cholinergic system + alzheimers

Question 1

what are the cholinergic neurons of the brain?

Answer 1

BASAL FOREBRAIN:
• located anterior + inferior to striatum
• septal nucleus
– ch1 = medial septal nucleus
– ch2 = vertical diagonal band of broca
– ch3 = horizontal " "
– ch4 = basal nucleus of meynert
– ch4p = substantia innominata (posterior)
• magnocellular nucleus

MESOPONTINE NUCLEI
• ch5 = pedunculopontine
• ch6 = lateral dorsal tegmentum

Question 2

describe the different cell types found in the basal forebrain

Answer 2

ch1 (medial septal nucleus) contains ~10% cholinergic neurons

ch2 (vertical diagonal band of broca) contains ~70% cholinergic neurons

ch3 (horizontal diagonal band of broca) contains ~1% cholinergic neurons → most heterogenous

ch4 (basal nucleus of meynert) contains >90% cholinergic neurons → least heterogenous

Question 3

where does the basal forebrain connect

Answer 3

ch1/ch2 (MSN/VDB) project to hippocampus via fornix and prefrontal cortex

ch3 (HDB) projects to olfactory bulb

ch4 (BNM) projects to amygdala

ch4p (SI) projects to cortex

Question 4

T or F

ACh only activates nicotinic receptors

Answer 4

FALSE

ACh can activate nicotinic AND muscarinc receptors, often on the same neuron

Question 5

the expression of which three genes is required for the synthesis + release of ACh

Answer 5

genes encoding:

1. acetyl transferase (ChAT)
2. vesicular acetylcholine transporter (VAChT)
3. choline transporter 1

Question 6

how do cholinergic neurons regulate attention?

Answer 6

ACh is released upon the detection of cues

ACh induced desynchronisation ehnaces the reliability of neuronal response
– frequency regulated by GABAergic innervation
– amplitude controlled by cholinergic innervation

despite desynchronisation, ACh release coordinated between different brain areas

Question 7

what is the difference between egocentric and allothetic navigation?

Answer 7

egocentric: navigating relative to self
allothetic: navigation relative to other objects

Question 8

how does a lesion to the basal forebrain impact learning and memory?

Answer 8

loss of cBF neurons or modulation of their number has little effect on basic cognitive processes and motor output

has significant effects on higher order functions including attention, spatial memory, executive functions, learning and memory

lesioned mice can perform morris water-maze test just as well as healthy mice

when placed in area with defined “shock-zone”, normal mice learn to avoid zone but lesioned mice do not

the lesioned mice do have fear learning but are unable to contextualise it (highly disorganised behaviour)
i.e. know there is a shock somewhere but can’t distinguish shock zone is to avoid it

Question 9

how do BF neurons increase the signal to noise ratio?

Answer 9

cholinergic neurons are inhibitory when inactive but become excitatory when there is simultaneous post-synaptic activity

∴ reduce the excitability of less active neurons and increase the excitability of more active neurons

this increases the signal to noise ratio of incoming information

Question 10

how does acetylcholine esterase act at the synapse?

Answer 10

acetylcholine esterase gobbles up ACh at the synapse so that the synapse is only active at precise times

i.e. attention is specific to salient cue → not all the time

Question 11

how does ACh control cortical disinhibition

Answer 11

incoming info from cortical neurons / thalamic axons form synapses on pyramidal neurons

inhibitory interneurons (GABA) block activity of dendrite or downstream neuron

output of pyramidal neuron strongly inhibited by active PV+ interneurons

interneurons inhibit PV+ interneuron = disinhibition = pyramidal neuron becomes active

activity of upstream neurons controlled by ACh
∴ ACh controls cortical disinhibition

ACh can:
• enhance release of glutamate from thalamic axons
• directly activate dendrites of pyramidal neurons
• disinhibit inhibitory neurons
∴ enhances incoming salient information

Question 12

what are the mechanisms of the different muscarinic receptors?

Answer 12

muscarinic are metabotrophic receptors which use G-proteins in their signalling mechanisms

M1, M3, M5:
• use Gq proteins
• Gq up-regulates phospholipase C
• ↑ intracellular [calcium]
• excitatory

M2, M4:
• use Gi/o proteins
• ↓ cAMP levels
• inhibition of VG calcium channels
• leads to efflux of K+ (hyperpolarise)
• inhibitory

Question 13

where are M1 and M2 receptors expressed?

Answer 13

M1 receptors are expressed on pyramidal neurons ∴ ACh can activate dendrites

M2 receptors are expressed on axons in the basal forebrain ∴ ACh can inhibit neurotransmission

Question 14

what are nicotinic (nACh) receptors and how are they related to alzheimers?

Answer 14

nAChRs are ligand-gated cation channels

all nicotinic receptors are excitatory

they contain at least nine subunits (⍺2-7 + β2-4)

⍺7 is dysfunctional in alzheimers

Question 15

what are the 3 main cholinergic regions in the brain?

Answer 15

1) mesopontine tegmentem
2) basal forebrain
3) striatum

Question 16

what are the 4 main subnuclei of the basal forebrain?

Answer 16

1) septal, magnocellular
2) medial/vertical diagnal band of broca
3) nucleus basalis
4) substantia innominata

Question 17

what pathology is observed in alzheimers?

Answer 17

atrophy of the cortex → damaging areas involved in thinking, planning and imagination

atrophy of the hippocampus → short-term memory deficits

atrophy of the basal forebrain → memory and attention deficits

enlarged ventricles

amyloid plaques (accumulation of amyloid beta)

neurofibrillary tangles (clumps of hyper-phosphorylated tau)

Question 18

what is the hypothesised disease cascade that leads to alzheimers?

where can possible treatments be implemented?

Answer 18

1) genetic mutations in APP, PSEN1, PSEN2

2) amyloid pathology
→ clinical trials

3) tau pathology

4) cognitive decline
→ treatments for basal forebrain + cholinergic neuron degeneration

5) alzheimers

Question 19

how is navigation impaired in those with alzheimers?

Answer 19

both allocentric and egocentric navigation is impaired in AD

significant correlation between navigation error and basal forebrain loss

Question 20

name some current drugs used to treat alzheimers

Answer 20

ACh esterase inhibitors to increase the amount of ACh at the synapse
–> these drugs do not work if administered too late, as there may be no ACh at the synapse at all

NMDA receptor agonists

cholinergic drugs can increase navigation ability

do not stop or reverse alzheimers, only treat symptoms

Question 21

give four reasons as to why the drugs may not work?

Answer 21

1) cells are dead ∴ no ACh for the drugs to enhance
2) cells become flooded with ACh and there is no location specific precision ∴ impaired cognitive function
3) timing of enhancement/inhibition is wrong and ACh is present for too long ∴ changes physiology
4) drugs block receptor meaning ACh cannot activate it