#191 - Revolutionizing our understanding of mental illness with optogenetics | Karl Deisseroth M.D., Ph.D.

Episode Summary

Executive Summary: Peter Attia interviews psychiatrist-neuroscientist Carl Deisseroth about his path from neurosurgery to psychiatry, the invention of optogenetics, and how cell-type-specific light control transformed neuroscience. They explore brain anatomy, neurotransmission, and how optogenetics clarified circuits underlying reward, anxiety, autism, depression, and mania, while also discussing Deisseroth’s book Projections and the evolutionary logic of mental illness.

Main Topics: Deisseroth’s training path and shift from neurosurgery to psychiatry (Priority: 5/5): He describes entering medicine to connect brain biology with human emotion, initially aiming for neurosurgery, then pivoting after a transformative locked-ward psychiatry rotation that revealed the mystery and suffering of mental illness. Brain organization and neurophysiology (Priority: 5/5): Deisseroth explains neurons, synapses, neurotransmitters, and the layered organization of the brain, contrasting ancient deep structures like the brainstem and hypothalamus with the elaborated cortex. How optogenetics was made possible (Priority: 5/5): The conversation details the technical breakthroughs that enabled optogenetics: microbial opsins, viral gene delivery, promoter-based cell-type targeting, and the use of light to activate or silence specific neurons. Optogenetics as a causal tool for neuroscience (Priority: 5/5): Deisseroth argues that optogenetics solved a central problem in neuroscience by allowing precise tests of sufficiency and necessity at the level of defined cell types, rather than broad brain regions. Circuit-level understanding of anxiety, depression, and social behavior (Priority: 5/5): They discuss how optogenetics separated different components of anxiety and depression, and how distinct circuits influence social motivation, cognition, anhedonia, and hopelessness. Autism, comorbidity, and future treatment directions (Priority: 4/5): Deisseroth explains why anxiety is common in autism, how social information overload may contribute, and why the field still lacks direct treatments for core autism symptoms despite improved circuit-level understanding. Projections, writing, and the evolutionary basis of mental illness (Priority: 4/5): The discussion turns to Deisseroth’s book Projections, which uses literary storytelling to convey altered mental states and explores evolutionary hypotheses for mania, depression, tears, and trauma.

Key Arguments: Optogenetics became possible only when three barriers were solved together: reliable gene delivery into neurons, cell-type-specific expression using promoters/enhancers, and sufficient opsin expression to generate meaningful currents. The major value of optogenetics is not as a routine therapy but as a discovery tool that establishes causal links between specific cell types and behavior, which then informs future drugs and stimulation therapies. Psychiatric disorders are best understood as composed of separable features; for example, anxiety includes physiology, avoidance behavior, and negative valence, which can be controlled by different circuits. Depression similarly contains distinct components such as anhedonia, hopelessness, and negative mood, and optogenetics has shown that some of these can be dissociated in animal models. Autism-related anxiety may arise because social interaction is a high-information, high-uncertainty environment that is difficult to predict and process, especially when social cognition is impaired. Mania and depression may have evolutionary roots as extreme ends of adaptive traits: sustained energy, risk-taking, withdrawal, and conservation of resources can be useful in certain contexts but become pathological when dysregulated. Trauma can produce lasting psychiatric effects through circuit changes, gene-expression changes, and possibly intergenerational mechanisms, though the latter remains controversial in humans. The brain’s immune privilege was crucial for optogenetics in the CNS, helping avoid immune rejection of foreign opsin proteins that would be more problematic in peripheral tissues.

Data Points: Lasker award recognition: Awarded "just this month" before the interview - Deisseroth received the prestigious Lasker award for optogenetic research. Lasker-to-Nobel historical conversion: About 50% - Attia notes roughly half of Lasker winners later win the Nobel Prize. Optogenetics first paper timing: 2005 - Deisseroth says his lab published the first paper using a microbial opsin to confer light sensitivity in 2005. Key generalization milestone: 2009 - By 2009, the promoter-based targeting strategy made optogenetics broadly generalizable and versatile. Approximate neuron count in the human brain: 90 billion - Used to illustrate the scale and complexity of brain wiring. Cortex thickness: A few millimeters - Deisseroth describes the cortex as a thin surface rind with six layers. Number of cortical layers: 6 - Human cortex is organized into six distinct layers of cells. Opsin copy number needed per cell: ~100,000 to 1,000,000 copies - High expression was needed to generate currents large enough to control neurons. Typical action potential triggering current: 100 to 200 picoamps - Deisseroth explains the approximate current range needed to drive neuronal firing. Typical reward preference in conditioned place tests: 70/30 to 80/20 - Mice typically prefer the chamber paired with reward or optogenetic dopamine activation. Bipolar type I twin concordance: Above 70% - Used to illustrate strong genetic determination of bipolar disorder. Depression twin concordance: About 50% - Deisseroth cites this as evidence of substantial heritability. Autism twin concordance: Just under bipolar type I - Presented as highly heritable, though not fully deterministic. ECT durability: About 3 months - Some patients require maintenance ECT after the initial benefit wanes. Interview length: About 2.5 hours - Attia notes they ran out of time after roughly two and a half hours. Deisseroth’s son’s birth year: 1996 - Mentioned in the discussion of balancing family and residency/lab work. Writing period for Projections: 2017 to 2020 - Deisseroth says he wrote the bulk of the book over a couple of years and finished in 2020.

Pivotal Quotes: "This tool is referred to as optogenetics." — Peter Atiyah: Attia introduces the central scientific breakthrough that the episode is built around. "This was actually why I came to medical school." — Carl Deisseroth: He reflects on realizing during psychiatry rotation that he wanted to understand emotion and feeling at the level of cells. "Optogenetics, in my view, is by far the most important aspect of it is it's a discovery and understanding tool." — Carl Deisseroth: He explains how he sees the technology’s primary role in neuroscience and psychiatry.

Implications: Optogenetics has shifted psychiatry and neuroscience from broad, nonspecific interventions toward circuit-level causality. For listeners, it suggests future treatments will likely be more targeted, while the technology itself remains most powerful as a discovery platform.