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Molekulare Biomedizin > Techniken der Neurobiologie > Flashcards

Techniken der Neurobiologie Flashcards

1
Q

EEG

A
  • surface potential
  • differential potential
  • 10-20 system
  • diagnostic of epileptic focal- and generalized seizures
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2
Q

evoked potentials -> different compartments

A

different components:
- subcortical
- primary cortex
- secondary cortex

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3
Q

sensory evoked potential

A

nerves -> Leg: tibialis, fibularis -> arm: median, ulnar
trigger -> square wave stimuli
intensity -> above the motor threshold
frequency -> 3 Hz
repetitions -> 1000-1200

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4
Q

visual evoked potentials (VEP)

A
  • the VEP tests the function of the visual pathway from the retina to the occipital cortex
  • it assesses the integrity of the visual pathways from the optic nerve, optic chasm and optic radiations to the occipital cortex
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5
Q

VEP

A

Waveforms
- the initial negative peak (N1 or N75)
- a large positive peak (P1 or P100) Negative peak (N2 or N145)

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6
Q

use of VEP in neurology

A
  • diagnosis of multiple sclerosis (MS) (optic nerve demyelination, optic neuropathy is often the first sign of MS, in definite cases of MS - abnormalities in VEP occur in about 85-90% of patients, the changes in the P100 response include interocular difference in latency, prolonged absolute latency, decreased amplitude and distorted shape)
  • compression of the optic nerve and chasm by tumors - decreased amplitude and prolonged latency of the P100 response
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7
Q

TMS Basics - single pulse TMS

A
  • corticospinal excitability
    -> motor threshold
    ->MEP Amplitude (NMDA, GABAa))
  • corticospinal inhibition
    -> contralateral silent period (at low TMS intensities GABAa; at high TMS intensities GABAb)
    -> ipsilateral silent period
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8
Q

TMS Basics - paired pulse TMS

A
  • sensorymotor integration
    -> short interval afferent inhibition (SAI)
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9
Q

TMS in Parkinsons Disease

A
  • short interval intracortical inhibition
    -> reduced SICI or enhanced ICF
  • short interval afferent inhibition (SAI)
    -> conflicting findings
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10
Q

The nervous system

A

the central (CNS) + the peripheral nervous system (PNS)

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11
Q

CNS

A

brain + spinal cord

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12
Q

PNS

A

somatic and autonomic nervous system

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13
Q

Human brain

A
  • weight = 1400 g
  • protected by the meninges, skull and cerebrospinal fluid (CSF)
  • shape of a walnut
  • on the surface: Gysi = bumps and various sulk (or fissures) = grooves
  • two hemispheres
  • grey and white matter: neurons and fibers
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14
Q

Structures of the brain

A
  • Corpus
  • Callosum
  • Pituitary
  • Pons
  • Medulla
  • Spinal Cord
  • Cerebellum
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15
Q

the Cerebrum

A

The cerebral cortex is responsible for many “higher-order” functions
- sulcus centralis
- main motor region (M1) and main sensory region (S1)

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16
Q

functional divisions of the cerebral cortex

A
  • auditory association area
  • auditory cortex
  • speech center
  • prefrontal cortex
  • motor association cortex
    -primary motor cortex
  • primary somatosensory cortex
  • sensory association cortex
  • visual association area
  • visual cortex
  • Wernickes area
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17
Q

Higher order function

A
  • frontal lobe (planning, decision making, problem solving, language)
  • occipital lobe (vision)
  • Parietal lobe (reception and processing of sensory information)
  • temporal lobe (memory, emotion, hearing, language)
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18
Q

Higher order function: language

A

• Most of the language processing takes place in the left hemsphere.
• Language comprehension: Wernicke’s area .
Without this area, people can hear the words or read the letters, but have difficulty attributing meaning to them.
• Speech production: Broca’s area.
When damaged, people are unable to produce language properly. They may speak in disconnected words, for example. Hence, broca’s area is most associated with.
Aphasia: Loss of the ability to produce and/or comprehend language

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19
Q

the basal ganglia - modification of movements

A

• Extrapyramidal System
• Various nuclei connected in a
complex network: putamen, caudate, globus pallidus, substantia nigra, subthalamic nucleus (and thalamus as output structure)
• Neurotransmitters:dopamine, acetylcholine, glutamate
“Too little or to many” -> movement disorders (hypokinetic / hyperkinetic)

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20
Q

the cerebellum

A

incoordination, imbalance, speech disorder (dysarthria), eye movement abnormalities

Causes: alcohol, strokes, tumors, neurodegenerative disease

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21
Q

anatomy of the cerebellum

A
  • Archicerebellum
  • Paleocerebellum
  • Neocerebellum
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22
Q

Cerebellar connections

A

Input
- inferior cerebellar peduncle (sensory)
- middle cerebellar peduncle (efference copy)

Output
- superior cerebellar peduncle (information to cortex)

Afferents
- Spinal cord -> Spinocerebellum
- Cerebral cortex -> Neocerebellum
- Vestibular nerves -> Vestibulocerebellum

Efferents
- dentate nucleus -> Thalamus
- Nucleus interpositus -> Nucleus ruber
- Ncl. fastgii -> Formation reticularis
- L. flocculonodularis -> Vestibular nuclei

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23
Q

Cerebellar systems

A
  • vestibulo cerebellar
  • reticulo cerebellar
  • rubro cerebellar
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24
Q

basic neurophysiology

A
  • identify mechanism that make the nervous system work
  • molecules, cells, groups of cells, functional systems
  • investivem time consuming, small number of “subjects” studied
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25
Q

clinical neurophysiology

A
  • diagnose disease in patients
  • correlates of functions of the intact human body
  • reliable, fast, cheap, benefit justifies the risk
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26
Q

parts of nerve cells

A
  • dendrites -> summation of input
  • cell body -> metabolism
  • axon -> propagation of the signal
  • synapse -> transmission of the signal
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27
Q

functions in nerve cells

A
  • reception of information (chemical and electrical)
  • calculation (electrical)
  • signal transport (electrical)
  • Signal transmission (chemical)
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28
Q

Biological membranes

A
  • lipid bilayer (glycerol ester)
    -> electrical isolation
    -> chemical isolation

membrane proteins
-> transport
-> signal transduction
-> mechanical stability
-> immune mechanisms

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29
Q

resting potential

A

initial situation
- concentration difference between intracellular and extracellular
- conduction across membrane only for kations

equilibrium
- zero NET current
- positive NET charges on the outside

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30
Q

action potential

A
  • increase in Na conductivity
  • reversal in the membrane potential: “depolarisation”
  • increase in the K conductivity
  • membrane potential returns to baseline: “depolarization”
  • Na channels inactivated
  • membrane potential below resting potential: “Hyperpolarisation”
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31
Q

voltage gated sodium channel

A
  • selectivity filter
  • voltage sensitive element (fast)
  • inactivation particle (slow)
  • activation gate (“a-gate”)
  • inactivation gate (“i-gate”)
32
Q

excitable membranes: voltage gated sodium channel

A

NaV1.1: Dravet-Syndrom (Epilepsy), familial hemiplegic migraine
NaV1.4: Paramyotonica congenitita, Hyper K periodic paralysis
NaV1.7: Congenital indifference to pain
NaV1.5: Brugada Syndrom, Long-GT III (Rythmusstörung)

33
Q

Example of diseases caused by channel mutations

A

periodic paralysis
usually normal muscle but attacks with severe generalized weakness of a few hours duration

hyperkalemic/hypokalemic
attacks precipitated by changes in potassium blood level

34
Q

Motor Neurography: Parameters

A

DML: distal motor latency
CMAP: Compound Muscle Action Potential
NCV: Nerve Conduction Velocity (distance/*)

35
Q

Synapse & synaptic spines -> structural plasticity and actin dynamics

A

Activity-dependent synaptic plasticity
LTP -> growth in the postsynaptic density (PSD) and the whole spine
LTD -> shrinkage
-> accompanied by a change in the number of AMPARs in the PSD and presynaptically the number of docked presynaptic vesicles

Actin filaments play a major role in the regulation of the spine dynamics.
LTP induction
-> actin polymerization increases close to the PSD
-> G-actin (globular actin, monomers) to F-actin (filamentous) ratio shifts towards the F-actin in spine head enlargement

36
Q

Induction of LTP (E-LTP)

A

• postsynaptic depolarization (AMPAR) • activation of NMDARs
• kinases
• retrograde messengers

37
Q

Maintenance and expression (L-LTP)

A

• increased neurotransmitter release
• increased number of AMPAR
•Protein synthesis (!)
• Activity dependent synthesis and release of BDNF (brain derived neurotrophic factor)
•Effects exerted on neighboring spines

38
Q

Strengthening of synapses can occur through

A

• An increase in the number of AMPAR
• Changes in the form and size of dendritic spines • Generation of new synapses

39
Q

The molecular impact of sleep deprivation on pathways critical for memory consolidation

A

Pathways:
- reduced glutamatergic signalling (while increasing adenosine levels)
- reduced phosphorylation of GluA1 containing AMPAR
-attenuated cAMP signalling
-atttenuated CREB mediated gene transcription
- attenuated translational processes through mTOR signalling
- attenuated phosphorylation of LIM kinase (LIMK) which modulates spine dynamics (structural plasticity)

downregulation LIMK phosphorylation -> down regulation coffin phosphorylation (corresponds to high coffin activity!) -> spine loss

40
Q

Genomic variations

A
  • Polymorphism – Generic term for genetic change
  • Variant – Same as polymorphism
  • SNP – Single nucleotide change with a MAF > 1% - -
  • Mutation – Variant with a MAF < 1%
  • Insertion/Deletion – Small scale change (few bases) -
  • Duplication/Triplication – Exon, gene, chromosome
  • Copy number – Generic term for duplications, etc. -
  • Minisatellite (VNTR) – >10 bp repeats >1 Kb
  • Microsatellite (STR) – <5 bp repeats and <500 bp
  • Missense – Change in amino acid sequence
  • Nonsense – Change from amino acid to stop
  • Silent – No change in protein sequence
  • Read-through – Change from stop to coding -
  • Synonymous – Same as silent
  • Nonsynonymous – Same as missense
  • Stop – Same as nonsense
  • Frameshift – a non-multiple of 3 indel
  • Non-frameshift substitution – multiple of 3 indel
41
Q

Parkinson’s disease

A

Clinical features:
- Resting tremor
- Bradykinesia Rigidity
- Postural instability
- 70 % Dopaminergic neuronal loss from substantia nigra
- prevalence: 1 % by 65 years, 5 % by 86 years

Non-motor symptoms:
- Hyposmia
- Gastrointestinal disorder
- Thermoregulation
- Depression
- REM sleep behavior disorder
- Cognitive decline dementia
- No drugs to delay onset or progression of the disease, only relieve symptoms

42
Q

Concept of recombination

A
  • Recombination is a process by which pieces of DNA are broken and recombined to produce new combination of alleles
  • Occurs during meiosis
  • Crossovers result in exchange of genetic material
43
Q

Linkage analysis

A
  • Method to identify genetic markers linked to a disease gene
  • Assess if the recombination frequency between a marker and disease
  • Logarithm of odds (LOD) score
    >3 is significant linkage
    >2 suggestive linkage
    <-2 is no linkage
44
Q

Linkage analysis -> parametric vs non-parametric

A

Parametric: model based linkage
- inheritance pattern
- disease prevalence
- disease allele frequency
- phenocopy rate
- allele risk
- marker distance

Non-parametric: model free linkage

45
Q

Second generation sequencing

A

Next generation sequencing: high-throughput sequencing
- Illumina -> HiSeq
- Proton

46
Q

Third generation sequencing

A
  • Oxford nanopore
    -> flow cell can generate up to 30 gb data
    -> 72 hours run for each flow cell
47
Q

Applications of NGS (Second generation)

A
  • Whole genome sequencing (WGS)
  • Targeted panel sequencing
  • Transcriptome analysis
  • Epigenetics
    -> ChIP (chromatin immunoprecipitation)
    -> Methylation
48
Q

After aligning and calling variants

A

Annotation to a number of databases
- EXAC/GnomAD – frequency of the variant in the general population
- ClinVar – is the variant implicated in disease?
- In-silico prediction tools: polyphen, SIFT, MutationTaster, CADD

49
Q

NAXE: neurometabolic disorders

A
  • fluctuating course, various movement disorders (ataxia, chorea, spastic tetraparesis), respiratory insufficiency and episodes of intermittent comatose states
50
Q

Odds ratio

A

likelihood of developing disease with a specific genetic trait

51
Q

Parkinson’s disease

A

• Parkinson’s disease (PD) is a progressive neurodegenerative disease
• The pathological hallmarks of PD are
• a loss of dopaminergic neurons of the substantia nigra
• a-synuclein-rich inclusions in the brain, called Lewy bodies
• The etiology of PD is mainly unknown

Impairment of electron transport chain (ETC) activity in multiple tissues from individuals with PD: brain, platelets, lymphocytes, muscle and fibroblasts.

can be idiopathic, sporadic and genetic, familial
can be monogenic: mutations in PINK1 and Parkin cause indistinguishable forms of PD -> strong link between mitochondrial dysfunction and PD

52
Q

Parkin

A
  • Parkin encodes a 465-aa cytosolic E3 ubiquitin ligase
  • Mutations in Parkin cause autosomal recessive PD
  • Parkin functions in the ubiquitin proteasome system (UPS), where it ubiquitinates a number of substrates
  • Parkin has a role in maintaining mitochondrial function and integrity
53
Q

PTEN induced putative kinase 1 (PINK1)

A
  • the PINK1 gene encodes a 581 aa mitochondrial kinase
  • mutations in PINK1 are a cause of autosomal recessive PD
  • loss of functional PINK1 leads to mitochondria-related abnormalities:
    -> electron transport chain dysfunction
    -> reduced mitochondrial membrane potential
    -> mitochondrial fragmentation
54
Q

Effect of PINK1 and Parkin

A
  • low levels of PINK1 on mitochondria
  • Parkin remains in the cytosol
  • PINK1 accumulates on damaged mitochondria
  • Parkin translocates to mitochondria
  • PD-causing mutations in PINK1 impair mitochondrial translocation of Parkin
55
Q

Mitochondrial dynamics

A

• Mfn1/2 are ubiquitinated upon loss of the mitochondrial membrane potential
• Both PINK1 and Parkin are necessary for the stress-induced ubiquitination of Mfn1/2
• PD-causing mutations in PINK1 or Parkin impair ubiquitination of Mfn1/2
• Ubiquitinated Mfn1/2 are degraded via the UPS

56
Q

Conclusion PINK1 and Parkin and mitochondrial dynamics

A

• Mitochondrial quality control via PINK1- and Parkin- mediated mitophagy removes damaged mitochondria
• Mutations in PINK1 and Parkin lead to the accumulation of damaged mitochondria
• Accumulation of damaged mitochondria leads to cell death and neurodegeneration

57
Q

Induction of pluripotency

A

• iPS cells can be derived from patient‘s fibroblasts (age-independent) using Oct4, Sox2, Klf4 and cMyc
• iPS cells can be differentiated into cells of the three embryonic germ layers
• iPS cells express a network of endogenous pluripotency genes
• Reprogramming is a rare and stochastic event that often leads to partially reprogrammed cells

58
Q

Neural induction

A

• During embryonic neural induction, the neuroepithelia is specified first in the head and extends caudally
• The first step in neural differentiation follows the neural induction principle. Therefore, the neuroepithelia differentiated from iPS cells carries an anterior forebrain identity (cerebral cortical neurons)
• Main caudalizing morphogens are WNTs, FGFs, and retinoic acid
• The dorsal-ventral patterning is governed by Sonic hedgehog (SHH) for
ventralizing and the activity of WNT and BMP pathways for dorsalization
• Activation of the pathways exerts a precise dose-dependent effect in patterning the neuroepithelia to forebrain, midbrain, hindbrain, and spinal cord.

59
Q

Dopaminergic neurons

A

• iPS cells can be differentiated into dopaminergic neurons by defined activation of the WNT and SHH pathways
• Dopaminergic neurons demonstrate the expression of neuronal subtype markers (e.g. tyrosine hydroxylase), synthesize and release dopamine
• Mutant VPS35 leads to defective receptor recycling in dopaminergic neurons

60
Q

Microglia in PD

A

• Neurohistological findings support the presence of neuroinflammatory processes in PD. Moreover, numerous studies of peripheral blood and cerebrospinal fluid from patients with PD suggest alterations in markers of inflammation and immune cell populations.
• iPSC-derived microglia express key microglia-specific markers and are phagocytic.
• Upon activation with mitochondrial and bacterial stressors microglia release inflammatory cytokines.
• Co-cultures with neurons represent a human-derived patient-specific model to study inflammation in PD.

61
Q

The drosophila genome

A

• 4 chromosomes vs 23
• ~15,500 genes vs 22,000
• ~140 million base pairs vs 3
billion

62
Q

Several tools exist to facilitate the work with flies

A
  1. Balancer chromosomes are genetically engineered chromosomes
    -> • Suppression of recombination
    • Homozygous lethal – Exception: X-chrom
    • Presence of markers (dominant and recessive)
  2. All genes are present but many are inverted
  3. Crossing over does not occur during meiosis
63
Q

Exception in male flies

A

crossing over does not occur

64
Q

Eyes of flies

A

heterozygous body -> homozygous eyes
- Alp system is often used in the eyes

65
Q

Knock down using RNAi lines in flies

A

tissue-, cell-, or stage-specific promoter -> 300-400bp inverted repeats -> hpRNAs -> siRNAs -> endogenous mRNA

66
Q

Oxy- and deoxygenated Hb

A

Oxygenated hemoglobin is converted to deoxygenated hemoglobin at a constant rate within the capillary bed.

When neurons become active
- the vascular system supplies more oxy- genated hemoglobin than is needed by the neurons, through an overcompen- satory increase in bloodflow.
- This results in a decrease in the amount of deoxygenated hemoglobin and a corresponding decrease in the signal loss due to T2* effects, leading to a brighter image.

67
Q

MRI

A

one image - high resolution

68
Q

fMRI

A

many images - lower resolution e.g. every 2 s 3 mm resolution

Blood Oxygenation Level Dependent (BOLD) signal
indirect measure of neural activity
­ up regulation neural activity -> upregulation ­ blood oxygen -> up regulation ­ fMRI signal

69
Q

Neurogenetics

A

• Many cognitive functions and personality traits are at least to some degree heritable.
-> What are the relevant genes?

Normal distribution of cognitive functions suggest that many genetic factors have to be involved.

70
Q

Neurotransmitters

A
  • Behavior (negative, positive) and mood are regulated by neurotransmitters. Dopamine and serotonin are central in reward pathways.
  • Reward pathways are activated by addictive drugs. The brain regions primarily involved are the prefrontal cortex (PFC), the nucleus accumbens (Nac), the ventral tegmental area (VTA), the striatum and the (hypo)thalamus.
  • Stimuli of the reward pathways may go via serotonin (hypothalamus) -> encephalin (substantia nigra) -> GABA (VTA) -> dopamine (Nac).
  • Addictive drugs increase the levels of dopamine; susceptibility to addiction involves polymorphisms in Dopamine receptors, dopamine and/or serotonin transporters, enzymes degrading dopamine and serotonin (these enzymes are: MAO; COMT).
71
Q

Dopamine synthetisation and signals

A
  • Dopamine is synthesized from tyrosine (or phenylalanine) in the catecholamine synthesis pathway), serotonin is generated from tryptophan. Both are stored in intracellular vesicles. VMAT (vesicular monoamine transporter) transports the neurotransmitters into the vesicles. The transport (= re-uptake) of dopamine from the synaptic cleft into the neuron is inhibited by DAT (dopamine transporter) inhibitors, such as Cocaine and Ritalin. VMAT2 inhibitors of the benazine group interfere with transport into the intracellular vesicles.
  • Dopamine signals via two receptor (DR) types, the D1-like DR type and the D2-like DR type.
  • the dopamine receptor D1 type signals via a Golf protein protein, which activates the Adenylyl cyclase, leading to production of cAMP, which in turn activates the protein kinase a (PKA). The PKA phosphorylates down-stream proteins.
  • the dopamine receptor D2 binds a Gi protein, which inhibits the Adenylyl cyclase. D2 receptor expression is reduced in addiction.
72
Q

Brain regions and dopamine signaling

A
  • The striatum takes a central role in dopamine signaling. It consist of a dorsal and a ventral part. The dorsal part has sensomotoric functions, the ventral part takes roles in cognition and rewarding (= mood, emotion, addiction, reward-related effects).
  • 95% of the neurons in the striatum are dopaminergic. However, they receive input from e.g. GABAergic or glutaminergic neurons.
  • Subgroup 1: striationigral [medium-sized spiny neurons; primarily D1 dopamine receptors; project directly to substantia nigra]
  • Subgroup 2: striatopallidal [medium-sized spiny neurons; primarily D2 dopamine receptors; project indirectly to substantia nigra]
73
Q

DARPP32

A
  • The activation of the D1 receptors results in the activation of the PKA via cAMP.
  • In neuron, the PKA phosphorylates target proteins: (1) CREB, (2) DARPP32 (3) some other proteins
  • DARPP32 = dopamine- and cAMP-regulated phosphoprotein of 32 kDa
  • DARPP32 integrates a variety of biochemical, electrophysiological and neurological processes
  • DARPP-32 integrates the signals that regulate emotion, mood, reward, and cognition
  • Hence, DAPRR32 is the bottle neck in reward, abuse and addiction
  • The N-terminus of DAPP32 shows a high similarity to PP1 (= Phosphatase I Inhibitor)
  • DARPP-32 is a PP1-Inhibitor
  • DARPP-32 is additionally an inhibitor of PKA
  • DARPP-32 is phosphorylated by PKA and 3 more kinases (CDK5, CK1, CK2) [CK = casein kinase]
  • DARPP-32 phosphorylated in Thr34 binds to and inhibits the function of the phosphatase PP1
  • Binding of DARPP32-Thr34-P to PP1 are involved: (i) the Thr34 region and (ii) N-terminal KKIQF motif
  • De-phosphorylation of Thr34 is mediated by PP-2B (Calcineurin)
  • DARPP-32 phosphorylated in Thr75 behaves differently
  • DARPP32- Thr75-P inhibits the PKA and inhibits phosphorylation of DARPP32 in Thr34
  • DARPP32- Thr75-P inhibits phosphorylation of additional PKA-substrates by PKA
  • Signals that lead to DARPP32 phosphorylation are initiated by neurotransmitters
  • Dopamine (via D1), serotonin (via 5HT4/6), GABA (via GABAa), and Adenosine (via A2A) lead to DARPP32—Thr34-P
  • Dopamine (via D2), glutamate (via mGlu1/5) lead to DARPP32—Thr75-P
74
Q

Knock out mice demonstrate: any disruption of DARPP32 function is critical

A
  • DARPP32 takes a role in Parkinson‘s disease (“movement disorders”)
  • DARPP32 mediates the effects of drugs of abuse
  • DARPP32 in involved in the response to psychostimulants
  • DARPP32 influences sexual behavior
  • DARPP32 impacts on the circadian rhythm
75
Q

Target proteins of DARPP32 are

A
  • proteins of the MAP kinase cascade such as MEK
  • Neurotransmitter receptors such as the AMPA receptor. Here, DARPP32 affect the phosphorylation state.
76
Q

Parkinson’s disease (PD)

A
  • PD is a locomotor disease. PD often starts 10 years before diagnosis.
  • Early symptoms are loss of the olfactory sense, constipation and anxiety.
  • Later, PD is characterized by e.g. tremor of hands, shuffling gait, muscular weakness, excessive salivation, upper airway obstruction.
  • Psychiatric symptoms include e.g. depression, anxiety, decline in intellectual functioning and sleep-awake dysregulation.
  • PD is treated pharmacologically (Levodopa or dopamine agonists) or by DBS (deep brain stimulation).
  • Treatment with Levodopa leads to neuro-adaptive and behavioral changes. All of these can be explained by known dopamine functions.
  • Dyskinesia and uncontrolled locomotion are observed.
  • behavioral changes: Under Levodopa treatment patients may show excessive shopping, gambling and eating disorders
  • Both the modified behavioral and locomotor aspects are explained by D1 signaling via cAMP and PKA. The PKA acts on DARPP32, which in turn interferes with the function of the phosphatase PP1. This affects glutamate signaling. In addition, the activity of ERK kinase on DNA is changed: Over time this leads to an imprinting in the DNA and changes in gene expression.

Molekulare Biomedizin (5 decks)

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