Lecture 17: Neuroendocrinology – Brain to Hormones Flashcards
What is a hormone?
any chemical that acts as a physiological signal AND is transported through the bloodstream
What is a neurohormone?
hormone produced and released by neuroendocrine cells into blood that signals throughout the body (anterograde neuroendocrine signals)
What is an endocrine organ?
structure that produces hormones
What is an endocrine cell?
structure that produces hormones
There are many different endocrine organs/organs that contain endocrine cells in our body. What are they controlled by?
most operate at least semi-independently
but some are quite directly controlled by neuroendocrine cells
What are anterograde neuroendocrine systems?
where neurons release hormones
What are 4 anterograde neuroendocrine systems?
- pineal gland
- hypothalamus
- hypophysis/pituitary gland
- medulla of adrenal gland
What hormone does the pineal gland release?
melatonin
What hormone does the hypothalamus release?
pituitary releasing hormones
What hormone does the hypophysis/pituitary gland release?
posterior pituitary hormones
What hormone does the medulla of the adrenal gland release?
epinephrine/adrenaline
What is the adrenal gland?
multi-layered structure that has two endocrine organs in one
What are the two layers of the adrenal gland?
cortex – outer layer
medulla – inner layer
What does the adrenal cortex do?
secrete multiple steroid hormones
What does the adrenal medulla contain?
chromaffin cells
What are chromaffin cells?
modified postganglionic sympathetic neurons that lack axons, dendrites, or neuron-like electrical responses
What is the function of chromaffin cells (which are in the adrenal medulla)?
secrete norepinephrine (NE) and epinephrine (E) into bloodstream via specialized large vesicles
What neurons target adrenal glands?
sympathetic preganglionic neurons – stimulate chromatin cells to release epinephrine (adrenaline) (80%) and norepinephrine (noradrenaline) (20%) into bloodstream
What type of receptors does epinephrine have? What is it used as?
metabotropic receptors, used as both hormone and neurotransmitter
How does epinephrine know whether to act as hormone or neurotransmitter?
sub-type of adrenergic receptor present on smooth muscle cells – differs depending on what part of the body they are located in
Adrenergic Receptor – Alpha 1 Subtype
- expressed by
- activation causes
- cascade type
- expressed by blood vessel smooth muscle in skin and visceral organs
- activation causes vasoconstriction
- G αq cascade
Adrenergic Receptor – Beta 2 Subtype
- expressed by
- activation causes
- cascade type
- expressed by blood vessel and bronchiole smooth muscle and cardiac myocytes
- activation causes reduced contractions (dilation) in smooth muscle
- activation causes enhanced contractions in cardiac muscle
- G αs cascade
How does a G αs cascade lead to muscle relaxation?
there are PKA- and PKA-activated kinases in these smooth muscles which lead to inhibition of contractile pathways when active
What is the hypothalamus?
cluster of nuclei (collections of associated neurons) located at base of forebrain, just above optic chiasm
What does the hypothalamus have control over?
almost every behaviour and non-behavioural physiological response vertebrates can make
What are the complex circuits of the hypothalamus?
complex circuits include: afferent neurons, interneurons, and efferent neurons
- widespread divergence and convergence of interneurons
- hypothalamic nuclei contain sensory neurons and effector neurons as well as interneurons
What do hypothalamic effector neurons act as?
act as neuroendocrine cells – secrete their neurotransmitter/hormones into bloodstream through pituitary gland (hypophysis)
do NOT synapse onto muscle cells
What are the two divisions of the pituitary gland (hypophysis)? How do they differ?
anterior and posterior – which are connected to different hypothalamic nuclei
the two systems of neuroendocrine cells secrete different hormones into blood through distinct networks of blood vessels
What does the posterior pituitary (neurohypophysis) contain?
axons that release neuropeptide hormones
Two of the hypothalamic nuclei (PVN and SON) contain neurons that release what?
either of two small peptides known as nonapeptides (vasopressin and oxytocin)
- nonapeptide is released as neuromodulator within CNS, OR are neuroendocrine effector cells
- the cells project their axons through the pituitary stalk (infundibulum) into the posterior pituitary where their axon terminals synapse onto blood vessels
What are nonapeptides?
small proteins released from axon terminals via specialized vesicles
What are the two types of nonapeptides? How are the similar and different?
vasopressin and oxytocin
synthesized from different genes, but their sequences are highly similar (and both have 9 amino acids each)
How are nonapeptides synthesized?
- (like any messenger peptide) synthesized as larger, inactive proteins on ribosome, then packaged into special dense core vesicles
- inside DCVs, pro-peptide is cleaved into final peptide
- final peptide is secreted via axon terminals, within brain or into blood via posterior pituitary
Vasopressin – Hormone
What is vasopressin called when it is acting as a hormone?
antidiuretic hormone (ADH)
Vasopressin – Hormone
Where are the receptors?
main receptors are in kidneys
Vasopressin – Hormone
What does it do?
acts to promote water retention – decreases urine production, and therefore decreases blood osmolarity
Vasopressin – Neuromodulator
Where is it released from?
axons inside the brain
Vasopressin – Neuromodulator
What is its function?
associated with neural circuits in brain that control sexual activity, aggression, and territoriality
As a peptide, does vasopressin cross the BBB easily? What are the consequences of this?
no – this means that the same molecule is able to be used in very different roles OUTSIDE (hormone) and INSIDE (neurotransmitter/neuromodulator) the CNS without having to worry about crosstalk when the molecule is released for one function
How do neural circuits regulate and control the secretion of neuroendocrine hormones?
Steps
- in several regions of the hypothalamus, BBB is somewhat leaky, allowing blood plasma to enter brain tissue
- a) sensory neurons in vascular organ of lamina terminalis (OVLT) have a variety of sensor proteins that detect plasma composition
- b) vasopressin (VP)-secreting neurons also have osmosensing receptors – activate in response to hypertonic solutions
- if blood plasma becomes hypertonic (by dehydration), this is sensed by osmoreceptor proteins on OVLT and VP neurons – neurons depolarize, increasing their AP firing
- receptor potential + EPSPs in VP neurons enhance release of vasopressin through axon terminals in posterior pituitary gland into bloodstream
- vasopressin acts on its receptors in kidneys, helping to conserve water, and therefore restore plasma osmolarity to stop activation of osmoreceptors
Oxytocin – Hormone
Where are the receptors?
in smooth muscle of mammary glands and uterus
Oxytocin – Hormone
What is its functions?
acts (via Gαq-coupled GPCRs) to promote smooth muscle contractions in smooth muscle of mammary glands and uterus
Oxytocin – Neuromodulator
Where is it released?
inside brain (like vasopressin)
Oxytocin – Neuromodulator
What is its function?
its CNS actions (via the same GPCR) are linked to maternal behaviour, social behaviour, and in some species sexual and pair bonding behaviours
also thought to have general anti-anxiety effects
Where do oxytocin (OT)-releasing neurons also send axons?
to the posterior pituitary, releasing the peptide as a neurohormone AND being used inside CNS as neuromodulator
Primary Data Slide – Female Mice Without Oxytocin (OXT gene)
can give birth – but can’t suckle
- have normal pregnancies, and (somewhat surprisingly) give birth normally (after the same amount of time and at the same rate (number of pups and litters) as wild type mice)
- their offspring die rapidly unless they are cross-fostered to WT mice because the dams’ teats make milk, but fail to eject it
- giving the dam (parent) oxytocin injections restores the pups’ feeding and survival
- oxytocin receptors (OTRs) are present in high density in myoepithelial cells of mammary glands in actively lactating animals
conclusion: basic physiological role of oxytocin conserved in mammals is milk letdown (ejection)
Primary Data Slide – Oxytocin and Auditory Stimulation
oxytocin is released into the blood after auditory stimulation – it can evoke an effect on a target organ (milk ducts) that does not contain motor neurons because milk letdown is triggered by oxytocin (neurohormone)
- oxytocin levels in the blood of lactating people rise within ~2 minutes of baby crying (this occurs before the baby begins to suck)
- prolactin (hormone which stimulates milk production) is not released by auditory stimulation, but its levels do increase after suckling
What is the anterior pituitary (adenohypophysis)?
endocrine organ that responds to hypothalamic releasing hormones
Is the anterior pituitary (adenohypophysis) part of the nervous system?
technically no – because it develops from the roof of the mouth
How does the hypothalamus supply neurohormones to the anterior pituitary?
neurons in hypothalamus (different ones from those that project to the posterior pituitary) secrete neurohormones into blood vessels at the median eminence
these blood vessels form a special portal vein system that supplies blood to only the anterior pituitary
What are hypothalamic releasing hormones? What is their function?
neurohormones released by hypothalamic neurons into median eminence
trigger (or inhibit) release of other hormones by anterior pituitary cells which enter the general bloodstream
Tumours located where can cause endocrine symptoms?
tumours that put pressure on the pituitary gland and portal veins
Why do tumours on the optic nerve cause non-neurological symptoms?
optic nerve enters the brain at the optic chiasm, directly anterior to the median eminence
Pressure on the area around the optic chiasm can affect neuroendocrine circuits in both parts of pituitary gland. How?
- pressure-induced activation of neuroendocrine cell APs = hypersecretion of releasing hormones or posterior pituitary hormones
- compression of blood posterior pituitary hormones vessels within the portal system prevents transport of releasing hormones into the anterior pituitary = hypersecretion or hyposecretion of anterior pituitary hormone
What is the release of anterior pituitary hormones controlled by?
hypothalamus
What do anterior pituitary hormones stimulate?
typically stimulate the secretion of other hormones from endocrine organs elsewhere in the body
What are axes?
three-hormone releasing sequences through the anterior pituitary
- releasing hormone
- pituitary hormone
- effector hormone
What are releasing hormones?
neurohormones that stimulate (or inhibit) the release of pituitary hormones
ie. CRH, TRH + SST, GnRH, dopamine (PrIH), GHRH + SST (GHIH)
What are pituitary hormones?
hormones released from anterior pituitary that stimulate the release of effector hormones
ie. ACTH, TSH, LH + FSH, prolactin (PRL) – acts like an effector hormone (directly on its target organ), GH
What are effector hormones?
hormones that have a variety of effects on many end organs (and inhibit further release of both releasing hormones and pituitary hormones)
ie. cortisol/corticosterone, T4/T3 , testosterone/inhibin, estrogen/progesterone/inhibin, IGF-1
What is the original form of combined oral contraceptive pills (birth control pill)?
series of small doses (vary over a 28 day cycle) of an estrogen and a progestogen (synthetic versions of ovarian steroid hormones)
How do combined oral contraceptive pills (birth control pills) work?
prevent ovulation from occurring
mechanism can initially seem counterintuitive because endogenous estrogens, in particular, are necessary for ovulation to occur
What are hypothalamic-pituitary-effector hormone systems?
xes that form negative feedback loops
Hypothalamic-Pituitary-Gonadal (HPG) Axis
Where are the receptors for gonadal steroids (ie. androgen receptor, estrogen receptors)?
- hypothalamic neurons that release GnRH
- anterior pituitary gonadotrophs (gonadotropin-secreting cells)
Hypothalamic-Pituitary-Gonadal (HPG) Axis
What happens when gonadal steroids bind to their receptors?
inhibit release of both GnRH and gonadotropins
Oral Contraceptive Mechanism
How do these pills work?
by blocking surges in GnRH and gonadotropin secretion
Oral Contraceptive Mechanism
What is GnRH? Where and when are they released?
peptide neurohormone (like oxytocin or vasopressin)
released from DCVs in GnRH-secreting neurons whenever they go through pulses – cyclic periods of intense bursting of AP firing
Oral Contraceptive Mechanism
What does an increase in GnRH neuron pulse frequencies (triggered by changes in activity of interneurons that synapse on GnRH neurons) lead to?
surge in LH and FSH secretion, which triggers ovulation
Oral Contraceptive Mechanism
What inhibits the activity of GnRH neurons (and/or the interneurons that synapse on them)?
low levels of progesterone and/or estrogen acting through steroid receptors in GnRH neurons
- GnRH neurons will be unable to build up to the high activity needed for a strong surge in secretion (which is needed to release LH from anterior pituitary)
- gonadotropin (LH) levels in blood will not reach the level required to trigger ovulation
Hypothalamic-Pituitary-Adrenal (HPA) Axis
What is this axis involved in?
regulating the response to stressful situations
Hypothalamic-Pituitary-Adrenal (HPA) Axis
What are some of the short-term responses?
- secretion of glucocorticoids helps mobilize energy stores – ie. help supply muscles with glucose for exertion
- because of negative feedback of cortisol on H and P, this is a self-limiting response
What are some properties of steroid hormones?
- derived from cholesterol
- hydrophobic, which means they are lipid soluble – can easily cross the blood-brain barrier (BBB)
What types of hormones are the effector hormones for both the HPA and HPG axes?
steroid hormones
How can negative feedback be altered?
by chronic elevations of the effector hormone
because cortisol and other glucocorticoids (steroid hormones) can cross BBB, they can access neurons throughout the brain
What does the hippocampus negatively regulate?
CRH cells in hypothalamus (except during chronic stress)
- loss in excitability isn’t great for hippocampal functions (ie. LTP and/or memory formation)
- some hippocampus neurons also project to hypothalamus, where they make excitatory synapses with circuits that inhibit the activity of CRH releasing cells in the PVN (hypothalamus) – reduction in hippocampal excitability from prolonged cortisol exposure will disinhibit CRH releasing neurons, compared to baseline, which enhances ACTH release, which enhances cortisol release, which amplifies reduction in hippocampal cell excitability (positive feedback)
What receptors do many hormones act through? What does this mean?
membrane-bound metabotropic receptors – this means that they can have different effects on target organs depending on receptor type
What is the release of posterior pituitary hormones regulated by?
sensory circuits, which can be either totally within the hypothalamus or relayed to it – leads to excitation or inhibition of hormone releasing neurons, and thus changes in their secretion
What is the release of anterior pituitary hormones regulated by?
hypothalamus – regulation is more complex
- brain circuits sense and direct hormonal release
- negative feedback loops – where effector hormones released by the action of anterior pituitary hormones inhibit the release of their releasing hormones
What is the source of the majority of neurohormones?
hypothalamus
contains sensory neurons, interneurons, and effector neurons, and its hormonal outputs (mostly through the two parts of the pituitary gland) act in parallel with its neural outputs through the brainstem and spinal cord to coordinate physiology and behaviour
Are NE (norepinephrine) and E (epinephrine) hormones or neurotransmitters?
both
- hormones: both are released from adrenal medulla (more E than NE) into bloodstream and can act on receptors in the body
- neurotransmitters: both are released from neurons in CNS – NE is absolutely released as a neurotransmitter, and any neuron in CNS that releases NE also releases a small fraction of E
