Revolutionizing our Understanding of Mental Illness with Optogenetics

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

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
• 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