Neurological Diseases Flashcards

1
Q

Describe the cellular organisation of the human neocortex and hippocampus:

A
  • Even within the neocortex, different parts e.g. visual cortex, motor cortex, have different cortical layering patterns
    e. g. visual cortex has 6 layers
  • Cellular layering is very important in the hippocampus
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2
Q

What are the cellular and molecular processes of neural development?

A
  1. Proliferation:
    - cell division to form billion of neurons, microglial cells and astrocytes
  2. Migration:
    - Movement of neurons from site of birth to final destination in brain (neurons are born in the subventricular zone, and must migrate out to their respective cortical layers)
  3. Aggregation:
    - Adhesion of similar cells into specific brain structures
  4. Differentiation:
    - Commitment to become a particular type of cell e.g. dopaminergic neurons will secrete dopamine
  5. Circuit formation:
    - Growth of axons and dendrites followed by synapse formation
  6. Pruning and programmed cell death:
    - Loss of extra neurons (many) and synapses
    - Deficits in this pruning stage can lead to autism
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3
Q

Describe the 2 different forms of neuronal migration in the cerebral neocortex:

A
  1. Radial migration:
    - Occurs in excitatory neurons
    - Use scaffold provided by radial gilal cells to move up to the dorsal surface of the brain
    - Inside-out organisation
  2. Tangential migration:
    - Occurs in inhibitory neurons (interneurons)
    - These neurons originate from the ganglion eminence- ventral surface of vesicles
    - They migrate tangentially and synapse of excitatory neurons that have previously migrated to regulate their activity
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4
Q

Describe prenatal neural development:

A
  1. Embryonic:
    - First 8 weeks of pregnancy
    - Primordium of the CNS arises
    - Development of neural tube and 3 ventricles
    - Vast majority of congenital abnormalities occur during this period
  2. Fetal:
    - Characterised by significant growth (40x increase in brain weight)
    - Appearance of sulci and gyri on brain surface
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5
Q

Describe postnatal brain development:

A
  1. Birth:
    - Gross anatomy of CNS resembles adult
    - Repertoire of neurons of neocortex largely established
  2. Infancy:
    - Massive outgrowth of dendrites and axons
    - Synaptogenesis, gliogenesis and myelination
    - Neurogenesis in cerebellum is still occurring
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6
Q

Describe the changes that take place in the adolescent brain:

A

Structural:

  • Reduction in grey matter in neocortex (due to pruning)
  • Increase in white matter (due to increased connectivity and myelination)
  • Axonal sprouting and growth in circuits in the amygdala and cortex (due to development of emotions and intelligence
  • In animal studies: overexpression in dopamine, 5-HT, adrenaline, GABA etc.

Social changes:

  • Increased social behaviour
  • Novelty and sensation seeking
  • Emotional instability
  • Impulsivity
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7
Q

What is a critical period in neural development?

A
  • A critical period in brain development is when neural circuits responsible for a particular process can be sculpted or radically changes by the environment of experiences
  • A period of time when the brain is most plastic

e. g. Critical period for processing sensory information:
- Infancy

e. g. Critical period for language:
- Between infancy and childhood

e. g. Critical period for higher cognition:
- Occurs during childhood

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8
Q

What is a neurodevelopmental disorder?

A
  • NDDs are a group of psychiatric illnesses that are the result of abnormal brain development
    e. g. deficit in neurogenesis, progenitor cell proliferation, migration, synapse formation and myelination
  • Symptoms include disabilities in cognitive, social, motor and effective function
  • Most common NDD is autism spectrum disorder
  • The impairment is generally detected at birth, during infancy e.g. ASD and sometimes adolescence e.g. schizophrenia usually manifests in adolescence
  • Have both a genetic and environmental component
  • Most NDDs are highly heritable (generally polygenic)
  • Examples of monogenic NDDs are Angelman’s and Fragile X syndrome
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9
Q

How are neurodevelopmental disorders treated?

A

Pharmacotherapy:
- Anti-psychotics to treat psychosis or ADHD by stimulating certain pathways

  • Stimulants to treat ADHD
  • Adjunct therapy to treat other co-morbidity such as OCD, depression, seizures
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10
Q

What is the excitatory/inhibitory imbalance theory for ASD and schizophrenia?

A
  • Behaviour symptoms of NDD are very similar: social interaction and cognitive deficits, emotion processing problems, executive dysfunction
  • Imbalances in excitatory and inhibitory neurons may manifest themselves in behavioural symptoms
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11
Q

What properties should a good animal model of NDD possess?

A
  1. Construct validity:
    - confirming to the underlying rationale of the disease e.g. for an animal to model ASD, they need to have an imbalance in excitatory and inhibitory neurons
  2. Face validity:
    - Mimicking some characteristics of the disease e.g. for an model to mimic ASD, there should be social interaction deficits
  3. Predictive validity:
    - Allow the prediction of novel disease symptoms e.g. for an animal to model ASD, there should be some hyperexcitability
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12
Q

How is Autism diagnosed?

A
  1. DSM:
    - Persistent deficits in social communication/interaction
    - Restricted, repetitive behaviours, interests and activities
  2. WHO ICD:
    - Abnormal development of receptive/expressive language
    - Impaired development of selective social attachments/reciprocal social interaction
    - Markedly restricted repertoire of activity and interests

Other symptoms of ASD:

  • Social anxiety
  • OCD
  • GI dysfunction
  • Sleep disturbances
  • Motor problems: lack refined coordination
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13
Q

What is the prevalence of ASD?

A
  • Estimated to affect 1 in 100 people worldwide
  • More prevalent in boys
  • Difficult to ascertain exact prevalence as it is a spectrum disorder with a broad range of phenotypes
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14
Q

What are the core, other behavioural and functional symptoms of ASD?

A
  • Core symptoms generally detectable in children before age of 3

Core symptoms:
- Persistent deficits in social communications and interactions

Other behavioural symptoms:

  • Anxiety
  • Hyperactivity
  • Agitation
  • Impulsivity
  • Aggressive behaviour

Functional symptoms:

  • Sensory hypersensitivity
  • Seizures
  • GI disorders
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15
Q

What are the phenotypes of ASD?

A
  • Intellectual disability (5%)
  • Language disorders (50%)
  • Epilepsy (5-15%)
  • ADHD
  • Anxiety disorders (up to 85%)
  • OCD (50%)
  • Motor disorders (95% of ASD patients with no intellectual disability)
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16
Q

What are the biomarkers for ASD?

A

Neuroimaging:

  • Young children with ASD have an enlarged and thickened cortical volume
  • Connectivity: young children have hypersensitivity to certain sensory stimuli as they have connections that have not been pruned
  • Functional: certain patterns in fMRI

Plasma:

  • Potential abnromal levels in BDNF (brain derived neurotrophic factor)
  • Serotonin consistently higher in 30% of ASD patients
  • Decreased nighttime production of melatonin
  • May not be correlated with changes to the brain
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17
Q

What is the neuropathology observed in ASD?

A
  1. Early brain enlargement between years 1 and 2:
    - Increased cortical thickness and folding in parietal love
    - Decreased pruning
    - Decerased GABA (inhibitory) expression in superior frontal lobe and parietal cortices
    - Abnormal columnar structure in neocortex
    - Hypometabolism in front regions
  2. Increased brain volume dissapears around ages 6-8
    - Due to abnormal slowness in brain growth
  3. Abnormaliites in limbic structures in older individuals:
    - Reduction in volume (smaller more tightly packed neurons)
    - In hippocampus, amygdala and cingulate cortex
  4. Cellular abnormalities:
    - Decreased volume, size and number of Purkinje cells (major cell type in cerebellum)
  5. Morphological/organisatioon deficits in cortex:
    - 5 year old autistic child has many more cells in the cortex, more defined smaller columns, more neural connection, more smaller cells
    - Leads to inflammatory response against structural abnormalities
    - Displacement of interneurons (disruption of excitatory/inhibitory ratio)
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18
Q

What are the genetic factors involved with ASD?

A
  • ASDs are highly heritable (approx 90%)
  • No identifiable chromosomal regions found
  • Large number of ASD susceptibility genes including:
    1. scaffold proteins (SHANK 2 and 3)
    2. Adhesion molecules (cadherins)
    3. GABA receptor subunits
    4. Voltage gates calcium subunits
    5. Regulators of chromatin remodelling
    6. Proteins involves in synapse formation
  • Many single nucleotide variants have been found- but each only has low risk
  • De novo copy mutations are also seen
  • It is hypothesised that many variants of genes contribute to tipping an individual into ASD diagnosis
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19
Q

What are the theories of ASD?

A
  1. Impeded plasticity:
    - Abnormal regulation of cell division and apoptosis
    - Hyper- followed by hypo- connectivity
    - Used to be very popular, less so now
  2. Excitation and inhibition dysregulation:
    - Imbalance of glutaminergic and GAGAergic synapses
    - Can explain epilepsy
    - Most favoured theory
  3. Theory of mind:
    - Impaired theory of mind leads to deficit in social behaviour and communications
  4. Mirror neurons:
    - Dysfunction in mirror neuron system is thought to generate social and cognitive impairments
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20
Q

What are the risk factors for ASD?

A
  1. Infection/Immune dysfunction:
    - CSF of ASD children contains atypical levels of autoantibodies against neural antigens
    - Maternal infection could play a role
  2. Endocrine factors:
    - Maternal stress: intrauterine expsosure to cortisol and thyroxine
  3. Obstetric factors:
    - Low birth weight, preterm/c-section delivery
    - Uterine bleeds
  4. Environmental factors:
    - Maternal exposure to prescription medications, illicit drugs, heavy metals (mercury), environmental toxins and cigarette smoke
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21
Q

How is oxytocin related to ASD?

A
  • At birth oxytocin mediates a sudden reduction in intracellular Cl- which dacilitates the shift which protects GABAergic neurons from anoxic episodes
  • The hormone plays an important role in social behaviour
  • ASD children have lower baseline levels of oxytocin
  • Intranasal administeration of oxytocin is being trialled as a therapy for the core symptoms of ASD
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22
Q

How is ASD treated behaviourally?

A

Intervention models:

  • Discrete trial training (early intensive behavioural training)
  • Naturalistic training (embedding teaching with play)
  • Learning experiences an alternative program: promote social interaction in curriculum of children with ASD
  • Early Start Denver Model: individualised interventions in consultation

Skill based models:
- Functional communication training, positive behaviour support, self-management, speech generation

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23
Q

How is ASD treated phamacologically?

A
  • Medications such as anti-psychotics and stimulants to treat symptoms (do not treat cause)
  • Intra-nasal oxytocin being trialed
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24
Q

How is ASD modelled in animals?

A
  • There are currently no ideal animal models (all models have major limitations)
  1. Neonatal lesions:
    - In amygdala, cerebellum and medial prefrontal cortex
  2. Maternal intervention:
    - Prenatal valpronic acid exposure: affects the epigenome at critical developmental stages
    - Prenatal expoure to infection
  3. Genetic models:
    - BDNF overexpression: high seizure susceptability, depression and anxiety behaviour, but no change in social behaviour
    - Fragile X mental retardation
    - GAGARB3 subunit KO: seizure susceptability, hyperactivity, stereotyped behaviour, learning and memory defects, impaired social interaction
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25
Q

What is schizophrenia?

A
  • A syndrome defined by observable signs of psychosis
  • No single defining symptom or laboratory test (heterogeneous syndrome)
  • Patients may present with paranoid delusion, hallucinations and thought disorders
  • Negative symptoms include diminished emotional expression and reaction, loss of participation, drive and interests
  • Affects 0.5-1% of the population
  • Usually diagnosed in young adults (18-25)
  • Highly heritable
  • Children with early onset schizophrenia have excessive grey matter loss
  • Disorder slightly more prevalent and severe in men
26
Q

How is schnizophrenia diagnosed?

A

DSM:

  • 2 or more of the following:
  • delusions
  • hallucinations
  • disorganised speech
  • catatonic behaviour
  • negative symptoms
  • Signs of disturbance must persist for 6 months
27
Q

What is the two-hit hypothesis of schizophrenia?

A

First hit:

  • Fetus undergoes some kind of trauma in utero that increases their risk e.g. maternal infection
  • Causes deficits in processes of neurogenesis, proliferation, migration, synaptogenesis etc.
  • Impacts structural proteins such as SHANK3

Second hit:

  • Person experiences trauma in early or late childhood e.g. social isolation, stress
  • Deficits in brain reorganisation such as dendritic arborization, synpatic pruning
  • Disrupts the excitatory/inhbitory balance
  • Can be followed by ‘booster hits’
  • The window when interventions are most effective is in adolescence, immediately after the second hit and before symptoms manifest
28
Q

What are the neuropathological signs of schizophrenia?

A
  1. Cortical thinning in the prefrontal region
  2. Cortical thickening in the parietal region
  3. Reduces dorsolateral prefrontal cortex interaction
  4. Decreased activation of hippocampal formation
  5. Connectivity of excitatory neurons and inhibitor neuron activity is reduced
29
Q

What are the risk factors for schizophrenia?

A

Prenatal/perinatal events:

  • Maternal malnutrition
  • Maternal infections
  • Maternal adverse life events
  • Labour and delivery complications

Premorbid risks:

  • Social adversities: physical and sexual abuse, neglect, bullying
  • Drug abuse- amphetamine, cocaine use
  • Urban environment
  • Migrant status
30
Q

Describe the genetic risk patterns in schizophrenia?

A

Monozygotic twins:
- 50% risk

Children of 2 affected parents
- 25% risk

Siblings
- 10%

Children of 1 affected parent:
-8%

Dizygotic twins:
- 5%

31
Q

What are the genetic links of schizophrenia?

A
  • Genetic predisposition
  • Heritability of 64-81%
  • At least 20 genes with strong linkage
  • Highly polygenic
    e. g. chromosome t 1;11 confers very high risk
    e. g. neruexin
    e. g. dopamine D2R
  • GWAS has identified 108 chromosomal loci
  • DISC1 i the best supported candidate gene
32
Q

How is schizophrenia treated phamacologically?

A
  • Used to manage symptoms
  1. Neuroleptics:
    e. g. haloperidol
    - DA2R anatagonists
    - Can cause rigidity and tremors
  2. Atypical anti-psychotics
    e. g. clozapine, rispiridone
    - exact mechanisms unknown, generally thought to antagonise DA2 receptors (also block 5HT2a receptors)
    - Decreased extrapyrimidal side effects
33
Q

How is schizophrenia treated behaviourally?

A

CBT:

  • Aims to reduce impact of positive symptoms
  • Used as an addition to anti-psychotic medication
  • Not effective for all patients

Supportive psychotherapy:
- Aims to help patients deal with loss, disability and stigma of living with schnizophrenia

34
Q

What are the animal models of schnizophrenia?

A

Pharmacological:
- NMDA R antagonists e.g. ketamine, produce range of schizophrenic symptoms

Lesion:
- Neonatal lesion of the ventral hippocampus- hyperlocomotion, social and working memory defects

Genetic:

  • DISC1 mutation mice: some but not all symptom
  • Neuregulin KO- some but not all symptoms
  • NMDAR knockdown
35
Q

What is the biopsychosocial model of health?

A

Takes into account biological factors e.g. genes, immunity, sex, social factors e.g. religeon, culture and relationships and psychological factors e.g. personality and self-esteem into the definition of health

36
Q

What is mental health?

A
  • Not only the absence of mental illness, but also the ability to live a harmonious and satisfying life
  • High levels of self-confidence
  • Positive thoughts
  • Low levels of stress and anxiety
  • Positive self-esteem
37
Q

What are affective disorders?

A
  • Mild, moderate and severe depression dysthymia and bipolar
  • Prevalence of 6.2%
  • Includes mood disorders
38
Q

What are anxiety disorders?

A
  • Panic disorder, agaraphobia, GAD, OCD and PTSD

- Prevalence 14.4%

39
Q

What are substance abuse disorders?

A
  • Abuse or harmful use and dependence on alcohol, cannabis, opiods, sedatitive and stimulants
  • Prevalence 5.1%
40
Q

What are psychotic disorders?

A
  • Group of psychiatric disoders characterized by severe disturbances in emotion, language, perception, thought processes etc.
  • Prevalence 1%
41
Q

What proportion of the population in Australia has experienced a mental disorder at some point in their lifetime?

A
  • 45.5%
42
Q

What is dementia?

A
  • A collection of symptoms caused by disorders affecting the brain
  • Marked by a decline in cognitive reasoning, losses in motor, emotional and social functioning
  • Permanent and progressive
  • Early onset is forgetfulness and confusion
  • 50 different causes including AD, vascular dementia, Huntington’s etc.
43
Q

What are the hallmarks of aging?

A
  1. Oxidative stress (production of ROS that is not counteracted with anti-oxidants)
  2. Mitochondrial dysfunction (complexes I and IV of ETC are particularly susceptible to dysfunction in ageing process
  3. Telomere shortening: more susceptible to DNA damage
  4. Epigenetic modifications: abnormalities in histone modifying enzymes and higher order chromatin remodelling factors leads to neurodegeneration
  5. Protein misfolfing (loss of proteostasis)
  6. Autophagy
44
Q

What are common features of neurodegenerative diseases?

A
  1. Delayed onset (age is a major risk factor)
  2. Selective neuronal vulnerability
  3. Abnormal protein processing and aggregation
  4. Cellular toxic effects involving both cell autonomous and cell-cell interaction mechanisms
  5. Unknown etiology (most)
45
Q

What are the principles of pathogenesis in neurodegnerative diseases?

A
  1. Accumulation of aberrant or misfolded proteins
  2. Defective protein handling- degredation
  3. Aberrant epigenetic mechanims
  4. Metabolic dysfunction- leads to ROS
  5. Neuroinflammation
46
Q

What are the primary target neurons of:

  1. AD
  2. PD
  3. HD
  4. Spinocerebellar ataxia
  5. Prion disease
A
  1. AD:
    - cortical and hippocampal neurons
  2. PD:
    - dopaminergic neurons (nigrostriatal)
  3. HD:
    - striatonigral neurons
  4. Spinocerebellar ataxia:
    - Purkinje cells in cerebellum
  5. Prion disease:
    - cortical neurons
47
Q

What is mTOR?

A
  • mTOR is a master regulator of cellular growth and metabolism in response to nutrient and hormonal cues
  • Activation of the mTOR pathway is linked to aging
  • Blocking of mTOR (e.g. via metformin which blocks AMPK) has been shown to: enhance stress resistance, stimulate autophagy and improve mitochondrial function
48
Q

How is dementia defined?

A
  • Significant loss of intellectual abilities severe enough to interfere with social or occupational functioning
  • Third leading cause of death in Australia
  • 1 in 4 people aged over 85 are affected
  • Most commonly the result of Alzheimer’s disease
49
Q

What is the typical and atypical presentation of AD?

A

Typical presentation:

  • Memory impairment
  • Executive dysfunction (issues with planning and problem solving)
  • Confusion and agitation
  • Mood and personality changes

Atypical presentation:

  • Language impairment
  • Visual problems
  • Motor dysfunction
50
Q

What are the pathological hallmarks of AD?

A
  1. Aggregation of B-amyeloid plaques (extracellular)
    - caused by actions of beta and gamma secretases forming AB1-42
    - thought to be causative
  2. Neurofibrillary tangles of hyperphosphorylated tau protein (intracellular)
    - correlate well with progression of AD
  3. Synaptic dysfunction and neuronal cell death
  4. Hippocampal atrophy and memory deficits
51
Q

How is AD diagnosed?

A
  1. Cognitive performance (to diagnose dementia
  2. No reliable biomarkers of disease in CSF
  3. Neuroimaging: hippocampal atrophy and amyloid pathology
52
Q

What are the treatments for AD?

A
  1. Symptomatic:
    - Cholinesterase inhibitors
    - NMDA receptor antagonists

2 .Disase modifying

  • Not currently used
  • A-B vaccine or y-secretase inhibitors to prevent amyloid plaque formation
  • Kinase inhibitors/phosphotases to prevent Tau hyperphosphorylation
  • Neuroprotective agents to prevent synaptic dysfunction -e.g. anti-inflammatory and anti-oxidant drugs
53
Q

What animal models are used to study ADD?

A
  • Animals that express the human transgene of mutated form of APP and preinsulin 1 and 2
  • Can be single (APP mutation), double (APP and preinsulin-1) or triple (APP, PS1 and Tau) transgenic
  • There are no good animal models
  • Mice generate AB proteins that do not aggregate
  • A human mutation must be introduced in mice
54
Q

What is PD?

A
  • Progressive neurodegenerative disease
  • Results from death of dopamingeric neurons in substania nigra (striatonigral neurons)
  • Result of degeneration of substantia nigra pars compacta
  • Characterised by accumulation of a-synuclein Lewy bodies and Lewy neurites in the dopamingergic neurons of the substantia nigra, ANS and olfactory bulb
55
Q

What are the clinical features of PD?

A

T - tremor at rest
R - muscular rigidity
A - akinesia
P - postural/gait instability (ataxia)

56
Q

What are some motor and non-motor symptoms of PD?

A
  • Non-motor symptoms precede motor symptoms by at least a decase (prodromal)
    1. Sleep dysfunction
    2. ANS dysfunction (constipation, daytime urinary urgency)
    3. Olfactory dysfunction- hyposmia
    4. Psychiatric symptoms
    5. Cognitive impairment-dementia
    6. Pain

Motor Symptoms:

  1. Bradykinesia
  2. Akinesia
  3. Tremor in fully resting limb
  4. Rigidity
57
Q

What are the genetic contributors of PD?

A

Autosomal dominant PD:

  • Mutations in a-synuclein
  • Leucine rich repeat kinase 2 mutations
  • Vps35 mutations

Autosomal recessive PD:

  • Parkin (major mutations in early onset)
  • DJ-1
58
Q

What are risk and protective factors for PD?

A

Environmental risk:

  • Pesticide exposure
  • Prior head injury
  • Rural living
  • Beta-blocker use
  • Agricultural occupation
  • Well water drinking

Environmental protective:

  • Tobacco smoking
  • Coffee drinking
  • NSAID use
  • Ca channel blocker use
  • Alcohol consumption
59
Q

What treatments are there for PD?

A
  • Currently only treatments to manage symptoms:
    e. g. Levodopa, dopamine agonists and monoamine oxidase B inhibitors to increase dopamine content and increase its effects
    e. g. anticholinergics for treatment of tremors
    e. g. cholinsterase inhibitors for treatment of dementia
    e. g. clozapine for treatment of tremors
60
Q

What are the pathways involved in PD associated reduced amplitude of movements?

A

Direct pathway:
- Degeneration of dopaminergic neurons means less activation of the direct pathway

Indirect pathway:

  • Degeneration of dopaminergic neurons means less inhibition of indirect pathway so there is greater inhibition of Gpe, less inhibition of the STN, greater stimulation of the GPi, more pronounced inhibitory outputs to thalamus
  • Results in motor dysfunction
61
Q

How is PD modelled in animals?

A
  1. Gene-based:
    - a-synuclein transgenic mice, do not show progressive loss of DA neurons, but show lewy-body like inclusions, neuronal atrophy and neurite dystrophy
  2. Toxin model:
    - Injecting toxins such as MPTP causes degeneration of DA neurons
    - Injection of 6-OHDA in rats