#191 - Revolutionizing our understanding of mental illness with optogenetics | Karl Deisseroth M.D., Ph.D.
Dr. Karl Deisseroth, a world-renowned clinical psychiatrist and neuroscientist, discusses his journey to developing optogenetics, a revolutionary tool to control specific neurons with light. The episode explores how this technology provides causal insights into mental illnesses like depression, anxiety, and autism, and its potential for future treatments.
Deep Dive Analysis
22 Topic Outline
Introduction to Carl Deisseroth and Optogenetics
Carl's Early Academic and Medical Journey
Transformative Psychiatry Rotation at the VA
Balancing Psychiatry Residency and Research
State of Psychiatry and Brain Stimulation Treatments (2004)
Neuroscience Fundamentals: Neurons, Synapses, Brain Structures
Limitations of Traditional Brain Stimulation Techniques
The Genesis of Optogenetics: Microbial Opsins and Gene Delivery
Viruses as Tools for Genetic Engineering in Neurons
Achieving Cell-Type Specificity with Promoters
First Causal Experiment: Dopamine Neurons and Reward
Scientific and Clinical Adoption of Optogenetics
Investigating Anxiety with Optogenetics: Deconstructing its Features
Optogenetics Insights into Parenting Behaviors
Understanding Autism and Comorbid Anxiety
Optogenetics: A Discovery Tool for Future Treatments
Writing "Projections" and the Evolutionary Basis of Mental Illness
Mania and Bipolar Disorder: Symptoms and Adaptive Value
Depression and Anhedonia: Insights from Optogenetics
Mental Illness in Non-Human Primates and Suicide
Impact of Early Life Trauma on Mental Health
Evolutionary Logic of Emotional Tears
7 Key Concepts
Optogenetics
A revolutionary neuroscience technique that uses genetic engineering to insert light-sensitive ion channels (microbial opsins) into specific neurons. This allows researchers to precisely control the activity of these neurons (turn them on or off) using light, enabling causal studies of brain function.
Neurons
The fundamental cells of the brain, approximately 90 billion in humans, capable of generating and transmitting electrical impulses. They communicate via electrochemical processes across synapses, sending information through axons and receiving it via dendrites.
Synapse
The interface between two neurons where information is transmitted. An electrical impulse in the presynaptic neuron triggers the release of neurotransmitters, which then cross a tiny gap and act on receptors in the postsynaptic neuron, generating a new electrical signal.
Promoter/Enhancer
A specific sequence of DNA located near a gene that doesn't code for a protein but dictates whether that gene gets expressed (turned into RNA and then protein). This allows for cell-type specific gene expression, crucial for targeting specific neurons in optogenetics.
Immune Privilege of the Brain
A unique property of the brain where immune cells like T cells and B cells have restricted access. This is leveraged in optogenetics to prevent the immune system from attacking neurons expressing foreign light-sensitive proteins.
Conditioned Place Preference Test
An experimental paradigm used in animal research where an animal learns to associate a specific environment (e.g., a room) with a positive or negative experience. The animal's subsequent preference or aversion for that environment reveals the valence of the experience.
Anhedonia
A core symptom of depression characterized by the absence of pleasure or joy from activities or stimuli that would normally be rewarding. It's considered so significant that its presence can lead to a diagnosis of major depressive disorder even without depressed mood.
11 Questions Answered
Optogenetics is a technique that uses genetic engineering to insert light-sensitive proteins (opsins) into specific neurons. These opsins act as light-activated ion channels, allowing researchers to precisely turn neurons on or off using light, thereby controlling their activity.
Viruses are used as vectors to deliver the DNA encoding the light-sensitive opsin gene into neurons. These viruses are engineered to be safe and to specifically target certain cell types by incorporating promoters that ensure the opsin gene is only expressed in the desired neurons.
In 2009, an experiment used optogenetics to activate dopamine neurons in mice. When these neurons were activated in one room of a two-room house, mice developed a strong preference for that room, demonstrating that dopamine neuron activity is inherently rewarding.
Optogenetics has shown that different components of anxiety—such as physiological changes (faster heart rate, breathing), behavioral avoidance, and the subjective negative feeling—are controlled by distinct sets of neurons. This allows researchers to manipulate each component independently.
The human social world is complex and overwhelming for individuals with autism, who often struggle to process rapid social information and cues. This difficulty in predicting and navigating social interactions creates significant anxiety.
While there are some therapeutic applications (e.g., restoring sight in blind individuals), Karl Deisseroth believes optogenetics' most important role is as a discovery and understanding tool. It provides causal insights into brain function at the cellular level, which then informs the development of new treatments.
Anhedonia is the inability to experience pleasure from normally enjoyable activities, a core symptom of depression. Optogenetics has shown that overactivity in certain prefrontal cortical areas can suppress the brain's reward circuitry, leading to anhedonia in rodents.
Depression, particularly its passive, withdrawn, and low-energy aspects, may have an evolutionary basis similar to hibernation, allowing an organism to conserve energy and avoid futile effort in genuinely hopeless or challenging environments. The negative feeling associated with it remains a mystery.
Non-human primates can exhibit maladaptive states resembling grief or depression, such as losing the motivation to feed after losing a mother. However, there is no clear evidence of true volitional suicide in other species, likely due to the complex cognitive understanding of life and death required.
Early life trauma has clear and lasting psychiatric influences, extending to conditions like depression and personality disorders. It can lead to changes in brain circuitry and gene expression (epigenetics), causing individuals to expect a harsh and unpredictable world, leading to maladaptive coping mechanisms.
Emotional tears, a unique human trait, act as an involuntary 'truth channel' that signals distress and vulnerability. They powerfully trigger a desire to help in others within a social grouping, making them an evolutionarily advantageous social cue.
14 Actionable Insights
1. Prioritize What Matters Most
To manage stress from demanding professional roles, cultivate something in your personal life that matters more than anything else, as this perspective can help reduce stress related to work challenges.
2. Embrace Scientific Mystery
Approach profound mysteries, especially those causing human suffering, with a scientific mindset, viewing them as positive challenges to be understood and solved, rather than aversive problems.
3. Causal Understanding Drives Treatment
Recognize that understanding the causal cellular mechanisms of brain function and dysfunction is the foundational step that unlocks the design of all future targeted treatments, including medications and brain stimulation.
4. Prioritize Creative Work
Dedicate consistent, protected time (e.g., two hours daily, even at unconventional times) to creative or fulfilling work, relishing the process of finding the right word or phrase, as this can be incredibly uplifting.
5. Read “Projections” Book
Read Carl Deisseroth’s book “Projections” to understand and feel altered mental states like mania, schizophrenia, pathological grief, and eating disorders, as it reads like poetry and offers a remarkable journey into mental illness.
6. Use Evolutionary Lens
When trying to understand complex human conditions, especially mental illness, consider thinking about them through an evolutionary lens to gain deeper insights into their origins and persistence.
7. Deconstruct Social Interaction
Understand social interaction as comprising distinct components, such as motivation/drive and cognitive understanding/insight, which may be controlled by different neural circuits.
8. Define Disorder by Impairment
Understand that in psychiatry, a symptom is only considered a disorder if it impairs social or occupational functioning, ensuring that only conditions requiring treatment are addressed.
9. Monitor Bipolar Transitions
Be aware that the transition from depression to mania can be the most risky time for self-harm in individuals with bipolar disorder, as they gain energy to act while still experiencing negative feelings.
10. Recognize Adaptive Passivity
Understand that withdrawing or entering a passive coping state can be adaptively beneficial up to a point, helping to conserve energy or avoid futile effort in genuinely hopeless situations.
11. Seek Supportive Mentorship
When pursuing a demanding dual path like physician-scientist, seek out mentors and environments that understand and accommodate the unique challenges, such as unpredictable hours and conflicting commitments.
12. Work Nights and Weekends
To pursue a demanding dual career path, be prepared to work nights and weekends, even if it means missing regular meetings, to keep both professional and research threads alive.
13. Integrate Life’s Demands
Strive to integrate demanding professional and personal commitments, finding ways for different parts of your life to work together and be compatible.
14. Consider Career Lifestyle
When choosing a career, consider the lifestyle and time commitment required, as some demanding specialties may reduce opportunities for deep philosophical thought or personal freedom over time.
8 Key Quotes
We were two people with intact bodies and brains who were next to each other. And we inhabited completely different realities.
Karl Deisseroth
Essentially the entire field was unmoored from scientific understanding.
Karl Deisseroth
Viruses... are professional introducers of genetic material in the cells. They are extremely good at that. They are evolved for that.
Karl Deisseroth
If you deliver light, you can get an animal to press a lever thousands of times a day to get that light.
Karl Deisseroth
Anxiety is not a small thing. Anxiety can be absolutely crushing to one's life, to one's interactions, to occupation, to even being able to go out in the world.
Karl Deisseroth
We could make animals avoid the open area... But the mice didn't care that this was happening. There was no negative valence to it.
Karl Deisseroth
The ending of the self is an extremely cognitively complex thing.
Karl Deisseroth
When we see tears, we want to help that person.
Karl Deisseroth