Pulsatile Hormone Release Flashcards
(38 cards)
How does OT trigger milk release? (4)
1) baby suckles = milk spurts out from both breasts
== milk ejection response isn’t local to to breast, but involves other mechanisms
2) sends sensory output to brain =
3) magnocellular neurons release oxytocin from posterior pituitary
4) Oxytocin (OT) triggers contraction of muscles in breasts = push milk out
Milk ejection testing info (7)
- stimulating the posterior pituitary also stimulated milk
- To confirm that OT neurons in hypo = responsible for mediating the milk ejection reflex
== they inserted electrodes in the supraoptic nucleus (SON) - Another electrode in posterior pituitary stim. to make sure the other electrode is recording from a magnocellular neuron.
== What they saw is that suckling stimulated massive bursts of spiking in OT neurons.
- 1000’s of magnocellular OT neurons in each nucleus = synchronized bursts create a large increase in blood OT.
- OT in turn stimulates contractions, as seen by the increase in mammary pressure following each OT burst.
- larger burst = releases more OT = larger increase in pressure = therefore more milk is ejected.
Suckling leads to pulsatile OT release pattern (4)
- unstimulated OT neurons spike at low frequencies, due to random excitatory and inhibitory synaptic inputs
- Following a suckling stimulation, nothing happens at first, but a few minutes later bursts of spiking occurs in OT neurons, at the same time in all the OT neurons. The bursts occur every few minutes.
- But other stimuli that also increase OT neuron activity, such as injection of cholecystokinin, produce an increase in electrical activity, but not bursts.
-vesicle depletion due to OT release, is responsible for the pulsatile pattern of OT release during the milk ejection reflex
How does suckling leads to dendritic priming? (7)
- OT neurons have vesicles that contain OT and endocannabinoids in their dendrites
-(dendrites of OT neurons form bundles = their axons are projecting in the posterior pituitary, the dendrites are involved in some this communication b/w OT neurons)
- OT triggers Ca2+ release, release of vesicles and increases excitability+ triggers movement of secretory vesicles to dendritic surface (this is priming)
This = before any electrical activity is detected at the axon level (not much is happening in the posterior pituitary during this phase
-Initially stimulation only releases a little bit of OT
- but the priming effect means that after a few mins= a massive amount of OT can be released (+tive feedback loop)
- massive release of OT = makes the neurons much more excitable and they all fire a burst of AP = leads to the release of a large amount of OT from the posterior pituitary
But what terminates the burst? (3)
-Bursts are controlled by store depletion
-model suggests: during burst the primed OT vesicles become depleted
= eventually terminates the burst, as there is no more OT to fuel further release of OT.
What sets the time between bursts? (2)
As new vesicles are formed and primed, a new burst will be able to start
= Here vesicle depletion is the -tive feedback process that terminates bursts and sets the time between bursts.
OT-mediated —- positive feedback produces bursts, slow —- feedback terminates bursts (2)
fast
negative
Why are hormones released in a pulsatile fashion? Reason 1 (3)
- One possibility is to match the pattern of release to target tissue requirements
- Oxytocin has many roles:
–secreted during sexual activity
–during parturition to stimulate uterus contraction. In rats
–also secreted in response to food intake: it promotes sodium excretion
–It also has many effects on behaviour and social attachment.
But only the pattern of OT observed during the milk ejection reflex can trigger milk let down: there needs to be a lot of OT (2 ng) to stimulate the contracting cells of the breast, which is the dose released by each burst. And if the application of OT is continuous, then milk let down stops: pulsatility is required.
Why are hormones released in a pulsatile fashion? Reason 2 (2)
- Hormone imbalance can cause serious health issues (infertility, growth hormone deficiency vs acromegaly, Cushing’s vs Addison’s, etc).
= organisms have many negative feedback loops to regulate hormone levels
What is the purpose of a negative feedback loop? (1)
Negative feedback loops allow to maintain the response of a target tissue, eg hormone levels, close to a set point by comparing that response to the setpoint and adjusting the input to the system (here endocrine gland) accordingly.
How do negative feedback loops can cause oscillations? thermostat e.g.(4)
imagine there are sources of delay in the therostat system (can happen if the room is very large and the sensor far away from the heater)
Let’s say T is 19, the thermostat turns the heater on. But if the sensor is far from the heater, the temperature will pass 20 before the sensor detects it has risen.
When finally the sensor detects the rise in temperature, that temperature is already much higher than 20, maybe 22 or 23.
So there will be large fluctuations in temperature caused by the delay in sensing. This is why delays can cause oscillations in negative feedback loops.
Why may there be oscillations in hormone levels? (3)
- Neuroendocrine axes involve multiple feedback loops
- and because hormone take time to be released, travel through the circulation, and act on their target
= delays between their release and their effects.
Draw the HPG axis - steps (5)
1) interneurons (KISS) act on ARC KNDy neurons
2) GnRH released from hypo into portal blood vessels + act on anterior pituitary
3) Releases LH/FSH from pituitary to act on gonads
4) gonads release sex steroid hormones
5) -tive feedback from Testo + E2 + proges.
What is the role of LH and FSH in males + females? (4)
LH:
F - stimulates E2
M - stimulates testo
FSH:
F - growth of follicles
M - sperm production
How long is the human and rat menstrual cycle? (2)
human : avg = 28 days (from 28-35)
rat : avg = 4-5 days
LH pulsatility monkey test (6)
- used radioimmunoassays to measure low hormone levels
- found LH released in slow pulses (pulsatility only starts at puberty)
- tried to measure GnRH = couldn’t = cut it out = no LH
- injected GnRH = no secretions
- injected pulsatile LH = LH pulses secreted
- little effect on FSH speed release - more effect with the LH:FSH ratio
LH + GnRH monkey test pt 2 (4)
-There is a GnRH pulse generator in the basal hypothalamus (near ME)
- found multi-unit activity peaked synchronously as the LH peak
= pulse generator (network of neurons) = generating synchronised bursts = GnRH release
- pulsatility confirmed in Ewes
where is the GnRH pulse generator? (3)
- neurons located in preotic area (POA)
- Some oscillations in intracellular Ca2+ observed in GnRH neuron cultures, but no strong evidence that GnRH neurons communicate w/ each other in vivo.
-E2 inhibits GnRH pulses through the ER𝜶 receptors, but GnRH neurons do not express it.
KISS info (6)
- discovered in 1996
- tumour supressor gene
- Mutation in KiSS1 gene are associated w/ hypogonadism (2003).
- 2 populations of Kisspeptin positive neurons that project to GnRH neurons - both express ER𝜶
- KNDy + ArN
- kisspeptin stimulates GnRH neuron spiking
KNDy neurons (2)
- express stim peptide Neurokinin B
- expresses endo opioid Dynorphin
NZ lab: LH + KNDy pulse generator (6)
- KNDy neurons in ARC form a pulse generator that drives LH pulses
– showed through fluorescent ca indicator into KNDy neurons + @ same time took blood samples to measure LH - Synchronous pulses in KNDy network match LH pulses
- Stimulation of KNDy neurons triggers LH pulses
– used channel rhodopsin - in blue light - Inhibition of KNDy neurons downregulates LH pulses
– through inhib light sensistiv channel using green light
Exeter researchers - mechanism of pulse generation in ARN KNDy (4)
- developed maths model
- abstracted electrical activity of each neuron = avg level of blue light = represented avg firing rate in network
- when firing rate high enough = NKB(green) released = further increasing firing rate (+tive feedback loop)
- High v alao released Dyn (orange) = feedsback to inhib release of NKB (slow -tve feedback though)
Why is exeter model useful? (4)
-The model demonstrates the role of basal firing rates and Dynorphin-mediated negative feedback
- Changing basal firing rate of KNDy neurons modulates pulse frequency
-Slow negative feedback sets the pulse time scale
-if we uncouple Dyn from the system = network cannot produce pulses
- network can only be in a high or low state, depending on the Dyn level
- vary Dyn levels manually = we can control when the network switches between high and low states, and this is what happens in the KNDy network when Dyn is coupled to v.
GnRH summary (3)
GnRH pulse generation is produced by fast positive feedback (NKB) and slow negative feedback (Dyn)
Pulse frequency encodes the amount of hormone released at the pituitary (LH) and gonads (estradiol/testosterone)
Gonadal steroids in turn modulate the pulse generator frequency
