All lectures - Hormones and the Nervous System (HANS)
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Course
Hormones And The Nervous System
Institution
Universiteit Leiden (UL)
Notes of all lectures given during the course Hormones and the Nervous System (HANS) in the bachelor biomedische wetenschappen at Leiden University (LUMC).
Introduction to Neuroendocrinology
Hormones signal the need for change. It maintains the homeostasis but also changes the
homeostatic setpoints. For adaptation to stress we have glucocorticoids. The brain also
listens to adipose tissue. Hormones can also come from other tissues than glandular tissue.
Leptin can be released by white adipose tissue. It leads to receptor-activation in the brain
and thereby affects the food intake. Affects the motivation, locate food and the consumption.
However, it also has an effect on reproduction; no fat, reproduction will stop. Motivation
consists of liking and wanting. Dopamine is a neurotransmitter that is closely related to the
wanting. Without, there is no goal directing behavior. The brain itself is also a gland, it makes
hormones. There are a lot of cascades. One of them is the regulation of cortisol secretion by
the Hypothalamus-Pituitary-Adrenal axis. Cortisol comes from the adrenal cortex and it
increases after stress. It is released when ACTH is released by the brain. Cortisol leads to
less ACTH release.
There is a direct pathway from the thalamus to the amygdala. Amygdala is very important for
emotion control and generation. Further processing by the cortex to control the emotions or
alter the response. Also alters excitability.
History of Neuroendocrinology and stress
Stress is about adaptation and this goes at a cost. Can lead to high blood pressure,
overshoot (when stressor is released) and loss of capability to adapt to other things. Stress
changes relative dominance of brain circuits so that you get different emotions and behavior.
Stress can also lead to uncoupling of certain brain regions. A single neuron can also change
their dendrites in the brain areas during more long time stress. The dendrites allow incoming
connections. Smaller and less dendrites; harder to excite. More and bigger dendrites; easier
to excite. Higher dendritic complexity leads to higher excitability. DLS (dorsal lateral striatum)
is for habitual behavior is more excitable during periods of stress. Stress thus pushes a brain
towards (old) habits.
Transmitters are; glutamate, GABA, serotonin, (nor)adrenalin, dopamine and acetylcholine.
The modulators are the neuropeptides and the hormones.
Hans Selye is the 'father of stress'. Stress leaded to bigger adrenal glands. Stress can be a
risk factor for disease when other coping and adaptation mechanism will start to fail. Physical
stressors go via the spinal cord to the brain stem. Same response can be started upon
psychological stressors. Lack of information and lack of control make things
more stressful.
Three components in processing stress; cognition (prefrontal cortex),
memory (hippocampus) and emotion (amygdala).
Any stressor will converge in the hypothalamus, the paraventricular nucleus.
Axons from the PVN will project to the bottom of the brain. Will release CRH
(cortisol releasing hormone). Is released straight into the blood. Then goes to
the pituitary gland that will then produce ACTH (adrenal corticotropic
hormone). The adrenal cortex will then secrete cortisol. The cortisol inhibits
,the production of ACTH. CRH is the main driver. Cortisol is the main output. The HPA axis
process is rather slow an takes around 15 minutes to peak. Is thus not lifesaving in the slow
run. Sympathetic nervous system is more important for the acute stress. By measuring the
CRH, however, you can measure the presence of the stress almost immediately. The Trier
Social Stress Test is a presentation to a non-responsive audience.
The hippocampus can bind corticosterone. Hippocampus is crucial for formation of new
memory and thus is responsive to stress. Stress is also important for memory formation.
Cortisol can bind to mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). These
receptors are everywhere. Cortisol can thus modulate the function of a lot of organs in
response to stress. MR has a higher affinity and leads to the initial response. GR has a lower
affinity and leads to the actual adaptation to stress. Does not necessarily cause a behavior,
but makes us more prone to behave a certain way. Cortisol is good because it make us able
to adapt. But too much cortisol (Cushing's disease) can lead to disease. Long term stress
can affect the brain and thereby potentially also affect brain diseases like anxiety,
depression, psychosis, neurodegeneration and addiction. Stress hormones can also program
our systems and thereby have an lifelong effect when it happens during early life. Also when
it happens later in life it can lead to permanent changes in the brain.
Stress is a state that is defined by neurotransmitters and hormones. Cortisol coordinates the
adaptation everywhere. The good an bad effects of cortisol can be separated based on the
receptor signal transduction pathways.
Introduction Chemical Neuroanatomy
During brain development the grey matter reduces, it is pruned, but the white matter is
increased as there is an increase in myelin. Leads to faster and more effective ways for
communication in the brain. There is not only physical, but also functional connectivity.
Techniques to study neurotransmitters is immunocytochemistry, in situ hybridization,
neuropharmacology, ligand binding molecules, molecular analysis and MRS.
With MRI you can also image connections. With spectroscopy you can suppress the signal
that comes from water. Because of this you can detect specific compounds. However, the
quantity of this is much lower than water so you need bigger volumes for enough signal.
N-acetyl-aspartate in high concentrations in neurons as a neuronal marker. Loss of this is a
sign of damage. Choline is a precursor for acetylcholine. Creatine and phosphocreatine
reflects the storage and transfer. Glutamate and glutamine are also important
neurotransmitters. Lipids are a marker of severe tissue damage. GABA overlaps with the
glutamate peak.
Special topic is about Duchenne muscular dystrophy. NOT part of the exam.
May 12th
RC Chemical Neuroanatomy
Three criteria must be met for a molecule to be considered a neurotransmitter:
1. The molecule must be synthesized and stored in the presynaptic neurons.
2. The molecule must be released by the presynaptic axon terminal upon stimulation.
, 3. The molecule, when experimentally applied, must produce a response in the
postsynaptic cell that mimics the response produced by the release of the
neurotransmitter from the presynaptic neuron.
Some ways to investigate neurotransmitter is pharmacological and ligand binding. Ligand
binding methods cover both antagonist, agonist and the neurotransmitter itself. Is more
broad. Neuropharmacological are mostly agonist.
Ionotropic receptors are ligand gated ion channels. The metabotropic receptors are the
GPCRs that are sensitive to the neurotransmitters.
MRS is not very detailed, but it is still performed as you can detect compounds non-
invasively in vivo. Can also detect responses overtime because of this in live individuals.
In ABA for the mice the 2 is the average expression. 2-4 is more high expression (red) and 0-
2 is lower expression (blue). For the human brain the values are compared to the rest of the
brain regions. In the mouse they compare it to an external reference.
Introduction Glutamate & GABA
The glycine receptor is formally a GABA receptor, but has more the effect in the spinal cord
instead of the brain. Ionotropic receptors for glutamate are AMPA (GluR1-4), Kainate
(KA1,KA2, GluR5-7) and NMDA (NMDAR1, 2A-D). The NMDA receptor is the only receptor
permeable to calcium. GABAA receptor is permeable to chloride so is hyperpolarizing.
Metabotropic receptors are the GPCRS. For glutamate this is mGluR1-8 and for GABA it is
the GABAB receptor.
Glutamate is an excitatory neuron so it must be removed quickly removed from the synaptic
cleft. It is transported by glutamate transporters in the astrocytes. Within the astrocyte, it is
metabolized by glutamine synthase to glutamine. Glutamine is then transported back into the
neuron so glutaminase can produce new glutamate with glutaminase. If these transporters
do not function properly, there can be excitotoxicity.
Downstream of the receptors there are many effects. The
glutamate receptors have both fast and slow effects.
NMDA receptor has a longer term effect by allowing
calcium into the cell. Also involved in learning and memory
formation. However, can also lead to the excitotoxicity
changes in neurodegenerative processes.
Potential drug targets:
− Transmitter synthesis and breakdown
− Vesicular transporters
− Transmitter release
− Glutamate receptors
− GABA receptors
− Receptor trafficking
− Transmitter inactivation
− Membrane transporters
GABAA receptors - Postsynaptic, most abundant,
, GABAB receptors - Both pre- and postsynaptic
GABAC - Only present in the retina
GABA is the main inhibitory neurotransmitter. It
mediates neurotransmission in 30% of the synapses
in the brain. It is involved in epilepsy, sleep and
anxiety. Also involved in learning, memory and
emotional behavior.
Glu R subtypes are the Kainate receptors for
glutamate. They have only limited distribution in the
brain. Are specific for certain neuronal input (like the
mossy fibers). Can have both a positive and negative
modulation of transmitter release via presynaptic
receptors. The frequency of stimulation can have a
different effect. Kainate receptors are probably
involved in modulation of more specific effects.
Metabotropic glutamate receptors are in three categories:
Group I - Mostly post-synaptic. Leads to an increase in postsynaptic calcium. Thereby there
can be activation of PLC, PKC, PLA2 and adenylate cyclase to get downstream actions that
can have long term effects. Also involved in the synaptic plasticity and excitotoxicity.
Group II and III are located mostly presynaptically. Are to reduce further glutamate release.
This for the reduction of synaptic transmission and excitability. Both decrease the activity of
adenylate cyclase. Group III also reduces the activity of cGMP-PDE.
GABAA receptor is a ligand gated ion channel that conducts Cl (also HCO3-). Mostly
postsynaptic, but also extrasynaptic. Is composed of 5 subunits. There are 17 subunit
variants. The receptor properties are controlled by the subunit composition and
the degree of phosphorylation. The GABAA receptor binds 2 GABA molecules
on a site covering an alpha and a beta subunit. There are many additional
sites that bind different drugs. Phasic and tonic inhibition. Phasic when the
receptor is directly facing the synapse. Tonic when it is more distant. Important
as the effects of the modulators will depend on the presence of different
subunits.
Some allosteric modulators are anticonvulsant, anxiolytic and muscle relaxants. Natural are
the hormonal neurosteroids. The compounds are often for a subunit and therefore have
specific effects.
The chloride concentration is normally very low so when GABAA opens there is influx. The
low concentration is a result of a chloride transporter; NKCC1 and KCC2. This is possible
because of the Na/K ATPase pump. When there is trauma, and also during development and
epilepsy, there is higher chloride concentration postsynaptically. So then when GABA binds
there will be efflux of chloride so there will be depolarization instead of hyperpolarization.
This is the case in chronic epilepsy and development.
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