In this class session, the great Robert Sapolsky recaps the important points covered by his teaching assistants in their lectures on neurology and endocrinology.
He begins by noting that his students that move on to medical school will hears tons about the spinal cord and cerebellum, but little about the upcoming topic, the limbic system, because therapeutic interventions are possible with the former, but difficult with the latter. Nevertheless, the limbic system is involved in the production of emotions and personality and is core to who we are.
Dale's Laws. Dale's second law begins with a neuron with the axon and axon terminal and states that each neuron has one characteristic neuron and releases only that type from its axon terminals. (This is not the same as stating it only has receptors for one type of neurotransmitter - it would still accept many.) Research in the 1980's showed Dale#2 was incorrect. Researchers discovered that not only would the neuron itself have more than one neurotransmitter, but the vesicles themselves would have two types. A few even have three types. Generally the types are structurally very different, perhaps a single amino acid and a complicated protein structure. This impacts speed of action. One of the neurotransmitters will have receptors for it on the neuron itself (bookkeeping).
He then sidesteps into his favorite topic - glucocorticoids. Why Zebras Don't Get Ulcers is mainly about these guys. In short they are stress hormones (hydrocortisone is the human equivalent - it's a steroid that is used for its anti-inflammatory and immuno-suppressant effects. These steroids are different than anabolic steroids that weightlifters use for increased strength). He cites the example of the stimulation of ACTH by the pituitary stimulating release of epinephrine and epinephrine (adrenaline and noradrenaline). These are activating hormones that tell your body to get ready for action, whether it be running, fighting, killing a squirrel or fretting about the mortgage. In the short term they redirect energy to your muscles, enhance your focus (mostly) and put you in a stimulated state. In the long term they burn you out and leave you vulnerable to cell damage and death (heart disease, stroke, Alzheimer's). It's a fight or flight stimulus mechanism that ignites under stress and, as such, is great for handling real stress but can be disastrous if turned on too often.
Corticotropin inhibiting factors contribute by inhibiting the release of ACTH by the pituitary, instead releasing, possibly, Delta 6 sleep inducing hormone (this is not known for sure). He points out that this makes sense because sleep time is a good time to turn off the stress response and do some repairs.
Dale's Law#1 states that once the action potential is reached and the neuron is turned on, it will result in the release of the neurotransmitter from all the axon terminals. (Action potentials work as all or none deals, so once the threshold is reached, it's off to the races.)
In the 1970's (probably) Jerry Letvin published a paper that provided examples of some exceptions to Dale's first law, with some of the action potentials being blocked at the axon terminal site.
The pituitary excretes seven major hormones that can be organized under the acronym FLATPeG. Why this is the best word is not at all clear. The hormones are follicle-stimulating hormone (FSH), luteinizing hormone (LH, ICSH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), prolactin (PRL), beta-endorphin and growth hormone (GH, STH).
There are specialized cells within the pituitary that release their specific type of hormone.
Within the hypothalamus, depending on the neighborhood that a cell lives in, the effects of the hormones will vary. There is a lot of communication between the cells and the hormones.
There are negative feedback systems that can sense amounts of the hormones in the bloodstream and turn off the activity when the appropriate level is reached. This is done in part by autoreceptors, which are on the neuron itself. So when the vesicle opens, one neurotransmitter floats across and others in the synapse will float back and hit that synapse. There's some internal calculation that the cells do that regulate what the conversion rate is. Disruptions of the correct calculation can cause hormonal imbalances and behavioral problems, for example depression. Often one of the neurotransmitters will work exclusively on the autoreceptor while the other heads out of town.
The brain regulates levels of hormones in the body. If there are too few, it sends an excitatory stimulus to the hypothalamus. If too many, an inhibitory stimulus is sent.
The brain also monitors and regulates the rate of change. This tends to happen more for the short term, while the amount of the hormone in the bloodstream is generally the longer term measurement. Exactly how the rate of change is counted by cells is not currently known.
Naturally there are also positive feedback systems in which the presence of a hormone stimulates more. Estrogen during pregnancy is an example that's easy to predict and understand.
Autoregulation can occur when an organism becomes used to large or small amounts of a stimulant an adjusts itself to it. If a lot of a hormone is present in the bloodstream, the body will begin to downregulate the amount of receptors for it (a sort of feedback control method in case the other system is producing too much). If there's too little, the body can increase the sensitivity of the receptors to the hormone. Problems come in when you don't compensate enough, or too much. He mentions that this is probably an issue with depression as it relates to the neurotransmitters dopamine, serotonin and epinephrine. Patients experience a lag time from starting to take the pills to feeling better. The amount of the neurotransmitter changes within minutes to hours while the receptors change in days to weeks (which is typically how long it takes for the pills to help).
This example actually makes little sense because it implies that the massive dose would lead to downregulation, not increased effectiveness and does not explain why there wasn't an upregulation. However, this is mainly because the point he is making has more to do with the regulation on the releasing axon terminal, which is better explored in the lecture on depression. (This is likely what the girl asks him at the 45 minute mark.)
He follows with a few minutes of classic, comedic Sapolsky featuring the best explanation of Type II diabetes you're likely to find.
A better example is Type II diabetes, in which cells grow resistant to insulin after being overstuffed and overstimulated for too long. Too much insulin leads to fat cells rebelling and no longer "accepting" insulin's requests. Thus even more insulin has to float around in order to find a cell that will take on the blood's sugar. If it doesn't the person becomes hyperglycemic and is at risk for a diabetic sugar coma. Eventually the pancreas can burn its insulin producing cells out from their overproduction.
He returns to the massively complicated point that the cells in the pituitary are more responsive to their type of hormonal signal from the hypothalamus and that the level of their sensitivity is based on the types of cells around them. In theory the hypothalamus can direct its signal to the type and type+sensitivity that they want.
The next point he makes scared me so much I couldn't drink a beer for weeks! He returns to the issue of glucocorticoids in the bloodstream and notes that the negative feedback will downregulate the release of CRH once the appropriate level of glucocorticoids has been hit and that each hormone has its own process going on that the brain is constantly up and down regulating through those feedback systems. Incredibly complicated and delicate in appearance. Start messing with any of that and the whole thing can be thrown out of whack. (In fact, this is what happens with some drug use, meth for example, in which the dopamine system gets so screwed up through the autoregulation process that normal amounts of dopamine have no effect and the person can't even feel good enough to feel crappy without meth because there's virtually no functional dopamine!)
Ligand - a neurotransmitter is a ligand for a neurotransmitter receptor, a hormone is a ligand for a hormone receptor. The ligand is whatever the receptor normally binds (like a baseball to a baseball glove, the baseball is the ligand).
Receptors are often made up of many different proteins, a complex of proteins. They have a lock and key pattern to receive their ligands. The shape is made from the proteins, which are coded for by the genes in the DNA. So if there are three protein shapes, we're talking three pieces of DNA. This introduces the potential for variation. And what follows is a range in working slower, faster or even not at depending on the gene expression in those proteins (harkens back to the earlier lectures on molecular genetics).
Cells can create changes by impacting their receptors and causing changes on the receptors. They can cause degrading of the proteins or replacement. This will in turn impact how well the receptor does its job.
Glutamate, for example, is involved in learning and part of how it works is by changing the shape and functioning of the glutamate receptor, making it more responsive.
Of course, this can also go wrong, for example by causing it to be way too receptive and easy to excite, such as is seen with epilepsy when a stimulus will provoke way too much of a response within a section of the brain.
Another complication is that receptors can bind more than one ligand. Gabba, for example, is the primary inhibitory neurotransmitter in the brain. It works by binding to the gabba receptor on the transmitting neuron and thus making that excitable neuron unable to send its message (like closing a gate). It works if and only if the transmitting neuron is attempting to send a message. It prevents that from completing.
The gabba receptor also binds major tranquilizers (barbiturates), minor tranquilizers (benzodiazepines - valium, librium), and derivatives of the hormone progesterone. This hormone - a shortage of it - may be implicated in the effects of PMS.
Gabba works by blocking the excitatory neuron, not the receiving end. It does so on the axon, not the dendrite.
Dale's Laws. Dale's second law begins with a neuron with the axon and axon terminal and states that each neuron has one characteristic neuron and releases only that type from its axon terminals. (This is not the same as stating it only has receptors for one type of neurotransmitter - it would still accept many.) Research in the 1980's showed Dale#2 was incorrect. Researchers discovered that not only would the neuron itself have more than one neurotransmitter, but the vesicles themselves would have two types. A few even have three types. Generally the types are structurally very different, perhaps a single amino acid and a complicated protein structure. This impacts speed of action. One of the neurotransmitters will have receptors for it on the neuron itself (bookkeeping).
He then sidesteps into his favorite topic - glucocorticoids. Why Zebras Don't Get Ulcers is mainly about these guys. In short they are stress hormones (hydrocortisone is the human equivalent - it's a steroid that is used for its anti-inflammatory and immuno-suppressant effects. These steroids are different than anabolic steroids that weightlifters use for increased strength). He cites the example of the stimulation of ACTH by the pituitary stimulating release of epinephrine and epinephrine (adrenaline and noradrenaline). These are activating hormones that tell your body to get ready for action, whether it be running, fighting, killing a squirrel or fretting about the mortgage. In the short term they redirect energy to your muscles, enhance your focus (mostly) and put you in a stimulated state. In the long term they burn you out and leave you vulnerable to cell damage and death (heart disease, stroke, Alzheimer's). It's a fight or flight stimulus mechanism that ignites under stress and, as such, is great for handling real stress but can be disastrous if turned on too often.
Corticotropin inhibiting factors contribute by inhibiting the release of ACTH by the pituitary, instead releasing, possibly, Delta 6 sleep inducing hormone (this is not known for sure). He points out that this makes sense because sleep time is a good time to turn off the stress response and do some repairs.
Dale's Law#1 states that once the action potential is reached and the neuron is turned on, it will result in the release of the neurotransmitter from all the axon terminals. (Action potentials work as all or none deals, so once the threshold is reached, it's off to the races.)
In the 1970's (probably) Jerry Letvin published a paper that provided examples of some exceptions to Dale's first law, with some of the action potentials being blocked at the axon terminal site.
The pituitary excretes seven major hormones that can be organized under the acronym FLATPeG. Why this is the best word is not at all clear. The hormones are follicle-stimulating hormone (FSH), luteinizing hormone (LH, ICSH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), prolactin (PRL), beta-endorphin and growth hormone (GH, STH).
There are specialized cells within the pituitary that release their specific type of hormone.
Within the hypothalamus, depending on the neighborhood that a cell lives in, the effects of the hormones will vary. There is a lot of communication between the cells and the hormones.
There are negative feedback systems that can sense amounts of the hormones in the bloodstream and turn off the activity when the appropriate level is reached. This is done in part by autoreceptors, which are on the neuron itself. So when the vesicle opens, one neurotransmitter floats across and others in the synapse will float back and hit that synapse. There's some internal calculation that the cells do that regulate what the conversion rate is. Disruptions of the correct calculation can cause hormonal imbalances and behavioral problems, for example depression. Often one of the neurotransmitters will work exclusively on the autoreceptor while the other heads out of town.
The brain regulates levels of hormones in the body. If there are too few, it sends an excitatory stimulus to the hypothalamus. If too many, an inhibitory stimulus is sent.
The brain also monitors and regulates the rate of change. This tends to happen more for the short term, while the amount of the hormone in the bloodstream is generally the longer term measurement. Exactly how the rate of change is counted by cells is not currently known.
Naturally there are also positive feedback systems in which the presence of a hormone stimulates more. Estrogen during pregnancy is an example that's easy to predict and understand.
Autoregulation can occur when an organism becomes used to large or small amounts of a stimulant an adjusts itself to it. If a lot of a hormone is present in the bloodstream, the body will begin to downregulate the amount of receptors for it (a sort of feedback control method in case the other system is producing too much). If there's too little, the body can increase the sensitivity of the receptors to the hormone. Problems come in when you don't compensate enough, or too much. He mentions that this is probably an issue with depression as it relates to the neurotransmitters dopamine, serotonin and epinephrine. Patients experience a lag time from starting to take the pills to feeling better. The amount of the neurotransmitter changes within minutes to hours while the receptors change in days to weeks (which is typically how long it takes for the pills to help).
This example actually makes little sense because it implies that the massive dose would lead to downregulation, not increased effectiveness and does not explain why there wasn't an upregulation. However, this is mainly because the point he is making has more to do with the regulation on the releasing axon terminal, which is better explored in the lecture on depression. (This is likely what the girl asks him at the 45 minute mark.)
He follows with a few minutes of classic, comedic Sapolsky featuring the best explanation of Type II diabetes you're likely to find.
A better example is Type II diabetes, in which cells grow resistant to insulin after being overstuffed and overstimulated for too long. Too much insulin leads to fat cells rebelling and no longer "accepting" insulin's requests. Thus even more insulin has to float around in order to find a cell that will take on the blood's sugar. If it doesn't the person becomes hyperglycemic and is at risk for a diabetic sugar coma. Eventually the pancreas can burn its insulin producing cells out from their overproduction.
He returns to the massively complicated point that the cells in the pituitary are more responsive to their type of hormonal signal from the hypothalamus and that the level of their sensitivity is based on the types of cells around them. In theory the hypothalamus can direct its signal to the type and type+sensitivity that they want.
The next point he makes scared me so much I couldn't drink a beer for weeks! He returns to the issue of glucocorticoids in the bloodstream and notes that the negative feedback will downregulate the release of CRH once the appropriate level of glucocorticoids has been hit and that each hormone has its own process going on that the brain is constantly up and down regulating through those feedback systems. Incredibly complicated and delicate in appearance. Start messing with any of that and the whole thing can be thrown out of whack. (In fact, this is what happens with some drug use, meth for example, in which the dopamine system gets so screwed up through the autoregulation process that normal amounts of dopamine have no effect and the person can't even feel good enough to feel crappy without meth because there's virtually no functional dopamine!)
Ligand - a neurotransmitter is a ligand for a neurotransmitter receptor, a hormone is a ligand for a hormone receptor. The ligand is whatever the receptor normally binds (like a baseball to a baseball glove, the baseball is the ligand).
Receptors are often made up of many different proteins, a complex of proteins. They have a lock and key pattern to receive their ligands. The shape is made from the proteins, which are coded for by the genes in the DNA. So if there are three protein shapes, we're talking three pieces of DNA. This introduces the potential for variation. And what follows is a range in working slower, faster or even not at depending on the gene expression in those proteins (harkens back to the earlier lectures on molecular genetics).
Cells can create changes by impacting their receptors and causing changes on the receptors. They can cause degrading of the proteins or replacement. This will in turn impact how well the receptor does its job.
Glutamate, for example, is involved in learning and part of how it works is by changing the shape and functioning of the glutamate receptor, making it more responsive.
Of course, this can also go wrong, for example by causing it to be way too receptive and easy to excite, such as is seen with epilepsy when a stimulus will provoke way too much of a response within a section of the brain.
Another complication is that receptors can bind more than one ligand. Gabba, for example, is the primary inhibitory neurotransmitter in the brain. It works by binding to the gabba receptor on the transmitting neuron and thus making that excitable neuron unable to send its message (like closing a gate). It works if and only if the transmitting neuron is attempting to send a message. It prevents that from completing.
The gabba receptor also binds major tranquilizers (barbiturates), minor tranquilizers (benzodiazepines - valium, librium), and derivatives of the hormone progesterone. This hormone - a shortage of it - may be implicated in the effects of PMS.
Gabba works by blocking the excitatory neuron, not the receiving end. It does so on the axon, not the dendrite.
