week 9- Acetylcholine (ACh) Attention, Memory & Alzheimer’s Flashcards
Acetylcholine (ACh) Central & Peripheral
Acetylcholine is a major neurotransmitter of the Central Nervous System (CNS) and Peripheral Nervous System toxin (PNS)
Acetylcholine Synthesis
Acetylecholine is made from choline (derived from the breakdown of lipids) + acetate (sometimes called acetic acids).
Acetylcholine (ACh) in the periphery
- In peripheral nervous system ACh is the primary neurotransmitter that acts at the neuromuscular junction.
- Ach transmits signal from the motor neuron and causes muscle to contract»_space; controlling muscular movement
- Botulinium toxin is produced by bacteria that grows in canned food (most acutely lethal toxin known). Causes death by paralyzing respiratory muscles.
- Prevents the release of ACh
botox
Botox is a VERY dilute solution of botulinum toxin injected directly into muscles. Causes muscle weakening for 3-6 months!
Can be used cosmetically to relax facial muscles (reducing wrinkles)
cerebrl palsy
Can treat spasticity (muscle tightening) in cerebral palsy (non-specific brain damage)
black widow spiders
-The venom of the black widow spider causes death by heart attack (very rarely)
Triggers/Stimulates the release of ACh
Together botulinium toxin & Black Widow venom show that too much or too little both have catastrophic consequences. A balance is required.
Acetylcholine in the Brain (CNS
Effects of ACh in brain are generally facilitatory (promoting neural firing)
Acetylcholine Receptors
Two types ACh Receptors – Ionotripic (Ion Channel) & metabotropic (G-protein coupled) receptors .
The ionotropic receptor
stimulated by
nicotine so is called Nicotinic Receptor
-In the PNS - muscle fibers must be able
to contract rapidly so they contain rapid,
ionotropic nicotinic receptors.
The metabotripic receptor
- stimulated
by muscarine (found in the poison
mushroom Amanita muscaria) so is
called the Miscarinic receptor.
In the CNS - both nicotinic and muscarinic
receptors exist but muscarinic receptors
predominate.
Alzheimer’s Disease
- It is believed that a reduction in ACh innervation is responsible for the cognitive decline observed in Alzheimer’s patients.
- Alzheimer’s is associated with massive loss of brain white matter and a specific reduction of ACh neurons in the basal forebrain which projects to the cortex and hippocampus. It plays a major role in cognitive functions such as memory and attention.
- ACh receptors and Acetylcholine acetyltransferase (involved in ACh production) are found to be affected in Alzheimer’s
ACh in memory
- Drugs blocking the ACh muscarinic receptor cause memory loss for period under the drug effects (blocks memory consolidation)
- Effect of ACh on memory is very complex - separating the encoding and retrieval of memories. Allowing for no interference between memories and for the separation of memories into clear segments which can be easily retrieved later.
ACh Attention Experiment
Question: Does ACh improve attention function in healthy people?
- Involuntary attention - also referred to as “bottom-up” or “pop-out” or “exogenous” attention
- Voluntary attention – also referred to as “sustained” or “top-down” “sustained” or “goal directed” or “exogenous” attention
Experiment Design
Drug = 5mg of donepezil / Aricept (used to treat dementia).
Cholinesterase inhibitor > increases levels of ACh in the synapse by blocking its breakdown
Experiment Design
- Placebo controlled = participants were given a tablet but did not know if it was the active drug or not
- Within subject / crossover design = All participants did both conditions
- Counter Balanced = 50% take placebo 1st, 50% take drug 1st (“pseudo randomised order” )
- Double Blind = Neither participant or experimenter were aware if it was the placebo or drug condition
- Other details – 20 healthy participants. Testing occurred 3 hours after pill was consumed > Peak plasma (i.e blood) levels of drug. Each session was separated by at least 2 weeks > to allow drug to completely leave the body.
Experiment Task
Initially - the cue (a highlighted box) attracts involuntary attention
Later - the cue directs voluntary attention away (towards opposite box) because subjects know the target will appear there in 80% of trials
Results: Short SOA (40ms)
People were slower when the target was in the opposite compared to the cue location
ACh drug had NO EFFECT on performance compared to placebo
Results: Long SOA (600ms)
People were faster when the target was in the opposite compared to the cue location
ACh drug IMPROVED performance compared to placebo when it was in the opposite location
Results: Involuntary Attention
-At short SOA’s - cue captures involuntary (bottom-up, pop-out, exogenous) attention & people don’t have time to move attention away to opposite location where they know the target will be 80% of the time.
Involuntary attention improves performance at cue location, but ACh drug makes no difference to this effect.
Results: Voluntary Attention
- At long SOA’s - cue captures involuntary attention but people DO have time to move voluntary (top-down, sustained, goal-directed, endogenous) attention to opposite location where they know target will be 80%.
- Directing voluntary/sustained attention improves performance and ACh drug INCREASES the improvement.
Ach and attention - mechanism
Why does ACh improved performance on the gabor tilt task
Attention > ACh
Boosts target response relative to other orientations
Improved discrimination “signal to noise” = easier to identify/select target
Ach found to reduce “spatial spread” of excitation in a range of cortical areas > makes the neural coding more sensitive/accurate/selective
Neuroethics – Cognitive Enhancement
- Medicines treat disease, Cognitive enhancers improve healthy function
- Drug companies are spending millions to design drugs that treat dementia / Alzheimer’s.
- Drugs that improve memory and attention in Alzheimer’s work BECAUSE they improve/facilitate the normal mechanisms underlying memory & attention.
summary
- Acetylcholine (ACh) has two main receptor types nicotinic and muscarinic.
- ACh in the periphery controls muscle contraction
- ACh in the brain is important for learning/memory & perception / attention.
- ACh function is impaired in Alzheimer’s disease.
- Drugs that improve memory & attention in Alzheimer’s also improve memory and attention in healthy people
