Lecture 18: Neuroendocrinology – Hormones to Brain Flashcards
What does it mean that the neuroendocrine relationships is reciprocal?
nervous system controls release of many different hormones, but many hormones also act on and influence activity of different neurons within the nervous system
ie. glucocorticoid hormones (ie. cortisol) can affect dendritic properties in hippocampus
What can gonadal steroid hormones powerfully modulate?
synaptic transmission and plasticity
How do hormones differ?
in their biochemical properties – including lipid solubility
What are the 3 biochemical classes of hormones?
- steroids
- peptides
- biogenic amines
What are steroids synthesized by?
modifications to cholesterol
What are peptides synthesized as?
gene products 3 to ~100 aa long
How are biogenic amines synthesized?
variable (but often derived from amino acids)
What is the solubility of steroids in lipids?
lipid soluble (diffuse through cell membranes)
What is the solubility of peptides in lipids?
not lipid soluble (must be transported around or across cell membranes)
What is the solubility of biogenic amines in lipids?
variable (depends on the hormone)
What are some examples of steroids?
testosterone, estrogen, cortisol
What are some examples of peptides?
oxytocin, CRH, leptin
What are some examples of biogenic amines?
epinephrine, melatonin, thyroxine
Which hormone classes can have retrograde neuroendocrine effects?
steroid and peptide hormones – both can influence behaviour by exerting actions within the CNS
Where is cortisol/corticosterone (steroid) released from?
What do these hormones affect?
released from adrenal cortex
affects stress, survival responses, memory
What is estrogen/testosterone/progesterone (steroid) derived from?
What do these hormones affect?
derived from gonads
affects reproductive and parental behaviour, aggression, (and memory)
Where is oxytocin/vasopressin (peptide) released from?
What do these hormones affect?
released from posterior pituitary gland
affects anxiety, aggression, social and parental behaviour
Where is leptin/ghrelin/CCK (peptide) released from?
What do these hormones affect?
released from adipocytes or various digestive tract organs
affect hunger, feeding, and satiety
What are the chemical properties of hormones that affect their ability to cross the BBB?
whether they are hydrophobic (lipid soluble) or hydrophilic (non-lipid soluble)
Can hydrophobic (lipid soluble) hormones cross the BBB?
can diffuse through membranes of endothelial cells, and therefore easily enter and interact with CNS – ie. steroids
Can hydrophilic (non-lipid soluble) hormones cross the BBB?
cannot diffuse through cell membranes, and cannot pass tight junctions that seal brain endothelial cells (BBB) – ie. peptides
How can a peptide hormone get access to the CNS to exert its effects?
What are the 3 different hypotheses that could account for the ‘CNS action’ of peptide hormones?
option 0: peripheral feedback
- hormones could affect the activity of neurons in CNS simply by interacting with sensory neurons outside the BBB, in the PNS, altering their activity
- changes in CNS activity are inherited from afferent neurons
option 1: selective transport
- certain peptide hormones could interact with specific receptors that trigger transcytosis, transporting them across endothelial cells
- changes in CNS activity are dependent on presence of special BBB transporter proteins
option 2: selective leakiness
- BBB is known to be leakier in some regions of the brain, particularly near sub-regions of hypothalamus – hormones may be able to enter brain in these specific locations
- changes in CNS activity occur only in certain leaky regions
Complication: Peptide Hormones are Also Often Released in CNS as Neuromodulators
(L17) oxytocin and vasopressin are peptide neurohormones that are released from hypothalamic neurons into the bloodstream via the posterior pituitary
- BUT they are also released (by distinct sets of neurons) within the CNS, where they act as neuromodulators – analogous to dopaminergic or serotonergic systems
these signalling molecules are known to be capable of affecting CNS activity (and behaviour)
- BUT because they are also able to be released inside the CNS, their effects are not necessarily because they are actually crossing the blood brain barrier (BBB)
Can intranasal oxytocin reach the brain?
- there are persistent reports in scientific (and non-scientific) literature that oxytocin inhaled through nasal passages can affect behaviour by making it into the brain and acting on OTRs within the CNS
- researchers have suggested that OT may be transported via axons of olfactory sensory neurons in the nose directly into the CNS
- this has been proposed (and sometimes directly marketed) as a potential treatment for autism, love potion, and enhancer of social trust
OVERALL: poor findings
- studies based on the idea of peripherally-administered oxytocin reaching the brain (including by intranasal routes) suffer both from issues with replication of behavioural findings, and the underwhelming physiological evidence that intranasal OT is able to actually reach the necessary sites in brain in meaningful concentrations
Primary Data Slide – Can intranasal oxytocin reach the brain?
studies with radiolabelled OT suggest you can maybe snort it into your brain
METHOD: to try to prove the claims about intranasal (IN) oxytocin (OT), researchers add a radioactive label to the hormone and then sample CSF in various parts of the brain in monkeys, looking for radioactivity
- control: compare results of IN OT to intravenously injected radio-labelled OT
- test: there are six individual subjects (2M, 4F) in this between-subjects design
OBSERVATION: some evidence that a small amount of labelled OT makes it to some regions of the brain, in at least some subjects
- some sites in the brain contain some neurons with OT receptors
How do we know that some peptide hormones must have mechanisms for crossing the BBB?
receptors for these peptide hormones can be found within the CNS, but they are secreted in the periphery and have no known source within the CNS
Which hormones can cross BBB?
several hormones that affect metabolism, glucose homeostasis, and feeding and fasting behaviour
these peptide hormones are secreted by cells in the digestive system (ie. CCK, ghrelin) or from fat-storing cells (leptin, adiponectin), but their receptors can be found in the brain – especially in hypothalamus
What are 4 peptide hormones that affect appetite?
- cholecystokinin (CCK)
- ghrelin
- leptin
- PYY
What is cholecystokinin (CCK) secreted by?
secreted by intestinal cells in response to fatty acids or amino acids in duodenum (ie. after a meal)
8 to 58 aa
What is ghrelin secreted by?
secreted by gastric cells when the stomach is empty – peaks in the bloodstream before meal times
28 aa, with pre-pro sequence
What is leptin secreted by?
secreted by adipocytes in proportion to their lipid volume (fullness)
167 aa
What is the function of leptin?
acts as a signal that energy stores are high
What is PYY secreted by?
secreted by cells in small and large intestines in response to stretch (ie. after a meal)
36 aa
What does ghrelin administration to the CNS stimulate?
stimulates appetite and weight gain – ghrelin levels peak just before mealtimes
Can the effects of ghrelin (weight gain and increased food intake) be controlled by the CNS?
yes – direct ghrelin injections into the brain show the same effects on weight as intravenous injections, indicating that these effects can be mediated by actions within the CNS
What do deficiencies in leptin signalling cause?
overeating and morbid obesity
Are there receptors for appetite-modifying peptide hormones present in the hypothalamus?
yes – wide distribution (in the brain) of metabotropic receptors for peptides that affect appetite and feeding behaviour
Where are metabotropic receptors for peptides that affect appetite and feeding behaviour found?
can be found in several different brain regions
key sites are thought to be in the hypothalamus – including in regions where it is known that stimulation and/or lesions can affect appetite
What is the key site within the hypothalamus for effects on appetite?
arcuate nucleus (ARC/ARH) – sub-region of the hypothalamus
What 2 key neuron types are leptin receptors present on in the arcuate nucleus (ARC/ARH)?
- POMC (pro-opiomelanocortin) neurons
- AgRP (agouti-related peptide) neurons
What do AgRP (agouti-related peptide) neurons do?
trigger food intake when activated
What do POMC (pro-opiomelanocortin) neurons do?
suppress food intake when active
Primary Data Slide – What does the selection of leptin receptors from arcuate POMC neurons do?
affects feeding
- mice that only lack leptin receptor in ARC POMC neurons show increased weight gain (plus food intake) compared to control animal
- this weight gain is significant, however it does not fully mimic the effect of global knockout of the leptin receptor
- these data do strongly indicate that endogenous leptin must be able to get into the CNS
Where is the BBB more leaky? What does this enable?
several locations near/within hypothalamus
this enables secretion of neurohormones and monitoring of plasma composition by osmosensing neurons by regions known as circumventricular organs
Where is leptin transported into the CNS? Does it travel via CSF or BBB?
leptin is transported efficiently into CSF and hypothalamus, especially ARH
- reaches the arcuate nucleus (ARH) more efficiently than other parts of the hypothalamus, including the ME
- it has a slow rise in most other regions of the brain
this suggests that peptide hormones like leptin could reach ARC somewhat more quickly via CSF, rather than the BBB
What can affect the leakiness of the BBB near ARH?
behavioural state
- in the fasting state, ME and ARH both show increased numbers of capillaries with fenestrations (pores through endothelial cells which allow plasma movement) – more movement/diffusion
- other structural rearrangements (ZO-1) at the ventricle suggest that ARH could become less accessible from CSF during fasting
Do lipid soluble steroid hormones influence CNS activity and behaviour?
yes – many of the best known examples of retrograde hormonal influences on the CNS come from lipid soluble, steroid hormones, which diffuse easily through the blood brain barrier
Do non-lipid soluble peptide hormones influence CNS activity and behaviour?
yes (a number of them can) – some of these effects may be due to the same molecule being released within the CNS and acting as a neuromodulator, and/or due to feedback through receptors in the periphery and PNS
for some peptide hormones, anatomical, physiological and behavioural evidence points to a model where the peptide hormone is able to cross the blood brain barrier in some locations within the CNS, binding to receptors in the brain and influencing neural activity
Which peptide hormone is likely to be a ‘hunger’ hormone?
ghrelin – released before meal times
NOT:
- leptin – released when fat stores (and therefore overall energy stores) are high – stop putting food in stomach
- CCK – stop putting food in stomach
- PYY – stretched, stop putting food in stomach
If leptin signals that fat stores are full, and the absence of leptin causes overeating… what effect do you predict leptin receptor activation would have on POMC and AgRP neuron activity?
↑ POMC activity, ↓ AgRP
- leptin is released when fat stores are full
- if there is no leptin signalling – overeating
- if there is leptin signalling – suppression of appetite
- if POMC neurons are activated, food intake is pressed
- if AgRP neurons are activated, food intake is activated
Refer back to the different hypotheses that could account for the ‘CNS action’ of peptide hormones. Which of these options can we eliminate in the case of leptin?
data showing effect from CNS manipulation allows us to eliminate option 0
the only way we can really explain the results seen with POMC receptor knockout is if endogenous leptins secreted by adipocytes actually gets into the brain
What does the ability of circulating peptide hormones to cross the BBB depend on?
behavioural state of the animal (ie. when fasting)
peptide hormones are sometimes able to cross BBB because sometimes the BBB goes away (structural rearrangements in the brain), depending on the behavioural state of the animal
Is the density of peptide hormone receptors within the arcuate nucleus altered by the behavioural state of the animal (ie. when fasting)?
no – don’t need to change the number of receptors
can have same number of receptors, but will have easier time getting the ligand
Would the secretion of appetite-modulating peptide hormones such as leptin be increased by the behavioural state of the animal (ie. when fasting)?
no – don’t need to change the amount secreted
what you normally secrete is now even more rapidly able to get into the brain and have effects
