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Index
Conditions
| Name | File | Summary |
|---|---|---|
| Depression (MDD) | wiki/conditions/depression.md |
Mood disorder defined by persistent depressed mood and anhedonia. ~40% heritable; environmental and epigenetic factors are critical. Covers DSM-5 criteria, subtypes, and epigenetic mechanisms across NAc, hippocampus, and PFC. |
| Schizophrenia | wiki/conditions/schizophrenia.md |
Severe chronic disorder with positive, negative, and cognitive symptom domains. ~80% heritable; complex polygenic risk. Covers GABAergic dysregulation, RELN/SOX10/GAD1 epigenetic findings, and 3D chromatin disruption. |
| Bipolar Disorder | wiki/conditions/bipolar-disorder.md |
Mood disorder with recurrent manic and depressive episodes. High heritability; substantial genetic and epigenetic overlap with SCZ. Covers HLA9 multi-tissue methylation and H3K4 methylation regulator GWAS findings. |
| Addiction (SUD) | wiki/conditions/addiction.md |
Chronically relapsing disorder of compulsive drug seeking and use. Defined by a three-stage cycle (binge/intoxication, withdrawal/negative affect, preoccupation/anticipation) across basal ganglia, extended amygdala, and PFC circuits. |
| Alzheimer’s Disease | wiki/conditions/alzheimers-disease.md |
Progressive neurodegenerative disorder with cognitive decline, Aβ plaques, and tauopathy. Covers the Amyloid Cascade Hypothesis, calcium dysregulation, cell-type-specific genetic risk, and viral associations. |
| Creutzfeldt-Jakob Disease (CJD) | wiki/conditions/cjd.md |
Rare, progressive, and fatal neurodegenerative disorder caused by prions. Characterized by spongiform change and rapidly progressive dementia. |
| Chronic Traumatic Encephalopathy (CTE) | wiki/conditions/cte.md |
Neurodegenerative disease linked to repetitive head impacts. Characterized by perivascular tau accumulation; now being identified in young athletes. |
Mechanisms
| Name | File | Summary |
|---|---|---|
| Epigenetic Regulation | wiki/mechanisms/epigenetic-regulation.md |
Overview of how chromatin organization controls gene expression without altering DNA sequence. Covers nucleosomes, histone modifications, DNA methylation, chromatin remodeling, 3D architecture, and the concept of “Histological Brain Age.” |
| Histone Modifications | wiki/mechanisms/histone-modifications.md |
Post-translational covalent modifications of histone tails (acetylation, methylation, phosphorylation) that regulate chromatin state. Covers writers, erasers, readers, the histone code hypothesis, and specific marks implicated in depression, SCZ, and bipolar disorder. |
| DNA Methylation | wiki/mechanisms/dna-methylation.md |
Addition of methyl groups to cytosine (5mC) at CpG sites; generally repressive at promoters. Covers DNMT writers, TET-mediated demethylation, the 5mC vs. 5hmC distinction, and psychiatric disorder findings. |
| Dopamine Reward System | wiki/mechanisms/dopamine-reward-system.md |
Mesocorticostriatal dopamine circuit underlying reward, incentive salience, and habit formation. Central target of all drugs of abuse. Covers D1/D2 receptor roles, phasic/tonic signalling, and D2 downregulation in addiction. |
| Aberrant Salience | wiki/mechanisms/aberrant-salience.md |
Neurocognitive framework linking presynaptic dopamine dysregulation to the formation of delusions and hallucinations in schizophrenia. Bridges biological “noise” with cognitive misinterpretation. |
| Glutamate Hypothesis | wiki/mechanisms/glutamate-hypothesis.md |
Proposes that schizophrenia is driven by NMDA receptor hypofunction, leading to cortical disinhibition and subsequent striatal dopamine hyperactivity. Explains cognitive and negative symptoms. |
| Amyloid Cascade Hypothesis | wiki/mechanisms/amyloid-cascade-hypothesis.md |
Leading model of AD pathogenesis proposing that Aβ accumulation is the primary initiating event. Covers APP processing, Aβ aggregation, and downstream pathological sequences. |
| Tau Tangles | wiki/mechanisms/tau-tangles.md |
Intracellular aggregates of hyperphosphorylated tau protein. Strongest pathological correlate of cognitive decline in AD. Covers microtubule collapse and Braak staging. |
| Calcium Homeostasis Dysregulation | wiki/mechanisms/calcium-homeostasis-dysregulation.md |
Disruption of neuronal calcium signaling by Aβ. Proposed as the critical link between amyloid deposition and tau hyperphosphorylation. |
| Prion Hypothesis | wiki/mechanisms/prion-hypothesis.md |
Proposes that transmissible spongiform encephalopathies are caused by “proteinaceous infectious particles” (prions) lacking nucleic acids. Covers misfolding of $PrP^C$ to $PrP^{Sc}$. |
| Protein-Only Inheritance | wiki/mechanisms/protein-only-inheritance.md |
Transmission of biological information through self-perpetuating protein conformations rather than DNA or RNA. Central to prion biology and yeast trait inheritance. |
| Viral Links to Neurodegeneration | wiki/mechanisms/viral-links-ndd.md |
Explores associations between systemic viral exposures (e.g., encephalitis, influenza) and the risk of neurodegenerative diseases like AD and PD. |
| Anti-Reward and Stress Systems | wiki/mechanisms/anti-reward-stress-systems.md |
Neurochemical systems (CRF, dynorphin, norepinephrine) recruited by chronic drug use to produce aversive states driving negative reinforcement. Overlaps with HPA axis and stress mechanisms in depression. |
| Executive Function Dysregulation | wiki/mechanisms/executive-function-dysregulation.md |
Prefrontal cortex hypofunction, glutamatergic dysregulation, and D2 deficits that impair inhibitory control, decision making, and craving suppression in addiction. Covers Go/Stop systems, insula, and mTORC1. |
Treatments
| Name | File | Summary |
|---|---|---|
| HDAC Inhibitors | wiki/treatments/hdac-inhibitors.md |
Compounds blocking histone deacetylases, promoting histone acetylation and gene expression. Strong antidepressant-like effects in animal models (sodium butyrate, MS275); weak human evidence. Overlapping mechanism with fluoxetine. Not in clinical use for psychiatry. |
| DNMT Inhibitors | wiki/treatments/dnmt-inhibitors.md |
Compounds blocking DNA methyltransferases, reducing cytosine methylation. Intra-NAc RG108 produces antidepressant effects in rodents; preclinical hypothesis for SCZ (RELN/GAD1). No clinical psychiatric application established. |
Debates
| Name | File | Summary |
|---|---|---|
| Epigenetics: Causation vs. Correlation | wiki/debates/epigenetics-causation-vs-correlation.md |
Do epigenetic changes in psychiatric disorders cause pathology or merely reflect it? Position A: locus-specific manipulations (zinc finger, CRISPR) produce disorder-relevant behaviors. Position B: postmortem studies cannot establish temporal order; medication and confounds are alternative explanations. |
| Peripheral vs. Brain Epigenetics | wiki/debates/peripheral-vs-brain-epigenetics.md |
Can blood or saliva epigenetic marks proxy for brain epigenetic state? Position A: shared methylation changes at RELN, GAD1 across tissues; NR3C1 detectable in cord blood. Position B: epigenetics is cell-type-specific; blood and brain are fundamentally different populations. No clinical biomarker validated. |
| Addiction as Brain Disease | wiki/debates/addiction-as-brain-disease.md |
Is addiction a chronic brain disease analogous to diabetes, or is that framing overstated? Position A: measurable circuit-level pathology, heritability, progressive worsening. Position B: most users don’t become addicted; recovery occurs without treatment; agency and social context are obscured. |
Sources
| Name | File | Summary |
|---|---|---|
| Nestler et al. (2016) | wiki/sources/nestler-2016-epigenetic-basis-mental-illness.md |
Review of epigenetic mechanisms in depression, SCZ, and bipolar disorder. The Neuroscientist 22(5):447–463. Synthesizes animal models and human postmortem data. Core thesis: transcriptional dysregulation via aberrant epigenetic regulation is a unifying theme across psychiatric disorders. |
| Koob & Volkow (2016) | wiki/sources/koob-volkow-2016-neurobiology-addiction.md |
Neurocircuitry analysis of addiction as a three-stage cycle. Lancet Psychiatry 3(8):760–773. Maps 18 neurochemically defined mini-circuits across basal ganglia, extended amygdala, and PFC. Integrates animal models, brain imaging, and molecular genetics. |
| Howes & Murray (2014) | wiki/sources/howes-murray-2014-schizophrenia-integrated-model.md |
Integrated sociodevelopmental-cognitive model of schizophrenia. Lancet 383(9929):1677–1687. Proposes that genetic and early hazards sensitize the dopamine system, while social adversity biases cognitive schemas, leading to a “vicious cycle” of aberrant salience and psychosis. |
| McCutcheon et al. (2020) | wiki/sources/mccutcheon-2020-dopamine-glutamate-schizophrenia.md |
Comprehensive review of dopamine-glutamate interactions in schizophrenia. World Psychiatry 19(1):15-33. Synthesizes evidence for striatal dopamine hyperactivity and cortical NMDA hypofunction, proposing a circuit-level model of the disorder. |
| Crary (2024) | wiki/sources/crary-2024-neurodegeneration-update.md |
Highlights of neurodegenerative disease research from 2023-2024. Free Neuropathology 5:31. Covers early CTE in athletes, viral associations with NDD risk, and cell-type-specific AD risk. |
| Hardy & Higgins (1992) | wiki/sources/hardy-higgins-1992-amyloid-cascade-hypothesis.md |
The foundational paper for the Amyloid Cascade Hypothesis. Science 256:184-185. Synthesizes genetic evidence from Down syndrome and FAD to place Aβ at the top of the AD pathogenic hierarchy. |
| Prusiner (1982) | wiki/sources/prusiner-1982-novel-proteinaceous-infectious-particles.md |
Foundational paper introducing the term “prion” and the Prion Hypothesis. Science 216:136-144. Provides evidence that the scrapie agent is proteinaceous and lacks nucleic acids. |