Locus Coeruleus Flashcards
TRUE or FALSE: the pre-BotC is necessary to keep us alive
TRUE
opiate vs opoid
opiate is natural; opioid is synthetic or natural
Which type of opioid receptor is most sensitive to analgesic effects of opiods?
mu-receptors
Why is the pre-BotC important for life?
rhythmogenic inspiratory center that results in rhythmic contraction of inspiratory muscles needed to ventilate the lungs
What does the locus coeruleus play a cruicial role in?
causing death in association with the effect of opioids on the activity of its neurons
TRUE or FALSE: pre-BotC is crucial for death and LC is crucial for life
FALSE: preBotC for life, LC for death
Explain how the LC and pre-BotC communicate with each other.
- pre-BotC neuron bursting evokes rhythmic inspiratory-related spike discharge or trains of IPSPs in LC neurons
- LC neurons release NTs inside pre-BotC can modultae pre-BotC bursting
Where are the pre-BotC and LC located?
- pre-BotC: ventrolateral brainstem
- LC: dorsal surface of brainstem (next to 4th ventricle)
function of pre-BotC vs LC?
- pre-BotC: generate inspiratory rhythm
- LC: tonic or bursting vs. phasic neuron activity
TRUE or FALSE: the LC only innervates the hypothalamus and the thalamus.
FALSE: LC innervates almost all brain structures
Which NT does the LC release?
NA
Effect of exogenous opioids on LC neurons
dependence; suicidal ideation; overdose
How does overdosing on opioids kill humans?
abolish preBotC rhythm that drives breathing movements
What does locus coeruleus mean in english?
sky in the brain
TRUE or FALSE: there are very few LC neurons.
TRUE
What did the injkection of the green fluorescent dye Fluo-4 into the LC slice reveal?
LC neurons have large soma diameters (dye did not differentiate between astrocytes and neurons)
How do you differentiate between neurons and astrocytes in the LC, when staining?
- stain TH antibody found in neurons red
- stain S-100B protein found in astrocytes green
What is ‘tonic’ spiking of a neurons?
non-phasic spontaneous discharge of single Na+ APs (spikes)
What is bursting of neurons?
slow rhythmic depolarizations, caused by prolonged excitatory synaptic inputs with activation of intrinsic ion channels
via recording in the reticulo-thalamic neuron, it was revealed that wakefulness is associated with bursting or tonic spiking?
tonic spiking
via recording in the reticulo-thalamic neuron, it was revealed that sleep is associated with bursting or tonic spiking?
bursting
At low attention, do we have spiking or bursting?
spiking
At high attention, do we have spiking or bursting?
bursting
Which is associated with good and poor performance, between spiking and bursting
- bursting = good performance
- spiking = poor performance
What type of drug is clonidine?
alpha 2 NA receptor agonist
when clonidine is administered:
a) spiking becomes bursting
b) bursting becomes spiking
a) spiking becomes bursting
What is clonidine used to treat? What is the mechanism?
- ADHD
- its action on LC can increase performance/attention (bursting)
neuronal firing patterns determine behaviour. How is this demonstrated in the LC?
- poor performance associated with spiking and low attention
- good performance associated with bursting and high attention
In what manner is NA released from the LC?
pulsatile
Which receptors does NA act on? Which ones are excitatory / inhibitory?
- alpha 1, beta 1 = excitatory
- alpha 2 = inhibitory
What is the effect of noradrenaline on the squirrel monkey auditory cortex?
inhibitory (decreased duration of spiking)
Describe the inhibitory effect of NE on the squirrel monkey auditory cortex.
- inhibit irregular firing
- decrease spiking amplitude
- decrease spiking duration
TRUE or FALSE: LC is only involved in the modulation of sensation of pain.
FALSE: senses of pain, audition, vision, gustation, olfaction
TRUE or FALSE: LC both projects and and receives info.
TRUE: receives info about internal state of the body (interoception) via brainstem nuclei
What is interoception? which 2 nuclei are involved?
visceral afferents from bladder, bowel, heart, gut to LC via Barrington’s nucleus and Paragigantocellularis
LC has a modular organization. What does this mean?
it has a preferred location of subpopulations of its neurons with different features.
In terms of cell morphology in the LC, where are noradrenaline-positive (NE+) fusiform neurons?
dorsal
In terms of cell morphology in the LC, where are noradrenaline-positive (NE+) multipolar neurons?
ventral
TRUE or FALSE: all LC neurons contain NE while thy also express another neurotransmitter (cotransmitters)
TRUE
WHat are the subsets of LC neurons that co-release peptides?
- NE+/galanin+
- NE+/NPY+
What are the subsets of LC neurons that express different subtypes of noradrenaline receptors?
- NE+/AR-alpha-1+
- NE+/AR-alpha-2+
In terms of projection target, where are Th-projecting LC neurons found?
posterior part of the dorsal LC
In terms of projection target, where are Hi-projecting LC neurons found?
medial and anterior part of the dorsal LC
In terms of projection target, where are Cb-projecting LC neurons found?
ventral part of LC
TRUE or FALSE: the hypothalamic nuclei has both afferents and efferents to the LC
FALSE: the amygdala has both afferents and efferents to the LC
Draw the afferent inputs to LC
slide 10
List the afferent inputs to the LC
- preBotC
- preoptic area
- nucleus paragigantocellularis
- cortex orbito-frontal and anterior cingulate
- amygdala
- hypothalamic nuclei
- dorsal and median raphe
which neurotransmitter is released from the preoptic area to the LC?
GABAa
which neurotransmitter is released from the nucleus paragigantocellularis to the LC?
glutamate
which neurotransmitter is released from the cortex orbito-frontal and anterier cingulate to the LC?
glutamate
which neurotransmitter is released from the amygdala to the LC?
glutamate and CRF
which neurotransmitter is released from the hypothalamic nuclei to the LC?
hypocretin and orexin
which neurotransmitter is released from the dorsal and median raphe to the LC?
5-HT
NA can be released via an axon collateral on the same, or neighbouring, LC neurons or on astrocytes to act on alpha 1 or alpha 2 ‘autoreceptors’. what does this imply about LC neurons, during ENHANCED ACTIVITY?
LC neurons also release NA next to neighbouring LC neurons and astrocytes and this MIGHT CHANGE THEIR ACTIVITES (slide 10)
Using optogenetic activation of LC neurons, compare tonic and phasic activity in terms of which:
- induce wake from sleep
- increase periods of wakefulness
- increase locomotion
- induce anxiety-like behaviour
- decrease locomotion
- both induce wake from sleep
- both increase periods of wakefulness
- tonic increases locomotion
- tonic induces anxiety-like behaviour
- PHASIC decrease locomotion
What is the difference between tonic and phasic spike discharge? draw them on a graph
- tonic = evoked by light pulses with regular pattern
- phasic = evoked by shorter sequence of briefer light pulses at HIGHER RATE
(slide 11)
What is the difference between ChAT+ and GABA+ LC output sites?
ChAT+ neuron
- express alpha1 and beta1 receptors that are both EXCITATORY
- NA released from LC onto these receptors –> excitation of ChAT+ neuron –> discharge more intensely –> release more ACh into cortex –> promote arousal
GABA+ neuron
- express INHIBITORY alpha2 receptor
- NA released from LC onto these receptors –> DEPRESSION of GABA+ neuron activity –> discharge less intensely –> release GABA into cortex –> inhibit arousal/promote sleep
How does morphine application change AP firing? (before and after)
- before morphine: unsynchronous tonic firing
- after morphine: synchronous slow bursting
TRUE or FALSE: alpha-2 agonists and mu-opioid agonists evoke similar discharge behaviour
TRUE
What kind of discharge behaviour do alpha-2 agonists and mu-opioid agonists evoke?
slow, synchronous bursting
TRUE or FALSE: the tonic spiking in LC neurons evoked by morphine helps alleviate pain
FALSE: slow, synchronous bursting alleviate pain
Why do clonidine and opioids exert the same transforming effect on LC neuron spiking?
- their receptors are both coupled to the same second-messenger signaling pathway (GPCR)
- both cause hyperpolarization of the cell due to K+ efflux via GIRK channels
TRUE or FALSE: activation of GIRK channels causes depolarization
FALSE: hyperpolarization via K+ efflux
What is the paradox of in vivo vs in vitro administration of opioids in the LC neurons?
- in vivo: opioids transform tonic spiking into synchronous bursting (NO INHIBITION)
- in vitro: opioids cause hyperpolarization and spike blockade (INHIBITION)
How does NA affect K+ currents? Same or different than opioid effect?
K+ outward current (like opioids)
What is metenkephalin? How does it affect K+ current
- opioid agonist
- induce K+ outward current
What is normorphine? How does it affect K+ current
CHECK GROUP CHAT
How does local injection of kynurenic acid into LC affect firing rate during steady-state effect of morphine? What does this indicate about morphine-evoked pattern transformation?
- morphine: tonic spiking –> bursting
- kynurenic acid = iGluR (ionotropic glutamate receptor) blocker
- kynurenic acid: bursting –> tonic spiking
- indication: morphine-evoked pattern transformation depends on iGLuR in the LC
What does the morphine-evoked pattern transformation depend on within the LC?
iGluR
TRUE or FALSE: LC has intrinsic capability to transform its burst pattern only in vivo.
FALSE: also in vitro and in newborns (as shown by iGluR involvement experiment)
What kind of recording can be used to pharmacologically analyze the LC network?
suction electrode recording of local field potential (LFP) in the LC
TRUE or FALSE: left and right LC fire synchronously
FALSE: left and right LC do NOT fire synchronously
