Neuroscience Flashcards
NS DEV - What is Semaphorin-3A an example of?
Chemoattractant, secreted by cells near the plial surface
NS DEV - What does Semaphorin-3A induce?
Helps establish neural polarity and orientation of cortical neurons
NS DEV - Tests examining the function of Semaphorin-3A
Mutant mice lacking Semaphorin-3A exhibited disrupted orientation of cortical neurons.
NS DEV - What is the key neuronal element for axonal growth?
Growth Cones
NS DEV OR - Who discovered Growth Cones?
Ramon y Cajal
NS DEV What are growth cones?
Sensory structures that receive directional cues from the environment and motor structure that drives axon elongation
NS DEV What are the main components of the growth cones?
Microtubules, Mitochondria and other organelles.
NS DEV How do growth cones sense their environment?
Through Filopodia
What are between Filopodia?
Lamellipodia, which are motile units and give the growth cone its ruffled appearance.
Which 3 ways does Actin drive filopodia movement?
- Actin polymerization, pushing filopodia forward
- Force generated by retrograde flow of actin
- Filopodium contacting adhesive cues, contracting, and pulling the growth cone forward
OR = What hypothesis did Roger Sperry have involvement in?
Chemospecificity Hypothesis
How did Roger Sperry experiment regarding chemospecificity?
Cut optic nerve in frog.
Rotated the frogs eye 180 degrees before the nerves regenerated.
Once healed, presented the frog with fly above head, would jump down, presented below, it would jump up.
RETINAL AXONS HAD REINNERVATED THEIR ORIGINAL TECTAL TARGETS
Where can guidance cues be presented?
Cell surface, Extracellular matrix or as soluble forms
What do guidance cues do?
Either promote or inhibit filopodia growth
Where do growth cones diverge with ganglion cells?
Optic Chiasm
What is able to act as a Scaffold for axons?
A pioneer axon
What happens once a growth cone reaches its target?
Synapse forms
What are neurotrophic molecules
Signal molecules released from targets that keep neurons alive.
E.G Nerve Growth factor, Brain derived Neurotrophic Factor, Neurotrophin 3.
Function of Netrins
Netrin-1 can act as both a chemoattractant and repellent
What does Netrin-1 removal lead to?
Misrouting of Axons
What does Netrin-1 removal lead to?
Misrouting of Axons
Function of SLITS
Chemorepellents, mediated by ROBO and Roundabout receptors
Function of Ephrins
Cell surface signalling molecules, short range, bind to Trks.
Act as repellents and Attractants
Morphogens definition
Specify cell fate during embryonic development
Attractive morphogens
HGF, FGF and GDNF
What are guidance cues?
Signaling molecules that influence cell biological mechanisms by which growth cones extend, turn and retract.
SYNAPSE FORMATION
- Growth cone approach newly fused myotube
- Forms unspecialised contact
- Nerve terminal accumulates synaptic vesicles, basal lamina forms in the synaptic cleft.
- Multiple axons converge on a single site.
- All axons but one are eliminated and surviving terminal matures.
Synaptic pruning
Developmental process by which the brain refines and removes extrasynaptic/redundant synapses within the brain. Whilst others get strengthened and retained.
How do neurons establish?
By trophic regulation, interactions continue to modulate the formation of synaptic connections.
How does synaptic pruning occur?
Through autophagy via microglia which engulf and digest unwanted or unnecessary synaptic connections = elimination.
What does pruning promote?
Strengthening of other synaptic connections.
How has Schizophrenia been linked to synaptic pruning?
Believed that Schizophrenia arises due to synaptic pruning faults. TOO MUCH PRUNING
Which chromosome defect has been linked to Schizophrenia?
Chromosome 6, in which a single nucleotide polymorphism affects the C4 gene.
What involvement does the microtubule cytoskeleton have in Filopodium growth?
Regulates elongation of the axon
What involvement does the actin cytoskeleton have in Filopodium growth?
Regulates changes in the growth cone
How is growth cone growth and movement generated?
By cytoskeleton rearrangements; polymerisation and depolymerisation of actin and tubulin.
Examples of non-diffusable guidance molecules?
Integrins, CAMs, cadherins and ephrins
Diffusable guidance molecules?
Netrins, Slits
Examples of neurotrophic receptors?
Trk - Tyrosine Kinase, promote cell survival, activated by neurotrophins.
p75 receptor - promotes cell death and is inhibited by neurotrophins.
Genetic factors involved in Schizophrenia?
C4 gene splits into C4a and C4b of the complement system.
Too many copies of C4a increase the risk of Schizophrenia.
How has the immune system been shown to have involvement in Schizophrenia?
C4a mediated molecules clear pathogens and debris.
C4 molecules tag synapses for pruning via microglia recruitment, which destroy synapses.
What would too many C4a copies lead to ?
Excessive pruning = schizophrenia.
Which NS is capable of axon regeneration?
PNS
What makes the PNS able to regenerate axons?
Schwan cells (Glial cells), which promote axonal regrowth.
Damaged axon disintegrates and Schwann cells remove fragments within 2-3 weeks.
What do Schwann cells do which prompts axonal regeneration?
Secrete basal lamina, which provides pro-generative Extracellular matrix.
What means the CNS cannot regenerate axons?
Oligodendrocytes of the CNS inhibit regrowth and promote glial scar formation.
- These inhibit nerve regeneration.
- Damage axons are therefore not disintegrated.
- They do not secrete basal lamina.
OR - What research has Dr Massimo Hilliard conducted on nerve cells?
- Looked at mechanisms of self repair.
- Stitched axons together through axonal fusion in C.elegans.
- Studied involvement of Fusogen which fuses the proteins.
Humans do not produce these proteins
Which region of the NS is constantly regenerated?
The olfactory bulb.
OR- what experiments have been conducted for repair of the spinal cord?
- Olfactory bulb removed and OB cells injected into cells of the spinal cord to bridge repair.
Slight success, functions regained in part.
Similarities between the Developmental and repair mechanisms of the NS
- Cellular processes are similar - both require neuronal proliferation, migration and differentiation of stem cells.
- Synaptogenesis - synapse formation is key. Need new neurons to form synapses for integration.
- Neuroplasticity - allows adaptation to new circumstances and recovery from injuries
Differences between the Developmental and repair mechanisms
Timing - developmental mechanisms occur during embryonic and early post-natal life, whilst repair occurs later following damage.
Complexity - there are more stages to developmental processes than repair.
Source of stem cells - during dev = specialized regions of the embryo (inner cell mass of the blastocyst). In adulthood = from specialised regions of the brain (Subventricular region, Cortex and Hippocampus).
Where do the Ventral Tegmental area dopaminergic neurons project to?
Amygdala, Hippocampus and Nucleus Accumbens
What role does the Amygdala have in reward pathway?
In emotion related to rewarding experiences
What role does Hippocampus have in reward pathways?
Memory related to rewarding experience
What role does the Nucleus Accumbens have in reward pathways?
Movement to, as in for repeating the reward pathway.
How did the reward pathway evolve?
To improve fitness and increase survival.
e,g water, food, sex
What are the molecular targets of Opiates?
u opoid receptor (agonist)
What are the molecular targets fo Nicotine?
Nicotinic acetylcholine receptors (agonist)
What are the molecular targets fo Cannabinoids?
CB1 cannabinoid receptors (agonist)
What is Addiction?
A chronic, relapsing disease. Involves both physical and psychological dependence
What is the cause of addiction?
Dysregulation of circuits for reward and emotion?
What do dopaminergic neurons carry information about in the reward pathway?
Reward related information from the ventral tegmental area
What do glutaminergic neurons carry information about in the reward pathway?
Sensorimotor information from the cerebral cortex to make excitatory synapses on dendritic spines
Where do dopamine and glutamate interact in the reward pathway?
Synaptic spines in the nucleus accumbens
What do drugs of abuse affect?
The projections from the VTA to the nucleus accumbens.
How do drugs affect dopamine ?
They can prolong the action of dopamine in the nucleus accumbens.
What effect does nicotine and ethyl alcohol have on dopamine?
They can cause dopamine to be released in the nucleus accumbens
What does chronic exposure to drugs result in?
Molecular and cellular changes in the brain
What have PET scans of addicted individuals brains shown?
Lower D2 receptor availability
What has fluorescence microscopy shown in addicted individuals brains?
Lower dendritic spine density
What does excessive dopamine stimulaiton lead to?
Remodelling of synapses
What is triggered by dopamine?
Intracellular signalling pathways
What do D1 receptor binding lead to?
Activation of adenylyl cyclase, production of cAMP and activation of Protein Kinase A
What does protein kinase A do in the D1 mediated pathway?
Phosphorylate the cAMP responsive element binding protein (CREB-1)
What does CREB-1 do in the D1 mediated pathway?
Bind to CRE which results in transcription of downstream genes. E
What does D1 mediated transcription of downstream genes lead to?
Alteration of cellular function
Which downstream genes are produced?
Arc, Homer, Fos and FosB
What are the cellular results of the downstream genes?
Homeostatic responses to excessive dopamine stimulation, synapse remodelling, behavioural changes and memory formation
What occurs with repeated drug use?
Increased tolerance as a result of decreased effect after repeated use.
How does dependence occur?
When neurons adapt to the repeated drug exposure.
How is dependence manifested physically?
Through withdrawal when the drug is removed
Why do symptoms of withdrawal occur?
As the neurons only function normally in the presence of the drug.
Which neurons does Alcohol bind?
Inhibitory GABAa on glutaminergic neurons
What does Alcohol binding to GABAa lead to?
Inhibition/sedation
What happens with chronic alcohol use?
GABAa receptors become desensitised and downregulated leading to tolerance.
Which receptors are upregulated with chronic GABAa use?
NMDA
What occurs in the absence of chronic alcohol use?
Inhibitory input is decrease which leads to overexcitation manifesting as withdrawal.
What is the reward pathway and what is its function?
Gives sensation of reward to generate and sustain behaviours that are evolutionary beneficial e.g. feeding, reproduction, bonding etc
How does Heroin affect the brain?
Mimics natural opiates and binds to their receptors. Turns off release of neurotransmitters that inhibit dopamine release, leading to increased dopamine levels.
How does marijuana affect short-term memory?
THC mimics anandamide and binds to cannabinoid receptors which increases dopamine release. Anandamide is involved in removing unnecessary short term memories.
How does LSD give rise to hallucinations?
Binds to serotonin receptors, inhibit and excite, complex sensory effects in the
Locus Celerius (LC). A single neuron from the LC branches to many sensory areas of the brain.
How does Alcohol generate a “double sedative punch”?
Alcohol interacts with GABA (inhibi) and glutamate (inhibit), preventing glutamate dependent excitation.
How does Cocaine affect the reward pathway?
Blocks dopamine transporters, inhibiting dopamine reuptake. Dopamine binds again and again to the receptor, continuously stimulating it.
What kind of mechanisms are involved in the effects of drugs on the brain?
- Increased dopamine signalling by binding to dopamine receptors or modifying dopamine transporters.
- Increased serotonin signalling via serotonin receptor/transporter binding
- Increased opiate signalling by binding to opiate receptors and reducing release of inhibitory neurtransmitters = dopamine release
How much do genetics account for drug abuse risk?
40-60%
Which gene is thought to contribute to addiction?
DRD2
What involvement does DRD2 have in addiction?
The A1 form of the dopamine receptor gene DRD2 is more common in those addicted to alcohol, cocaine and opioids.
Which gene affects alcohol addiction?
ALDH2 - alcohol dehydrogenase 2 gene
How do ALDH2 polymorphisms affect addiction?
ALDH2 encodes a protein that breaks down alcohol. Polymorphisms lead to failed alcohol metabolism leading to symptoms of nausea, headaches, rapid heartbeats.
Which genes lead to individuals being more likely to become nicotine dependent?
CHRNA5, homozygotes are 2x as likely.
How can our social environment impact on how vulnerable we are to the effects of drugs?
Studies in monkeys show that Individuals who don’t receive enough natural rewards from their social environments are more likely to stimulate their neglected reward pathways with drugs.
