What were the limitations of traditional neuroscience tools before optogenetics?

Before optogenetics, tools like electrodes could listen to or stimulate neurons, but lacked cell-type specificity. Sending electrical currents into the brain affected all nearby neurons and their wiring indiscriminately, making it difficult to establish causal links between specific cell types and behaviors or emotions.

What are microbial opsins and how are they relevant to optogenetics?

Microbial opsins are light-activated electricity-generating proteins found in single-celled algae and ancient bacteria. Carl Deisseroth and his team realized these proteins could be genetically introduced into neurons to make them light-sensitive, providing the 'digital switch' needed for cell-type specific control.

How did Carl Deisseroth achieve cell-type specificity with optogenetics?

He used modified viruses to deliver the opsin gene into neurons. Crucially, he employed specific 'promoters' or 'enhancers' – bits of DNA that determine when and where a gene is expressed – from genes unique to particular neuron types (e.g., dopamine-producing enzymes). This ensured the opsin was only made in the targeted cells, like dopamine neurons, even if the virus infected others.

Why doesn't the immune system reject the foreign opsin proteins in the brain?

The brain is an 'immune-privileged' organ, meaning T cells and B cells, which normally patrol the body for foreign invaders, have limited access to it. This unique characteristic of the brain allows the opsin proteins to be expressed without triggering a significant immune response that would destroy the genetically modified neurons.

What was the first major discovery made using optogenetics regarding dopamine neurons?

The first major experiment, conducted in 2009, showed that directly activating dopamine neurons in the ventral tegmental area (VTA) of mice using light could induce a 'conditioned place preference.' Animals would actively seek out and spend time in environments where their dopamine neurons were stimulated, proving a causal link between dopamine neuron activity and positive reinforcement/reward.

How did optogenetics reveal the multi-component nature of anxiety?

By targeting different cell types within the anxiety pathway, optogenetics showed that anxiety is not a monolithic state. Researchers could selectively control distinct features like physiological changes (e.g., breathing), behavioral avoidance (e.g., avoiding open spaces), and the negative subjective feeling (negative valence) independently in mice, suggesting different neural circuits govern each component.

What is the relationship between autism and anxiety?

Patients with Autism Spectrum Disorder (ASD) frequently experience high levels of anxiety. This co-occurrence is thought to stem from the overwhelming and confusing nature of human social interactions for individuals with ASD, leading to difficulty predicting outcomes and increased anxiety in social settings.

Will optogenetics be a direct treatment for mental illness in the future?

While there have been exciting direct therapeutic applications, such as restoring sight in a blind person with retinal degeneration, Carl Deisseroth primarily views optogenetics as a powerful discovery and understanding tool. The insights gained into specific cells and circuits causing symptoms can then guide the design of more targeted medications and brain stimulation therapies.

What is Carl Deisseroth's book 'Projections' about?

'Projections: A Story of Human Emotions' is a book where Carl Deisseroth aims to help readers understand and feel various altered mental states, from the exuberance of mania to the fragmentation of schizophrenia. It blends scientific explanations with evocative writing and personal patient stories.

What is the hypothesized evolutionary basis for depression?

One theory suggests that the passivity and withdrawal associated with depression might have had adaptive value in certain evolutionary contexts, similar to a 'hibernation' state during harsh times (e.g., winter). By reducing energy expenditure and seeking less, an organism might conserve resources. However, the 'negative aspect' or psychic pain of depression remains harder to explain evolutionarily.

Do non-human primates experience depression or suicide?

Non-human primates can exhibit maladaptive states resembling grief, such as a young primate dying after losing its mother due to a loss of motivation. However, there is no clear evidence of true volitional suicide in non-human animals, possibly because the act requires a complex cognitive understanding of self and mortality that may be unique to humans.

What is the evolutionary purpose of emotional tears?

Emotional tears, unique to humans among great apes, are thought to be a powerful, largely involuntary social signal. They can trigger a strong desire in observers to help the person crying, serving as a 'truth channel' of distress or need within social groups, fostering care and support.

Key Moments

191 - Revolutionizing our understanding of mental illness with optogenetics

Peter Attia MD

Science & Technology4 min read163 min video

Jan 17, 2022|25,479 views|596|45

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Key Moments

TL;DR

Optogenetics allows precise control of neurons, revolutionizing mental illness research and understanding.

Key Insights

Optogenetics uses light-sensitive proteins to control specific neurons, offering unprecedented precision in neuroscience research.

Karl Deisseroth's career path, influenced by a pivotal psychiatry rotation, led him to combine clinical practice with neuroscience research.

The development of optogenetics required overcoming technical challenges in gene delivery to neurons and achieving cell-type specificity.

Early experiments with optogenetics confirmed the positive valence of dopamine neuron activity, previously inferred through behavioral studies.

Optogenetics has enabled the dissection of complex behaviors like anxiety and parenting into distinct, controllable features.

The technology is crucial for understanding the biological underpinnings of mental illnesses like depression and autism, paving the way for targeted treatments.

Deisseroth's book, 'Projections,' uses evocative writing to convey the subjective experiences of altered mental states, making complex conditions accessible.

A UNIQUE PATH FROM NEUROSURGERY TO PSYCHIATRY

Karl Deisseroth recounts his early fascination with the brain, initially drawn to neurosurgery for its direct access to the organ of thought and emotion. However, a transformative psychiatry rotation in a locked ward, confronting severe mental illness, shifted his focus. Witnessing profound suffering and the limitations of current treatments, he realized the urgent need for deeper scientific understanding and novel tools to unravel the complexities of the mind.

THE BIRTH OF OPTOGENETICS: A TECHNOLOGICAL LEAP

The development of optogenetics, a technique allowing precise control of neuronal activity using light, was a confluence of existing knowledge and technological advancement. Deisseroth leveraged research on light-sensitive microbial opsins, known for decades, and combined it with breakthroughs in viral gene delivery. This enabled the insertion of genes for these opsins into specific neurons, effectively creating light-activated 'digital switches' within the brain.

OVERCOMING TECHNICAL HURDLES FOR CELLULAR SPECIFICITY

Translating the concept of optogenetics into a usable tool involved overcoming significant technical challenges. A key hurdle was achieving cell-type specificity; simply introducing genes wasn't enough as many cell types exist intermingled. The solution involved using promoter and enhancer DNA sequences unique to specific cell types, ensuring that the light-sensitive opsin gene was only expressed in the targeted neurons, a breakthrough that solidified the technology's versatility.

EARLY EXPERIMENTS AND THE DAWN OF CAUSAL UNDERSTANDING

Initial experiments with optogenetics focused on fundamental questions, such as the role of dopamine neurons in reward. By selectively activating dopamine neurons in mice, researchers demonstrated a clear behavioral preference for the stimulated environment, providing direct causal evidence for dopamine's role in positive valence. This confirmed long-held hypotheses and showcased optogenetics' power to establish causality, moving beyond correlational observations.

DISSECTING COMPLEX BEHAVIORS: ANXIETY AND PARENTING

Optogenetics has been instrumental in dissecting complex behaviors into their constituent neural components. Studies on anxiety revealed that different neuronal populations control distinct features, such as physiological changes, behavioral avoidance, and the subjective negative valence. Similarly, research on parenting demonstrated that actions like finding offspring and grooming them are governed by separate neural circuits, highlighting the modular nature of complex mammalian states.

IMPLICATIONS FOR MENTAL ILLNESS: FROM AUTISM TO DEPRESSION

The precision of optogenetics offers profound insights into mental illnesses like autism and depression. For autism, it helps understand the anxiety often co-occurring with social deficits, potentially by illuminating how sensory information processing is altered. In depression, it has shed light on anhedonia and hopelessness, identifying specific neuronal pathways, including those involving dopamine and the prefrontal cortex, that contribute to these debilitating symptoms and could guide future therapeutic strategies.

THE POWER OF 'PROJECTIONS': BRIDGING SCIENCE AND SUBJECTIVITY

Deisseroth's book, 'Projections: A Story of Human Emotions,' aims to make the subjective experience of mental illness accessible to a broader audience. Through evocative and diverse writing styles tailored to each condition, he illustrates states like mania, schizophrenia, and eating disorders. This narrative approach, rooted in scientific understanding but expressed with literary flair, bridges the gap between complex neurobiology and the deeply personal reality of mental health challenges.

EVOLUTIONARY PERSPECTIVES ON MENTAL STATES

The discussion explores the evolutionary basis of various mental states, including mania and depression. Mania, characterized by elevated energy and risk-taking, is posited to have conferred advantages in historical contexts, such as migration. Depression, though seemingly counter-evolutionary, might serve adaptive functions of withdrawal or energy conservation during harsh conditions, though its extreme negative valence remains a puzzle. Understanding these evolutionary roots is crucial for comprehending their biological underpinnings.

THE FUTURE OF TREATMENT: FROM DISCOVERY TO THERAPY

While optogenetics is primarily a discovery tool, its insights are paving the way for novel treatments. By identifying specific cell types and circuits involved in disease, researchers can design targeted medications or brain stimulation therapies. Although direct optogenetic interventions are still largely experimental, recent successes in restoring vision in blind individuals demonstrate its therapeutic potential. The ultimate goal is to translate fundamental understanding into effective clinical interventions for a range of psychiatric disorders.

Mentioned in This Episode

●Software & Apps

●Organizations

●Books

●Concepts

●People Referenced

Common Questions

Carl initially pursued neurosurgery to gain direct access to the human brain, but a mandatory psychiatry rotation at the VA hospital, specifically in the locked unit, exposed him to the profound suffering and mystery of severe mental illness, which completely changed his career path. He saw it as a profound scientific mystery to be solved.

Topics

Neuroscience & the Brain Mental Health & Psychology Science & Mathematics Evolutionary Psychology Bipolar Disorder Brain Stimulation Mental Illness Research Autism Spectrum Disorders Genetics Of Mental Illness

Mentioned in this video

Concepts

MD PhD Program

A dual degree program combining medical and doctoral studies, highly selective and preparing students for physician-scientist careers.

Ventral Tegmental Area

A midbrain region containing dopamine neurons, targeted in early optogenetics experiments to study reward and motivation.

Autism Spectrum Disorder

A neurodevelopmental disorder clinically focused on by Dr. Deisseroth, characterized by social interaction difficulties and often co-occurring with anxiety.

anhedonia

A core symptom of depression, described as the absence of pleasure or joy from activities that normally bring it, studied using optogenetics to understand its neural basis.

Optogenetics

A breakthrough technology that uses light to control genetically modified neurons, enabling precise, cell-type specific manipulation and causal study of brain function.

Bipolar I Disorder

A highly genetic psychiatric disorder characterized by at least one manic episode, often paired with depressive episodes.

neuroscience

The scientific study of the nervous system, focusing on understanding brain function at the cellular and systems level.

Major Depressive Disorder

A psychiatric disorder diagnosed based on symptoms including anhedonia, hopelessness, and depressed mood, which optogenetics has helped to study at a cellular level.

Books

Nature Medicine

A scientific journal where Botond Roska's work on restoring sight using optogenetics was published.

Projections: A Story of Human Emotions

Carl Deisseroth's book, praised for its accessible and artistic exploration of altered mental states, blending scientific insight with personal stories.

Organizations

Stanford University

The institution where the host and guest attended medical school, and where Dr. Deisseroth later conducted his research and residency.

People

Catherine Dulac

A researcher at Harvard who used optogenetics to dissect parent-infant interactions in mice, showing distinct neural circuits for different parenting behaviors.

Paul Conti

A mutual medical school friend and colleague who also chose psychiatry, recently authored a book on trauma.

Francis Crick

Co-discoverer of the DNA double helix, who in 1999 suggested the need for cell-type specific neural control using light, foreshadowing optogenetics.

Botond Roska

A colleague of Carl Deisseroth who used optogenetics to restore a form of sight to a blind person suffering from retinal degeneration, published in Nature Medicine.

Studies & Research

Harvard University

The institution where Carl Deisseroth completed his undergraduate studies, majoring in biochemical sciences.

Supplements

Benzodiazepines

A class of anti-anxiety medications (e.g., Valium, Xanax, Ativan) that work by enhancing GABAergic neurotransmission but can be addictive and cause side effects.

Software & Apps

Conditioned Place Preference Test

A behavioral test used in animal models to assess the rewarding or aversive value of a stimulus by observing an animal's preference for a specific environment.