Brain Disorders and Diversity Notes

Brain Disorders and Diversity

Final Exam Information

  • Wednesday, June 11, 12:00-1:30 PM.

  • Same format as midterms.

  • 50% of questions from material covered since midterm 2 (Emotions, memory, and psychiatric conditions).

  • No retake.

  • Open notes.

  • Questions should be emailed to Emily, Sam, and the instructor.

Academic Integrity

  • Strict prohibition against using AI on exams.

  • Using AI-generated content violates academic integrity.

  • Submitting AI-created work may result in a report to the Office of Student Conduct and Community Standards and a grade penalty.

Extra Credit Options

Option #1: Human Subjects Pool

  • Serve as a subject in the Human Subjects Pool.

  • One point of extra credit per hour of service, up to 3 points.

Option #2: Extra Credit Paper

  • 2 pages, double-spaced, due by the day of the final exam.

  • Possible topics:

    • Talk in the ION or Psychology seminar series.

    • Neuro-related topic of interest (check with the instructor for appropriateness).

Seminar Announcement

  • The evolution and development of cephalopod brains and body plans.

  • Caroline Albertin, Woods Hole Laboratory.

  • Thursday, Jun 5, 4 PM, 110 Willamette.

Course Topics

  • Today: Disorders

  • Thursday: Autism and neurodiversity

Genetic Basis of Brain Differences

  • What causes brains to be different? DNA is a key factor.

Heritability and Concordance Ratios

  • Monozygotic (identical) twins: chance of both having a condition given one does (100% shared genome).

  • Dizygotic (fraternal) twins: chance of both having a condition given one does (50% shared genome).

  • If identical probability > fraternal, indicates a genetic component to the condition.

DNA Structure

  • DNA is a double helix composed of A, T, C, and G.

  • A pairs with T, and C pairs with G.

  • The double helix unwraps, and proteins copy the strands by pairing letters.

Genetic Code

  • Genes instruct cells to make proteins using 3-letter codons.

  • A gene is a string of codons that tells the cell how to string together amino acids to make proteins (e.g., neurotransmitter receptors).

  • A polymorphism may change the amino acid sequence of a protein, which may alter its function.

Genetic Polymorphisms

  • Polymorphisms occur when different people have different letters at the same position in the genome.

  • Arise from copying "errors" = mutations.

  • Humans differ by an average of 3 million polymorphisms (10% of the genome).

  • Most mutations are neutral, but some change protein function, for better or worse.

Identifying Bad Polymorphisms

  • Statistical association between genetic polymorphism and disorder

    • if you have a polymorphism in a given gene, what is the probability of having the disorder given a polymorphism in a gene?

  • Across the population, probabilities for almost all genes are low; many hyped findings have turned out to be false.

Heritability

  • Twin studies vs. molecular estimates show a "missing heritability" gap.

  • Examples:

    • Schizophrenia

    • Bipolar disorder

    • ASD (Autism Spectrum Disorder)

    • PTSD (Post-Traumatic Stress Disorder)

    • Major depression

    • Anxiety disorders

  • Concordance indicates a genetic basis, but identifying specific genes is difficult.

Schizophrenia

Symptoms

  • "Positive" symptoms:

    • Delusions

    • Hallucinations

  • "Negative" symptoms:

    • Depression

    • Motivational impairment

    • Cognitive impairments

Brain Abnormalities for Schizophrenia

  • Enlarged ventricles.

  • Reduction in white matter tracts (Fornix, Arcuate fasciculus, Inferior occipito-frontal fasciculus, Anterior limb of the internal capsule, Superior occipito-frontal fasciculus, Parietal portion of the cingulum bundle).

  • Schizophrenia Mouse Model: Transgenic mice expressing DISC1 mutation develop enlarged lateral ventricles.

Schizophrenia Treatment

  • Drug Development: FDA approves Cobenfy (KarXT), a first-in-class schizophrenia drug.

  • KarXT consists of xanomeline and trospium.

Acetylcholine In The Brain

  • Cholinergic Neurons

    • Act on learning, arousal, and reward.

    • Damaged in Alzheimer’s disease.

Acetylcholine Receptors

  • Postsynaptic receptors:

    • Nicotinic receptors (ionotropic):

      • Agonist = nicotine

      • Antagonist = curare (paralyzing poison)

      • 19 different subunit genes; each receptor is a combination of 5 subunits.

    • Muscarinic receptors (metabotropic):

      • Agonist = muscarine (from poison mushrooms)

      • Antagonist = atropine (from belladonna lily)

      • 5 subtypes.

Xanomeline and Trospium

  • Xanomeline: Muscarinic agonist (acts in the brain and brainstem).

  • Trospium chloride: Muscarinic antagonist (acts in the brainstem); blocks side effects.

Phase 3 Clinical Trial

  • Placebo: Negative control (everything is the same but without the drug).

  • "Double-blind": Clinicians and patients don’t know who receives the drug vs. placebo.

  • Randomized: Patients randomly assigned to drug vs. placebo groups.

  • Consolidated Standards of Reporting Trials (CONSORT) Flow Diagram for the EMERGENT-3 Trial.

Clinical Trial Results

  • Cobenfy/KarXT significantly improves positive and negative symptoms.

Bipolar Disorder

Symptoms

  • Depression

  • Mania: Overactivity, talkativeness, grandiosity

  • Women = men

  • Ventricles enlarged as in Schizophrenia

Depression

Symptoms

  • Unhappy mood

  • Reduced energy

  • Learned helplessness (giving up)

  • Anhedonia (lack of pleasure)

  • Women > Men

Anhedonia

  • people with this show a reduced response to reward

  • Depressed brains give weaker responses to reward in the ventral striatum.

Genetics of Depression

  • Concordance ratios indicate a strong genetic component:

    • 50% in identical twins

    • 20% in fraternal twins

  • Still no genes strongly implicated!

Approaches to Genetics

  • Candidate gene approach: Test a hypothesis about a specific gene you think might be involved.

  • Genome-wide association study: Test a hypothesis across the whole genome across the population.

    • Measure statistical association between a given polymorphism in a given gene and the condition.

    • Requires a lot of genome sequencing!

Genome-Wide Association Study
(GWAS) for Major Depression → the hypothesis-free approach

  • Statistical threshold corrected for multiple comparisons (p<10−6p<10^{-6}).

  • Many gene variants are significantly associated with depression.

  • Effects are very small (Variance explained and odds ratio).

  • Not predictive enough for individuals.

Animal Models of Depression

  • Restraint stress gives mice "depression".

  • Behavioral measures distinguish "susceptible" and "resilient" mice.

Neural Code of Stress and Anhedonia

  • Decoding stay vs. switch intention using hidden states in the BLA (Basolateral Amygdala).

  • Chemogenetic activation of vCA1→BLA pathway.

Treating Depression

  • Electroconvulsive therapy:

    • Very effective

    • Works right away

  • SSRIs (Selective Serotonin Reuptake Inhibitors):

    • Very effective in a subset of patients

    • Takes weeks for effects to be seen

  • Ketamine:

    • Works right away

    • Found that a ketamine metabolite mediates the effect

  • Cognitive-behavioral therapy:

    • As effective as SSRI

    • Most effective when combined with medicine

SSRI Mechanism

  • SSRI inhibits the serotonin reuptake transporter.

  • Prozac targets the transporters and its supposed to increase serotonin but this may be wrong

Ketamine Mechanism

  • Ketamine acts via the lateral habenula (LHb).

  • Ketamine excites inhibitory GABA neurons, which inhibit dopamine neurons.

  • LHb excites inhibitory GABA neurons, which inhibit DA neurons, which may implement the prediction.​

  • Dopamine = actual reward – expected reward.

  • Ketamine affects signaling in the LHb, which may be the reason for its therapeutic effectiveness!

  • At the molecular level, ketamine is thought to act through NMDA receptors.

BDNF and TrkB

  • BDNF: Brain-Derived Neurotrophic Factor

  • TrkB: Tyrosine receptor kinase B

  • Mainly thought to be important for development.

  • A lot of evidence implicates this system in depression but has been thought to play a secondary role to serotonin (SSRIs) and NMDA receptors (ketamine).

TrkB as a Target of Antidepressants

  • Prozac, ketamine, and other antidepressants all bind to a particular part of TrkB.

  • Mice engineered to have a mutation in this part of the receptor don’t respond to Prozac or Ketamine treatment.

  • Mice with no serotonin transporter gene (SERT KO) still respond!

Serendipity in Science

  • Serendipity - the art of discovering things by observing and learning from encountering unexpected information.

  • Louis Pasteur: Chance favors only the prepared mind.

  • Most (all?) psychiatric medicines in use today were discovered serendipitously ("This pill does something good, we don’t know why but let’s roll with it").

Neurodegenerative Disorders

  • Conditions that cause visualizable brain damage:

    • Alzheimer’s disease (AD):

      • Memory

      • Cognitive problems

    • Parkinson’s:

      • Movement

      • Perceptual learning

    • Frontotemporal dementia:

      • Cognitive, emotional problems

Alzheimer's Disease

  • A neurodegenerative disorder often attributed to amyloid plaques.

Amyloid Plaques

  • Accumulations of a fragment of a protein called APP.

  • APP fragments accumulate and form plaques.

  • These are thought to be neurotoxic.

Inflations in Alzheimer's Research

  • First publication on amyloid pathology based on 1 case.

  • National Institute on Aging broadened the definition.

  • Diagnostic criteria modified to include amyloid.

Mouse Models of AD

  • Aβ plaque deposition

  • Normal lifespan

  • Not aggressive

  • Aβ42

  • Neuroinflammation

  • AB/astrocyte/microglia

  • Memory impairment

  • Immunological therapies can clear plaques and rescue memory in mice, BUT…

Failed Clinical Trials

  • Numerous failed clinical trials targeting amyloid plaques have cost billions of dollars.

GWAS of AD

  • APOE locus has pp-values less than 10−10010^{-100}!!

  • Amyloid-related genes are not significantly associated.

Apolipoprotein E (APOE)

  • APOE transports free fatty acids from astrocytes to neurons.

  • Also involved in microglial function.

  • Lipid metabolism is implicated by other evidence in AD.

Anxiety Disorders

Types

  • Phobic disorders: fear of particular object, activity, or situation.

  • Panic disorder: Transient attacks of intense fearfulness.

  • Generalized anxiety disorder: Persistent, excessive fearfulness.

Prevalence

  • Affects up to 30% of the population in their life.

  • Twice as common in females.

Brain Areas Implicated in Anxiety

  • Amygdala and BNST (Bed Nucleus of Stria Terminalis).

Anxiety Tests

  • Pavlovian fear conditioning

  • Ethological tests (approach-avoidance conflict)

  • Acoustic startle response

  • Elevated plus maze

  • Open field test

  • Light-dark box

  • An extensive network.

  • Brain areas are heterogeneous: Different populations in the amygdala have opposite effects on anxiety.