prompted by the story of Alexander in the book, Peter shares his own hypomania diagnosis and a theory linking hypomania to immigrant populations. Karl discusses the genetics of bipolar disorder, the features of mania, its possible adaptive value, and open questions about why depression pairs with it.
- •Alexander developed full-blown mania after 9/11 with no prior psychiatric or family history
- •Bipolar type 1 shows over 50%, verging on 70%, twin concordance
- •Mania involves elevated mood, energy, risk-taking, and little need for sleep, and can be dangerous
- •Sustained energy may have helped people who migrate and take life risks
- •Why mania is paired with depression is unknown, and anxiety disorders are the most common psychiatric disorders
- 2:14:24 – 2:31:03
Depression: Anhedonia, Hopelessness, and Evolutionary Speculation
Karl describes the components of depression, including depressed mood, hopelessness, and anhedonia, and how optogenetics in rodents has linked prefrontal overactivity to reduced reward. He offers a speculative evolutionary view of depression as adaptive passivity and discusses depression in primates and the absence of suicide in animals.
- •Anhedonia is so central that major depression can be diagnosed with it even without depressed mood
- •Stressed mice lose their preference for sugar water
- •Overactive frontal cortex can cause anhedonia in rodents by suppressing dopamine reward circuitry
- •Giving-up behavior in an inescapable situation models hopelessness
- •Karl speculates depression may resemble hibernation-like passivity, while non-human primates show grief-like states but no suicide model exists
- 2:31:03 – 2:42:05
Early-Life Trauma and the Evolutionary Basis of Tears
Peter raises Paul Conti's book on trauma, and Karl discusses the lasting effects of early trauma through circuit wiring and epigenetic mechanisms, with intergenerational transfer still controversial. Karl then discusses emotional tears as a human trait and an involuntary signal that prompts others to help, before the conversation wraps up with plans to discuss psychedelics next time.
- •Early-life trauma has lasting psychiatric effects, extending to personality disorders like borderline
- •Possible mechanisms include circuit wiring, transcription-factor changes, and intergenerational effects
- •Emotional tears appear to be uniquely human and trigger a desire to help
- •Tear ducts sit near breathing-control regions, so a small rewiring could link emotion to tears
- •Peter and Karl plan a future conversation covering personality disorders and psychedelics
