Neurobiology of Psychiatric Disorders

What is an emotional state?

A neurobiological state produced by coordinated, physiological, behavioural, cognitive responses.
→ they prepare the body to react in a certain way, an internal motive that produces action tendencies

List the major brain regions involved in emotion and anxiety

• Amygdala

• Prefrontal cortex

  • LATERAL: dlPFC + vlPFC

  • MEDIAL: vmPFC + OFC, also mPFC

• Hippocampus

• Ventral striatum (NAc)

• Cingulate gyrus (ACC)

• Insula

• HPA axis

Primary, secondary & tertiary emotional systems (3-parted brain theory)

‘Lizard brain’ = brainstem + cerebellum → primary emotions

• Evolutionary responses hardwired into all animals (born with the ability)

• Innate, automatic, universal

• i.e., body language of threat, autopilot, homeostatic functions, fight or flight, reflexes
  
  ‘Mammal brain’ = subcortical/limbic system → secondary emotions

• Associative learning between stimuli

• Still automatic, but not reflexive

• i.e., emotions, memories, habits, attachments
  
  ‘Human brain’ = neocortex → tertiary emotions

• Flexibility to facilitate social interactions and decision-making, higher order emotions

• Dampens primary and secondary impulses, cognition > emotion

• i.e., language, abstract thought, consciousness, imagination, reasoning, rationalising, guilt, empathy, assessing environment

Amygdala in affective circuitry

NOT the home of fear, but a NOVELTY CENTRE
→ has one of the highest degrees of connectivity, no region is more than 2 steps away

13 nuclei, 3 key regions:

• Basolateral (BLA) complex: lateral nucleus (LA) + basal nucleus (BA) + accessory basal nucleus (AB)

  • Receives sensory information, either directly from sensory pathways or via sensory cortex

  • Performs memory association between stimuli and emotional significance

• Corticomedial

  • Receives olfactory input, odour-related emotional responses (pheromones, food, danger/defence)

  • Ancient and highly conserved, still strong link in humans but more prioritised in other animals

• Central nucleus (CeA):

  • Major output to other subcortical areas like brainstem and hypothalamus for physiological responses

  • Defensive emotional reactions like HR, sweating, freezing

PATHWAYS:

1. High road: sensory information → spinal/cranial nerve → spinal tract → thalamus → cortex → amygdala

   • Cortical analysis produces the generated feeling = subjective emotional experience (requires PFC)

2. Low road: bypasses cortex, straight from thalamus → amygdala

   • Fast, subconscious threat detection = behavioural & physiological response

   • Rapid survival response before you’re consciously aware something’s happening

PFC in affective circuitry

Executive functions, cognitive control over other cognitive regions

Separated into affective and cognitive regions with opposite effects on emotional regulation

MEDIAL = processes POSITIVE affect, emotion, reward value in decision-making and reward learning
→ stimulates action

• OFC: assigns emotional and motivational value to events, information, outcomes, top-down regulation of the amygdala

  • Updates values CONSTANTLY

  • OFC and amygdala receive nearly identical information, humans have greater OFC development that overshadows the amygdala

• vmPFC + mPFC: introspection, social cognition, a broader program of how to behave in the world, context of environment

  • Keeps values for LONGER TERM = beliefs, social relationships, ethics
    

LATERAL = process NEGATIVE affect, encodes punishment and negative feedback, drives analytical thinking in humans
→ inhibits action

• dlPFC + vlPFC: maintain and manipulate information, plan actions, inhibit impulses

Hippocampus in affective circuitry

Integrating contextual information + emotional valence

• Encoding of episodic and contextual memory

  • Emotional memories are much more likely to be encoded, or ‘stick’

• Input from the BLA encoding emotional valence information

• High expression of glucocorticoid receptors, interpretation and termination of stress response

Ventral striatum (NAc) in affective circuitry

• Interface between emotion, motivation, and action (DA regulated circuits)

  • Processes emotional valence

  • Receives inputs from BLA, hippocampus and VTA

• Key role (+ basal ganglia) in stimulus-response habit learning)

  • ‘Habitual’ functions to reduce cognitive load and re-delegate attention

  • Outputs driving motor responses like VP, LH and SNr

ACC in affective circuitry

1. Pregenual (pACC) ← input from medial OFC (positive rewards)

2. Supracallosal or midcingulate (dACC) ← input from lateral OFC (punishment, non-reward)

• Designing and planning the best action for current goal or outcome

  • Strong link to insula (body states), amygdala (emotional salience), oPFC (outcome values), and hippocampus

  • Most adjacent to OFC and insular

• Generates “subjective feeling” from emotional motor associaiton areas

  • Emotional component of physical and emotional pain, suffering (activates same region)

• Monitors conflicts between competing actions, sustaining attention on the one that has the best outcome

Insula in affective circuitry

• , the brain’s response to internal changes

1. Posterior insula: the primary interoceptive cortex
   → visceral sensory input

2. Mid-insula: integrates interoceptive signals with affective and motivational states
   → attaches to affect, how much motivation do I have to do things?

3. Anterior insula ( ACC): links bodily/emotional awareness to cognitive control, unconscious ‘gut feelings’
   → combine with cognitive processes, decision-making, conscious experiences, evaluating action options

   • Adjacent to ACC and PFC

HPA axis in affective circuitry

PFC has top-down inhibition over amygdala
↓
Amygdala identifies threats
↓
Projects to hypothalamus
↓ CRH
Anterior pituitary
↓ ACTH
Adrenal cortex
↓ Glucocorticoids

Amg, PFC and HiF all contain GRs

• Cortisol ↑ amygdala activity, ↓ PFC & HiF activity

• Cortisol generates an integrated response by influencing the degree of APH activity

  • Severe acute stress creates temporary amygdala > PFC imbalance to allow automatic, reflexive survival response

  • Chronic stress can cause hormonal imbalance and structural changes
    (i.e., dendritic shrinkage in HiF and PFC, amygdala enlargement)

Connections in the amygdala-PFC-hippocampal circuit that support affective behaviour

AMYGDALA: emotionally relevant stimuli, automatic responses

↓ _{(sends information to be evaluated and regulated)} ↑ _{(top-down regulating, flexible updating of value, conflict monitoring)}

PFC: assigning value to potential outcomes, decision-making, updating/extinction learning

↓ _{(guides memory search, encodes bias)} ↑ _{(memory retrieval)}

HIPPOCAMPUS: episodic and contextual memory

↓ _{(context/scenario to form emotional memories)} ↑ _{(amygdala activation enhances encoding but causes narrow attention)}

[to AMYGDALA]

Roles of default mode vs salience networks in affective processing and threat detection

Default Mode Network (DMN) = PCC + mPFC + precuneus + angular gyrus + PHC + inferior parietal lobule
→ at rest, daydreaming, rumination, social cognition, self-referential thought, planning

Salience Network (SN) = dACC + amygdala + SN + VTA + insula (bilateral anterior)
→ mediator, identifies relevant stimuli, regulates emotional vs cognitive resources

Executive Control Network (ECN) = dlPFC + PPC + aPFC
→ goal-directed behaviour, action execution after stimuli detection, working memory, external tasks

Role of amygdala vs PFC in different types of fear

AMYGDALA: detects threats and initiates automatic, defensive behaviours

act in opposition

PFC: regulates amygdala via top-down inhibition, evaluates whether fear response is appropriate using context

Basic circuitry of Pavlovian fear conditioning

with respect to amygdala

Inputs:

• LOW ROAD: thalamic sensory information → amygdala

• HIGH ROAD: cortically processed sensory information → amygdala

  • From medial PFC:
    - Prelimbic (PL) → BA and CeA = fear expression
    - Infralimbic (IL) → CeA = fear inhibition/extinction

• Contextual and spatial information from hippocampus → amygdala

Outputs:

• Brainstem: physiological responses like freeze, startle, increased respiration (PAG, PnC, PBN)

• Hypothalamus: triggers HPA axis (via PVN) and SNS (via LH)

• Basal forebrain: arousal and attention

Modulatory regions:

• mPFC/OFC: overrides/regulates amygdala fear response

• Hippocampus modulates: response based on context, extinction recall

• VTA: dopaminergic projections facilitate plasticity during fear learning

• LC: enhances consolidation via NAD, drives arousal during threat

Related symptoms of altered system circuits in psychiatric disorders

• PTSD/depressive disorders: in HPA axis, elevated cortisol and structural changes (hippocampal and PFC atrophy, amygdala enlargement)

• Mood disorders/emotional dysregulation: overactive amygdala, lack of top-down regulation by PFC

• Major depressive disorder: medial < lateral OFC imbalance

  • Lateral overconnectivity causes negative thoughts and ruminations

  • Medial underactivity causes apathy, reduced pleasure and motivation

  • Brain analyses most events as negative, encoding punishment

Barrett’s Theory of Constructed Emotion

The purpose of the brain is not learning but to ‘run a budget for the body’ = maintain homeostasis

1. The brain is a predictive system, serves allostasis (maintains stability by anticipating and predicting → comparing → adjusting to environment)
   → the best model of managing energy consumption and resources is predictive, not reactive

2. The brain is degenerative, no region or network is uniquely responsible for a single function or emotion
   → natural selection prefers high complexity systems = more robust, multiple different structures can perform the same function

How to macrostructural changes on neuroimaging relate to underlying cellular alterations

molecular → cellular → circuit → system → behaviour

Tells us volume-based metrics

• Broad cortical-wide effects caused by something on a smaller scale

• i.e., total volume, regional grey matter volume, cortical thickness, surface area

• Can indicate neurodegenerative patterns, pathological volumetric changes, following maturation in development and ageing
  

Hints at microstructural proxies, but can’t be directly observed
→ i.e., white matter integrity, tissue contrast ratios, lesion burden

Key structural findings on MRI in depression + cellular correlates

The OFC: decision-making, reward & punishment (m/l), integration of sensory information to guide behaviour

1. Structural: reduced grey matter, cortical thinning
   → suggests tissue loss or abnormal development
   [cellular correlate] = ↓ neuronal & glial density, ↓ neuropil

2. Functional: hyperactive mOFC, hypoactive lOFC
   → core symptoms of rumination, negative thinking, anhedonia
   [cellular correlate] = glial dysfunction & changes in expression

3. Connective: alterations between limbic (amygdala/HiF) and prefrontal regions
   → disrupted emotional regulation and stress response
   [cellular correlate] = ↓ dendritic spines, changes to dendritic arbour

Strengths VS limitations of human postmortem brain studies in understanding disease pathology

STRENGTHS

• Allows insight into human-specific biology

• Shows molecular mechanisms in actual disease context, validates in vivo findings

• Layer and cell-type specific pathology

• Shows lifetime trajectory of disease

• Helps identify targets for treatment + individual variation for personalised medicine
  

LIMITATIONS

• Observational and correlational

• Cannot manipulate system therefore cannot probe function

• Logistically challenging (can’t capture entire system, uncontrolled circumstances, misattributing causes)

  1. Sample collection & processing (brain banks and tissue recovery)

  2. Confounding variables (individual-specific effects of death i.e., pH measurements and RNA integrity, clinical/demographic variables, medication)

  3. Post-mortem interval (minimise and store at -80^oC to prevent tissue degradation)

Translation of environmental stressors into measurable cytoarchitectural changes

• HPA axis release of glucocorticoids

  • GC receptors translocate into somatic cell nuclei (ligand-dependent transcription factor)

  • DNA binding (GC response elements) can activate or repress expression

  • Induces transcriptome-wide (large-scale) changes in gene expression (min and hrs/days)

• Cellular changes:

  • Reduced GR expression = impaired negative feedback

  • FKBP5 dysregulation (polymorphism) = altered stress sensitivity

  • GR resistance = reduced responsiveness

• Molecular consequences:

  • Impaired BDNF expression (suppressed by cortisol)
    → reduction of dendritic spines in the OFC (exacerbated for early life adversity)

  • Enhanced inflammatory signalling
    → cell death/reduced cell number

  • Altered mitochondrial function & cellular metabolism

  • Epigenetic modifications

Key layers of molecular regulation

1. Transcription factors
   i.e., PU.1 → microglia identity

   • DNA-binding proteins that switch genes on/off

   • Master regulators specifying cell lineage or state, reprogramming, lots of downstream targets
     

2. Epigenetic modifications

   • Chemical marks on DNA and histones, signal whether genes are accessible by transcription machinery to produce RNA

   • Open vs closed chromatin (combined DNA and histone coil), density and acetyl/methylation determines activity

   • Altered by stress, drugs, environment
     

3. Signalling pathways
   i.e., growth factors

   • External signals, trigger → intracellular cascades, affect → gene expression

   • Autoregulatory loop: neurotrophic factors → bind and activate TrkB Rs → kinase pathway (MAPK/ERK) → CREB phosphorylation → translocates, binding to BDNF promoters → BNDF gene induced and synthesised
     

4. Post-transcriptional regulation

   • Stability vs degradation of RNA (how long it’s active in the cytoplasm)

   • Alternative splicing (multiple, distinct mRNA transcripts/proteins from one gene = different isoforms, varying functions, diversity)

   • MicroRNAs silencing specific transcripts (guide silencing complexes to specific cytoplasm mRNAs = inhibits protein synthesis/induces degradation)

Why does cell-type specificity matter?

Every neuron has the same DNA but express different subsets = different populations of cells

• Different cell populations have different molecular signals in pathology

• Gene expression isn’t static (changes spatially, temporally, and by state)

Research: identifying and targeting cells of interest (excitatory/inhibitory, astrocytes, microglia, oligodendrocytes)

Clinical: pathology often only affects specific cell types, need to understand specific molecular disruptions for system-level disorders

Pharmacological: cell-type specificity can reduce side effects (which off-target effects are produced depends on where targets are expressed)

Drug target identification and validation

• Establishing causality (not correlation) requires VALIDATION

  • Dose-response (severity of molecular change correlates with symptom severity)

  • Temporal sequence (change preceding illness onset)

  • Biological plausibility (mechanism makes sense)

  • Experimental manipulation (does changing the molecule change the phenotype)

• Technical parameters of druggability:

  • Accessible (by small molecules or biologics)

  • Can be modulated (inc/dec acitivty)

  • Specific (can be targeted without off-target effects)

  • Stable (does the drug maintain appropriate levels?)

• Biological parameters of druggability:

  • Causal (not just correlated with pathology)

  • Sufficient (modulation creates meaningful effect)

  • Safe (large window between efficacy and toxicity)

  • Tolerable (side effects if used chronically)

Discovery i.e., postmortem studies
↓
Validation (preclinical) i.e., animal models, cell culture
↓
Drug development (identify candidate targets)
↓
Clinical testing
↓
Personalized application

i.e., Ketamine = strong preclinical evidence, clear MOA, known safety profile, measurable clinical effects

Personalized medicine approaches (current field research)

• Molecular subtypes are emerging from psychiatric disorder research

  • i.e., DEPRESSION: inflammatory, treatment-resistant, atypical, melancholic

  • Diagnosing biological subtype → target only affected system

• Current trial-and-error approach to medication

• Future goal of matching treatment based on mechanism identified in molecular profiling

  • + biomarkers to predict treatment response = faster administration of effective treatment

  • i.e., single-cell transcriptomics, blood biomarkers, neuroimaging + molecular profiles, machine learning (large datasets)

What does neuroimaging tell us?

• T1-weighted: structural anatomy, volumes (grey-white contrast)

• T2-weighted & FLAIR: lesions, inflammation, pathology, damage

• Diffusion Tensor Imaging (DTI): connectivity, white matter tract integrity

LIMITATIONS: very coarse resolution, indirect measure (volume, not function), small effect sizes in stat analysis, interpretation gap

1. Ambiguity of signal (what’s the actual cellular mechanism?)

2. Causality problem (cause vs consequence vs marker)

3. Group vs individual translatability

4. Development vs degeneration mechanisms

Single cell vs single nucleus RNA sequencing

scRNA-seq = total cellular RNA (cytoplasm + nuclear)

• Using fresh samples

• Higher sensitivity, pprovides comprehensive transcriptome
  

snRNA-seq = isolates only nuclear transcript

• Using frozen samples*

• Mostly pre-RNA, good for multi-nucleated cells or neuronal subtypes
  

*after freezing, expanding water causes cells of the brain to burst once defrosted (cytoplasm is lost but nucleus remains)

Cell-type specific approaches

Laser capture microdissection: microscope + laser (can cut out a certain cell type for experimentation)

Flow cytometry/FACS: uses antibodies to separate and identify specific cell population using markers for protein expression

Single cell RNA seq: profile individual cell expression in complex tissue

Spatial transcriptomic profiles: transcriptome sequencing on preserved tissue section, preserving location source

Altered neuronal structure in depression

Physical properties are controlled by molecular cascades:

1. Cytoarchitectural proteins, actin microfilaments
   = structure and dynamic spines

   • ↓ actin regulators in depression

   • causes fewer, smaller spines
     

2. Adhesion molecules, cadherins
   = cell-cell adhesion, spine and synapse stability

   • ↓ cadherin expression

   • causes unstable/lost synapses, weak bonding, synapses can’t be maintained
     

3. Molecular-level signalling cascades, BNDF/TrkB pathway
   = dendritic growth, brain fertiliser (activity-dependent)

   • ↓ BNDF levels and of mRNA protein in cortex/HiF and serum (periphery)
     1) PI3K/Akt: normally drives protein synthesis, survival, growth
     2) MAPK/ERK & CREB: regulates transcription, turning on plasticity genes, differentiation

   • Causes dendritic atrophy, impaired plasticity, less stimulus to build structures
     

4. Inflammatory hypothesis, microglia
   = drive immune response via homeostatic/inflammatory state

   • Chronic stress activates microglia → cytokines → neurotoxic environment → impairs function

   • M1-like shift causes excess synaptic pruning, excitotoxicity, astrocyte activation (neuronal death), reduced BNDF

Genes implicated in depression structural changes

Plasticity genes

• PRESYNAPTIC: manage NT release
  → vesicle trafficking and release, vesicle membranes, vesicle fusion

• POSTSYNAPTIC: accepting NTs, response transmission
  → scaffolding protein organisation, glutamate signalling

• PLASTICITY REGULATORY: model synapses based on experiences
  → activity-regulated cytoskeleton proteins, remodelling, trans-synaptic adhesion

Major theories of what depression is

PATHOLOGICAL = reaction is disengaged from environment

Behavioural shutdown model: energy conservation in response unavoidable stress, learned helplessness until environment changes

Analytical rumination hypothesis: rumination is crucial to look internally and dissect long-term issues but requires shutting down of environmental stimuli

Chronic inflammatory hypothesis: a response to interoceptive signals like chronic inflammation causing 'sickness behaviour’

Serotonin hypothesis: in 1960s, monoamine ↓ drugs were discovered to induce depressive symptoms (vs ↑ drugs alleviated symptoms)

Plasticity hypothesis: 5-HT levels are not elevated after 2 weeks
→ plasticity loss in cortical pyramidal neurons causes dec. cognitive flexibility, top-down regulation & increased reactivity/anhedonia

Depression risk factors and prognosis

Risk factors: age (24-26), stress exposure (early childhood, chronic), genetics, gender, low socioeconomic status, previous depressive episode, other health comorbidities
→ 40% runs in families (polymorphisms or environment?)

Prognosis: lifetime prognosis of 20% (f), 12% (m)

• Mood disturbances: anhedonia/low mood + sadness, irritability etc.

• Somatic changes : insomnia/hypersomnia, endocrine dysfunction, HR and BP, weight gain/loss

• Cognitive changes: behavioural etc.

Role of genetics in the aetiology of depression

40% of depression runs in families based on genome-wide association studies, whole-genome sequencing, twin studies

NO CAUSATIVE EFFECT (only predisposing upon stress exposure):

• HPA axis: receptor stimulation/termination

• Mitochondrial function: free radical homeostasis, oxidative damage

• Chronic inflammation: pro-inflammatory cytokines

• Methylation: enzymes, folate

• Circadian rhythm: endocrine system

• BDNF: 5-HT receptors etc.

• Serotonin system: tryptophan, receptors, also DA

Psychedelic mechanism(s) for depressive symptoms

• 5-HT_2A receptor agonist (higher-order/multimodal association cortices)

  • Excitatory on Layer V pyramidal

  • Restructuring, increases imagination, learning, absorption, suggestibility, environmental sensitivity

  • 2A recpetor-expressing regions are the most desynchronized in depression

• 5-HT_1A receptor partial agonist (limbic/stress circuitry)

  • Inhibitory, reduces excitability

  • Reduces stress, reactivity, impulsivity, aggression, anxiety

  • Increases patience, resilience, emotional blunting

• Changes in resting state network dynamics

  • Uncoupling, cross-communication

  • Increased randomness and sensory experiences

  • Collapse of ‘principal gradient’/hierarchy, less segregation

• Also lipid soluble (highest 2A concentration is intracellular)
  

Fast-acting → 1 dose of psilocybin can create antidepressant effects in 30 mins for up to 12 months (very effective for treatment-resistance)
^upregulated dendritic spines and dendrites via BDNF^

Ketamine mechanism(s) for depressive symptoms

• NMDA receptor antagonist

  • Blocks receptors on GABAergic interneurons

  • Prevents glu neuronal inhibition = ↑ pyramidal excitation

  • Activates AMPA to increase BDNF release

• Sub-anesthetic dose has rapid (hrs) and sustained (7 days) antidepressant effects

  • Restores network connectivity and switching flexibility

  • Also effective in treatment resistance

  • Recover

DBS mechanism(s) for depressive symptoms

Brain stimulation treatments used for depression
+ influence on large network dynamics

Default Mode Network (DMN)
[regions, function, alterations in depression aetiology]

Function: when at rest and not actively doing anything, looking inward, self-thought, daydreaming, rumination

Regions: mPFC, PCC, temporal, parietal (angular gyrus), medial OFC

Pathology: hyperactive in depression = negative self-evaluation

Salience Network (SN)
[regions, function, alterations in depression aetiology]

Function: switching between DMN & CEN, balance/mediation

Regions: anterior insula, ACC

Pathology: weakened, inability to switch

Central Executive Network (CEN)
[regions, function, alterations in depression aetiology]

Function: for engaging in specific tasks, externally-directed action

Regions: dlPFC, posterior parietal, lateral OFC (sensory/motor cortices)

Pathology: underactive, lack of ‘getting up and doing’, attention deficits, anhedonia

Affective Network (AF)
[regions, function, alterations in depression aetiology]

Function: identify/patterns, process, assign emotional significance to stimuli, motivating behaviour, (works with SN)
→ enables emotional engagement when homeostatic relevant information is identified

Regions: amygdala, subgenual & pregenual cingulate, insula

Pathology: hyperactivity causes vegetative (bodily) symptoms i.e., sleep, appetite, fatigue, weight fluctuations

Structural MRI findings for CNS region alterations in depression

Regional changes in volume/arrangement

• HYPORTROPHY

  • a/p cingulate

  • oPFC (assigning stimuli value)

  • mPFC (long-term goals, sustained effort, top-down control)

  • Insula & temporal lobe

• HYPERTROPHY

  • Amygdala (>oPFC, choices are rigid, less cognitively-driven)

  • Ventral striatum

Diffusor Tensor Imaging (DTI) findings for CNS region alterations in depression

White matter quantification

• Reduction in corpus callosum (connecting l/r PFC)

  • Loss of communication between different functions (stuck)

• Right cerebellum (cognitive & emotional regions)

• Frontal, temporal, parietal connectivity (AF, SLF)

• Right anterior thalamic projections (thalamus to limbic, PFC, aCC)

Molecular imaging PET findings for CNS region alterations in depression

Metabolism/function for a specific receptor/protein

• Serotonergic receptor dysfunction (2A and 1B)

• Decreased metabolism:

  • insula (interception into cognition/emotion)

  • PFC and limbic lobes

• Increased metabolism:

  • Thalamus

  • Cerebellum

Task-related fMRI findings for CNS region alterations in depression

Blood oxygenation levels, regions with simultaneous activity

3 subtypes/symptom clusters:
—task-dependent under vs overactivity—
^not pure physical degeneration, but circuit dysfunction^

1. Emotional processing & regulation
   → mood, emotional assigning of value to stimuli, motivation

2. Reward processing
   → want, willingness for work, liking

3. Cognitive control
   → overactive primitive limbic regions (less cognition)

Plasticity hypothesis of depression

Loss of plasticity in layer V cortical pyramidal neurons causes:

• Lack of output = poor subcortical control

  • ↓ amygdala inhibition = increased reactivity/anxiety

  • ↑ ventral striatum inhibition = anhedonia, reduced reward anticipation and pleasure

• Inability to learn something is no longer bad (updating predictions, reappraisal of stimuli)

• Loss of cognitive flexibility

• Desynchronization of brain networks, lack of switching
  → brain makes the same negaitve predictions about the future
  

BDNF production
↓
TrkB receptors
↓
Intracellular mTOR pathway (plasticity gene)
↓
Synaptogenesis