Revolutionizing our Understanding of Mental Illness with Optogenetics
Attia explores Karl Deisseroth’s pioneering work in clinical psychiatry and neuroscience, focusing on his development of optogenetics—a revolutionary technique for controlling neural activity. Karl discusses its applications in understanding mental illness, identifying neurons related to behaviors, and guiding new treatments. Attia delves into the intersection of psychiatry and optogenetics to uncover insights into various mental health disorders.
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Intro
- Carl and Peter were friends in med school at Stanford
- Carl was in the MDPhD program, which is highly selective
- Carl majored in biochemical sciences at Harvard
- Carl was interested in the brain and wanted to understand it at the cellular level
- Carl initially wanted to go into neurosurgery to have direct access to the human brain
- Carl did his PhD in the same lab as two other friends of Peter’s
- Peter initially wanted to do pediatric oncology but didn’t enjoy it
- Peter fell in love with neurosurgery during a rotation at Hopkins
- Carl enjoyed his neurosurgery rotation and found it fascinating
- Carl noticed a decline in willingness to philosophize among neurosurgery residents as they progressed through their training
Psychiatry Rotation Experience - Initially had a “get me through it” attitude
- Rotation in the locked unit at the VA Hospital
- Patients with severe mental illnesses
- Exposure to acute schizophrenia, schizoaffective disorder, etc.
- Transformative experience
- Witnessed immense suffering and disability
- Intrigued by the difference in realities between patient and doctor
- Compelled by the mystery of emotions and feelings in the brain
Decision to Pursue Psychiatry
- Shift from neurosurgery to psychiatry
- Driven by the desire to understand and solve the mysteries of the brain
- Motivated by the instinct to help and heal
- Acknowledged that current tools and treatments were limited
- Hoped for progress in science and medicine to improve patient care
- Adjustment period
- Had to reshape personal and professional trajectory
- Friends and family had to adjust their expectations
- Ultimately found fulfillment in pursuing psychiatry
Balancing Residency and Research
- Residencies were demanding, especially 20 years ago
- Research moves quickly, stepping aside for even a year can make it difficult to catch up
- MD-PhD students often face the hard choice between focusing on being a physician or a researcher
- Research track residencies help keep scientific minds alive during residency, but not enough to gain momentum
Personal Challenges
- Balancing residency, lab work, and being a single father
- Having a child helped prioritize what mattered most and reduced stress from lab and clinic work
Setting Up a Lab
- Lab started to be set up in 2004, hit full steam between 2006 and 2009
- Clinical training and residency shaped the problems to be solved in the lab
Psychiatry Treatments and Their Limitations
- Electroconvulsive therapy (ECT) is effective for treatment-resistant depression but has side effects and is not a permanent fix
- Vagus nerve stimulation and transcranial magnetic stimulation had small effects on the population level and were not fully understood
- No medications fully understood in terms of their mechanisms of action
The Need for Basic Science
- Psychiatry field was unmoored from scientific understanding
- No specific way of causing something to happen to a particular kind of cell
- Goal: build an approach to provide precise causality and understanding of brain structure and cells
Neuroanatomy and Neurophysiology - The brain has approximately 90 billion neurons
- Neurons are complex, self-contained units that generate electricity
- Neurons send information through axons (outgoing connections) and receive information through dendrites
- The interface between neurons is called a synapse, where information is transmitted through chemicals
- The brain has conserved deep structures (e.g., hypothalamus) and a more advanced cortex in humans
Brain Layers and Evolution
- Vertebrates (e.g., fish, mice, humans) share a basic brain plan
- Evolution has scaled up the brain and added new structures
- The cortex is a thin layer on the surface of the brain, responsible for complex cognitive functions
- Deeper structures, like the hypothalamus, govern primary needs (e.g., salt balance, avoiding danger, mating, sleeping, thermoregulation)
Brain Stem and Neurons
- The brain stem is highly conserved across vertebrates
- Neurons can release multiple neurotransmitters (e.g., dopamine, serotonin, glutamate, GABA)
- Neurons can also release neuropeptides
- Different cells have different receptors for chemicals, leading to various effects
Establishing Causality in Brain Function
- Prior to recent advancements, electrodes were used to listen to and stimulate neurons
- This method lacked cell specificity, as all neurons are electrical
- Stimulating regions of the brain provided some information, but uncertainty remained regarding which cells were responsible for specific functions
- Turning off specific neurons was also a challenge
Optogenetics and Channelrhodopsins - Optogenetics: technology that allows for cell type-specific control using light
- Channelrhodopsins: light-activated proteins found in single-celled algae and bacteria
- Known since 1971, discovered by Dieter Osterhelt and Walter Stokenius
- Receive a photon of light and move charged particles (ions) across the cell membrane
- Late 1990s: better ways to introduce genes into neurons developed
- Viruses used to introduce DNA or RNA into cells
- Safe, modified viruses used to shuttle DNA into cells without further propagation
Introducing Genes into Neurons
- DNA: instruction manual for making proteins
- Each gene is a sequence of nucleotides (A, G, C, T)
- The order of nucleotides dictates which protein will be made
- RNA: intermediate step between DNA and protein
- Viruses: professional introducers of genetic material into cells
- Some work with DNA, some with RNA
- Evolved to introduce genetic material into cells
- Safe, modified viruses used to introduce genes into neurons
- Dose of virus determines how many cells will pick up the channel
- Higher concentration of viral particles results in more cells being affected
Optogenetics and Viral Gene Introduction
- Optogenetics: using light to control neurons
- Viral gene introduction: using viruses to introduce genes into cells
- Can get hundreds or more copies of the gene per cell
- Generates bigger currents with microbial options
- Challenges in targeting specific cell types
- Engineering virus capsid proteins to target specific cells
- Difficult due to lack of understanding of cell surface proteins
- Using promoters and enhancers in DNA
- Define cell types by their jobs (e.g., dopamine-producing cells)
- Borrow promoters from specific genes (e.g., tyrosine hydroxylase gene for dopamine)
- Put the promoter in front of the channelrhodopsin gene and package it into a virus
- Inject the virus into cells, and the gene is only expressed in the targeted cells
- Engineering virus capsid proteins to target specific cells
Immune System Response to Viral Gene Introduction
- Immune system recognizes foreign antigens presented on the surface of infected cells
- How to prevent the immune system from destroying cells with introduced genes?
- Potential strategies include:
- Using immunosuppressive drugs to reduce immune response
- Modifying viral vectors to reduce immunogenicity
- Using non-viral methods for gene delivery
Optogenetics and Dopamine Neurons
- Potential strategies include:
- Optogenetics: a technique that allows scientists to control specific neurons using light
- In 2009, researchers used optogenetics to study dopamine neurons in mice
- Introduced excitatory channelrhodopsin into dopamine neurons in the ventral tegmental area (VTA)
- Tested mice in a two-room house, activating dopamine neurons with light in one room only
- Mice preferred the room where the light was applied, showing positive valence
- Conditioned place preference test: an old test where animals reveal their preference for positive or negative experiences based on where they choose to spend time
- Can be adapted to make animals work for light by pressing a lever or poking their nose in a hole
- Mice will work hard for light that activates dopamine neurons, showing the activity is positive and valuable
Appreciation of Optogenetics in Psychiatry
- Scientific psychiatry community quickly appreciated the potential of optogenetics
- Recognized the need for specificity in the field
- By 2009, the generality of targeting methods made the technique widely applicable
- Thousands of labs around the world adopted optogenetics, leading to many discoveries
- Funding for optogenetics research came from various sources, including NIH, DARPA, National Science Foundation, and private donors
Anxiety and Psychiatry - Anxiety can be normal or maladaptive
- Normal anxiety has an evolutionary basis for self-preservation
- Maladaptive anxiety impairs social or occupational functioning
- Anxiety disorders are treated with medications like Valium, Xanax, and Adavan
- Effective but can be addictive and cause cognitive slowing and sedation
- Work through GABA agonism, but specific neurons targeted are not well understood
Optogenetics and Anxiety
- Anxiety has different components: physiology, behavior, and negative valence
- Optogenetics experiments in 2013 targeted different parts of the anxiety pathway
- Different cells control each component of anxiety
- Behavioral avoidance of anxiety can be separated from negative valence in mice
Optogenetics and Parenting
- Catherine Dulac at Harvard used optogenetics to study parenting in mice
- Parenting broken down into sub-features: retrieving young and grooming them
- Different cells control each aspect of parenting
Autism and Anxiety
- Autism has a significant genetic component and a wide spectrum of functionality
- Anxiety often tracks closely with autism, but the exact relationship is not well understood
Autism and Anxiety - Autism is a complex condition with no specific medication to treat it
- Anxiety is a common comorbid symptom in people with autism
- Social interactions are complicated and can be overwhelming for those with autism
- Difficulty in keeping up with the fast rate of social information and making sense of it
- Anxiety in autism can be treated with medications like benzodiazepines
Autism and Genetics
- Autism has a strong genetic component, but it involves many different genes
- The genetic underpinnings are complex and have not yet led to specific treatments
Future Autism Treatments
- Optogenetics has provided a window into potential autism treatments
- Studying social interaction in mice with autism-related mutations
- Identifying specific cells and circuits in the brain that can improve social interaction
- Future treatments may involve medications designed to target specific cells important for social interaction
Optogenetics as a Treatment Tool
- Optogenetics is primarily a discovery and understanding tool
- Helps identify causal cellular relationships in the brain
- Opens doors for various treatment options, including medications and brain stimulation
- Optogenetics has been used to restore some sight in a blind person, but its primary importance is as a discovery tool
Projections: A Book on Mental Illness
- The book “Projections” by Dr. Karl Deisseroth explores various mental illnesses through an accessible and artistic writing style
- The goal is to help readers understand and feel what altered states like mania, schizophrenia, and eating disorders might be like
- The writing style is adapted in each chapter to evoke the feeling of the specific mental state being discussed
Writing Process and Personal Experience with Psychiatry - Author’s passion for writing and sharing knowledge
- Wrote the book between 2017 and 2020
- Looked forward to writing sessions, enjoyed finding the right words and phrases
Evolutionary Basis for Mental Illness
- Discussion of mania and its evolutionary basis
- Connection between recent immigrants and higher prevalence of hypomania in North America
- Bipolar disorder is highly genetic, with strong links to other psychiatric disorders
- Monozygotic twins have a high concordance rate for bipolar type one, autism, depression, and schizophrenia
Mania and Bipolar Disorder
- Mania is the positive pole of bipolar disorder, with depression being the negative pole
- Manic episodes can be characterized by elevated mood, increased goal-directed activity, risk-taking, and reduced need for sleep
- Mania can lead to poor decisions and self-harm, especially during the transition from depression to mania
- Some people with bipolar disorder may not experience depression, but most do
Spectrum of Mania and Hypomania
- Hypomanic state may be beneficial for immigrants who need sustained energy and motivation to adapt to new environments
- Mania and hypomania exist on a spectrum, and understanding the full spectrum is important for understanding human behavior
Depression and Bipolar Disorder
- The reason for the pairing of depression and mania in bipolar disorder is not well understood
-
Possible explanations include the exhaustion of neural resources or a neural circuit state that becomes depleted over time
Optogenetics and Depression - Anxiety disorders are the most common psychiatric disorders, followed by depression
- Depression has various components:
- Depressed mood
- Hopelessness
- Anhedonia (absence of pleasure)
- Optogenetics has helped understand depression and its components
- Anhedonia: Overactivity in the prefrontal cortical areas can cause anhedonia, affecting dopamine neurons and reward circuitry
- Hopelessness: Can be measured in animals by observing their behavior in inescapable situations
Evolutionary Basis for Depression
- Depression may have evolved as a form of withdrawal or passivity, similar to hibernation
- Conserving energy during difficult times
- Reducing drive for social interaction and seeking rewards
- The negative aspect of depression (psychic pain) is not well understood
- Depression may be an evolutionary “hack” that is not fully evolved or under the right controls
Depression in Primates
-
Non-human primates can experience maladaptive states similar to grief
Depression in Non-Human Primates - Bereaved states in non-human primates can result in maladaptive behaviors
- Example: a young primate losing its mother may lose motivation to feed and protect itself, leading to death
- This could be considered a depressed-like state due to grief from bereavement
- No clear evidence of self-harm or suicide in non-human primates
- Some animals may exhibit less severe self-harm behaviors, like head banging
- True suicide requires a complex understanding of the self and the universe, which may not be present in non-human animals
Trauma and Depression
- Early childhood trauma has lasting effects on mental health, including depression and personality disorders
- Trauma may cause changes in brain circuitry or gene expression throughout life
- Intergenerational transfer of trauma is still controversial, but there are mechanisms in animals
- Emotional tears are unique to humans and can trigger a desire to help in others
- Involuntary expression of tears may have evolved as a social signal for needing help or support
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