What are Dale's Laws?
- Each neuron releases one and only one type of neurotransmitter
- It turns out that some neurons release two types of neurotransmitters from their axon terminals but Dale is still right that neurons release that pair form ALL of their axons
What are the criteria for neurotransmitterhood?
- In the axon terminal
- Released by action potentialism
- Have effects on the post-synaptic neurons
- If you block that novel compound from reaching the post-synaptic neuron, something is going to work differently.
Why would a vesicle contain multiple neurotransmitters?
- When there are pairs, they tend to be of very different classes of chemical structures, they work at different speeds, so this is a way to get a more complex/multi-faceted set of messages
- Endocrine example: People used to think that for each hormone in the pituitary, there would be one releasing hormone for it in the hypothalamus or one inhibiting factor. But, we see that there are multiple uses and meanings of the same messenger. A bunch of hypothalamic hormones release ACTH and these hormones do other things elsewhere.
Different stressors cause different ________
combinations to be released.
Why the multiplicity of these hormones, given that all release ACTH?
- Different combinations of hypothalamic hormones cause different patterns of ACTH release, which is desirable for different types of stressors. The stress response is the same in all these different stressors, but there will be a distinctive stress response signature in response to a particular stressor
- Different combinations of these hypothalamic hormones collectively release ACTH but they probably also do additional but different things to other pituitary hormones.
What is a projection signature?
- The pathways in the brain that carry the stress information need to project differentially to those nuclei depending on the stressor
- The neural pathway carrying information about a burn, and the pathway carrying info about anxiety are not going to be distributing their projections in the same way in the hypothalamus.
What is Dale's second law?
An action potential will propagate down all the branchs of the axonal tree and causing the release of the neurotransmitter from all of them
What is the phenomenon of selective propagation?
- First observed in the 1960s by a guy at MIT named Jerry Lettvin
- preferential input from certain dendritic ends
- Excitation from some spines can be made to propagate further than from others.
What is specialization?
- Not every pituitary cell releases each of those hormones
- Corticotrophs release ACTH etc.
Is there a region in the pituitary for the lactotrophs and another region in the brain for gonadotrophs?
No, instead there is a mosaic throughout the pituitary
How does the mosaic effect in the pituitary influence how much neurotransmitter is released?
- It depends on the neighborhood that the gonadtrophlives in. If it is surrounded by corticotrophs, the size and the speed of its LH secretory response may differ than if it is surrounded by lactotrophs.
- Individual adjanent pituitary cells communicate with each other changing their response properties
Describe the portal circulation system in relation to the mosaic
The portal circulation consists of a dense tree of branching blood vessels going to the pituitary and the hypothalamus can direct levels of hormone into different branches of the portal system, thus tapping into different pituitary neighborhoods to different extents.
There is a __________ capacity to shape the pattern of hormonal responses
What is an autoreceptor?
A receptor on the pre-synaptic axon terminal that keeps track of how many molecules of X it has released.
What is an example of an autoreceptor acting in the case that two neurotransmitters are released from the same axon terminal?
All of the receptors for neurotransmitter A might be postsynaptic, and all the ones for B would be presynaptic autoreceptors. So as long as the ratio of the number of molecules of the two types of neurotransmitters released are relatively constant, this can serve as a bookkeeping system also.
Why do you need to have negative feedback regulation in the endocrine system?
- The brain has to know how much of some hormone has been dumped in the bloodstream in order to decide what to tell the pituitary to do next.
- The higher the circulating levels of a hormone, the more likely the brain is to stop secreting the hypothalamic hormones that started the process.
What is an example of a positive feedback regulation?
- The more of a peripheral hormone, the more the brain is stimulated to trigger that cascade.
- This is what happens at the onset of puberty.
Does the brain make decisions based on ratios of two hormones or absolute levels of each?
- Ratios: this is what goes on with estrogen and progesterone.
When does rate-sensitive feedback occur?
- At the early phase of mobilizing a hormone.
- It turns out to be a more sensitive way to make minor corrections when levels are changing fast.
When does level-sensitive feedback take over?
At less dramatic times.
What is autoregulation?
- The number of receptors for a neurotransmitter can change in response to dramatic changes in levels of the neurotransmitter.
- If there are massive levels of a neurotransmitter being cranked out long term, the postsynaptic neuron down-regulates receptor number.
- A chronic decrease in release of some neurotransmitter will up-regulate receptor number as a means of detecting a signal more readily.
What is a complication of how some antidepressants work?
- Drug A works by changing the amount of neurotransmitter X in the synapse. Consequences are obvious and immediate
- Drug A increases the levels of neurotransmitter X leading to the eventual down-regulation of the number of receptors for neurotransmitter X and the down regulation is the thing that actually changes behavior.
- BUT, it is the down regulation which is the critical step, but the key this is actually the down regulation of the pre-synaptic autoreceptor not a regular post synaptic receptor.
Describe how autoregulation occurs in adult onset diabetes
- Increased sugar in the bloodstream triggers insulin secretion, insulin stimulates the uptake of nutrients into fat cells
- You eat too much, this causes fat cells to become full, they cant store anymore so they stop listening to insulin. Sugar isnt cleared from the bloodstream so the pancreas secretes more insulin which causes the fat cells to downregulate the number of insulin receptors.
What are the two ways autoregulation can affect the receptor?
- Increase or decrease the number of copies of a receptor
- Increase or decrease the sensitivity of the receptor
What is heterologous regulation?
- one hormone (or neurotransmitter) will change the levels of another hormones (neurotransmitter) receptor
- There are also cases where hormones change the levels of neurotransmitter receptors.
How does the idea of subunits complicate the number of different possible versions of a receptor?
If the receptor coded for by a single gene and the gene comes in two versions, there's two different versions of the gene possible. But if the receptor is made of two subunits arising from two genes, each gene comes in two versions which produces four different possible versions of the receptor
What are some different classes of glutamate receptors?
NMDA, AMPA, kainate, metabotropic receptors
The glutamate system is central to aspects of ____________
Learning and memory
How doe some subunit compositions of glutamate receptors mediate learning better than others?
Different situation circumstances (stress for example) promote the construction of receptors with different subunit compositions over others, thereby modulating the ease with which learning occurs.
What is one implication of receptors being multi-subunit complexes?
They often bind more than just one ligand
What is GABA?
The major inhibitory neurotransmitter in the brain.
What makes the GABA receptor particularly complex?
- It binds other compounds as well, which amplify the effects of GABA.
- One component of the GABA receptor binds benzodiazepines (minor tranquilizers) like valium
- Valium makes GABA more potent in its inhibitory effects.
- One component binds major tranquilizers like barbituates (even more dramatic example of the same)
- Another component binds breakdown products of the steroid progesterone which also potentiates the inhibitory effects of GABA.
How did something like the GABA receptor come about?
The ancient version of the receptor was not sensitive to these cofactors and these arose from macroevolutionary events (a splicing enzyme shift that caused a BDZ binding related exon to get pulled into the GABA receptor arena.
What is an endocrine example of multiple binding sites on a receptor?
- Some steroid receptors bind various things in addition to their hormone ligands called cofactors.
- these can change the avidity with which the receptor binds the hormone and even can affect which DNA promoter the activated receptor then binds to.
- The glucocorticoid receptor is identical in all cell types but the array of cofactors will differ, meaning that the hormone has different sorts of effects.
What is an example of different glucocoricoid receptor having different effects on different areas of the brain?
- Glucocorticoids bind to GR and its array of cofactors in the hippocampus, leading to the decreased growth factor expression and atrophy of neurons there
- This explains how stress can disrupt learning and memory.
- In the amygdala, glucocorticoids bind to GR and a different cofactor array, leading to increased growth factor expression and expansion of neurons there.
- This helps explain how stress worsens anxiety
Explain the idea of modulation rather than activation
Factor 1 makes X more likely to occur if and only if Factor 2 is occurring at the same time
Barbituates decrease the excitability of neurons if and only if ______________
GAB is also binding to the receptor.
How do other minor ligands of the GABA receptor potentiate GABA action?
Make the receptor bind GABA for a longer time, strengthening the GABA signal
Vasopressin is not a releaser in and of themselves, but they____________
synergize with CRH. They are secretagogs.