More Sleep Notes
Delta power refers to the dominance of delta slow waves in the EEG of a sleeping person. The magnitude of delta power in the EEG is determined by the duration of prior wakefulness. Delta power seems to be a measure of sleep need. If we can understand the mechanisms behind these EEG changes, about the homeostatic drive to sleep, maybe we can understand the function of sleep. A function of sleep has to involve mechanisms at the cellular level. Organ function is a factor of the function of the cells that make up the organ. Likewise, the brain is made of neurons, and we need to understand their function in regards to sleep in order to understand sleep. Wakefulness is producing changes in the cells of the brain that is influencing their activity during sleep, and during sleep, those cellular changes are being reversed. Slow waves on an EEG are generated when whole groups of neurons fire together in a synchronized rhythmic pattern. We can then ask, what is happening at the cellular level that is making the neurons fire together?
A neuron is like a battery, it is negative on the inside and positive on the outside. The membrane of the neuron is like the insulation on a wire, it keeps the electrical charge from crossing it. There are small channels in the membrane that can be opened and closed, which are like the on/off switch of a flashlight, allowing electrical current to flow. In neurons the current is carried by charged chemical ions rather than electrons, such as in electrical currents. Channels in the membrane are specific to certain ions (i.e. calcium channels, potassium channels, etc). Sodium, potassium, and calcium ions are positively charged, while chloride is negatively charged. Channels can also be opened in several ways. When a channel is open a little bit, all the time, it's called a "weak channel". Voltage-gated channels are opened by a change in electrical charge across the membrane. Chemically gated channels are opened by a neurotransmitter.
There are also ion pumps in the cell membrane. Pumps require energy to exchange potassium ions for sodium ions. They move sodium out of the cell and potassium into the cell, so there is a higher concentration of potassium ions inside the neuron, and a higher concentration of sodium ions outside the neuron. Neurons have channels that leak potassium slowly, leaving behind an unbalanced negative charge.
Neurons turn on and off to send signals (called nerve impulses or action potentials), the way a flashlight can send signals by being turned on and off. The sodium channels are the switch that is used to turn them on or off. Sodium channels open, allowing sodium to rush into the cell, and the area around the gate becomes positively charged. This positive charge is the action potential, which then travels down the axon of the neuron to where it ends at another neuron and causes the release of a neurotransmitter. The voltage of a neuron is variable, and can be changed by the action of the various channels. And, the changes in voltage across the membrane influence the opening and closing of voltage gated channels. The sodium channel is a voltage gated channel. After sodium channels let sodium into the cell, potassium channels open to move potassium out of the cell, to reestablish the resting voltage. Anything that causes the resting potential of the membrane to be less negative will increase the sensitivity of the neuron and increase the likelihood that it will fire. Anything that makes the membrane potential more negative will decrease the chance of the neuron firing.
The neurotransmitters of the wake-promoting nucleii in the brain increase the sensitivity of the cortex, making it more excitable, and the neurons more likely to fire. These neuromodulators can be said to be raising the resting potential of these neurons (making them less negative). When you go to sleep, and the levels of those neuromodulators go down, the resting potential of the cortical neurons becomes more negative. They are less likely to fire when receiving input. The cortex is less activated so that a person can go to sleep, and becomes reactivated during REM sleep so that a person can dream.
Calcium channels are what allow the neurons to fire in waves to create delta waves. these calcium channels are called low-threshold voltage gated calcium channels. They can be activated at a much lower threshold than the sodium channel threshold. Once it opens, it becomes inactivated and closes until it is "de-inactivated", which essentially means that it can be turned on again by another stimulus. It cannot be turned back on- open again- until it is de-inactivated. When we are awake, these calcium channels are inactivated. They are de-inactivated when the membrane potential becomes very negative. An analogy of de-inactivation is that of a mousetrap, that needs to be reset once it has sprung. When these calcium gates open, calcium rushes into the cell, making the inside of the neuron more positive, which then allows the membrane to reach the voltage that opens the sodium channels, resulting in a burst of sodium action potentials. The calcium channels then inactivate and close, which makes the resting potential more negative, stops the sodium channels from firing, and if it becomes negative enough, will de-inactivate the calcium channels. This cyclical pattern is what causes the slow waves that are recorded in the EEG.
We can now ask what happens during sleep that causes the action potentials of the cortical neurons to become so negative that they de-inactivate the calcium channels, and what happens when we are awake that influences this process. At the onset of sleep, the withdrawal of the excitatory neuromodulators from the wakefulness promoting nucleii in the brain stem and the hypothalamus increases the negative resting potential of these neurons, but even if all of these neurotransmitters were removed, it would not result in a low enough resting negative potential to generate intense slow-wave activity. Chloride and potassium channels could increase the negativity of the resting potential. Chloride channels are the targets of benzodiazapines and GABA, the major inhibitory neurotransmitter. Chloride channels are also not enough to explain this, even if all of them were open, the membrane potential would still not be negative enough to de-inactivate the calcium channels.
This leaves potassium. The membrane potential that is low enough to stop the movement of potassium ions can cause efficient de-inactivation of the calcium channels. So something that occurs during wakefulness has to be able to open potassium channels during subsequent sleep. The chemical that can do this is adenosine, the same adenosine that is found in ATP, the molecule that stores energy from food in our bodies. Adenosine also acts as a neurotransmitter. One thing it can do is increase the leak of potassium through a special class of potassium channels. When cells are energy-challenged, they increase the production and release of adenosine through a metabolic process that makes more ATP out of ADP. Adenosine in circulation gets taken up by cells and converted back to ATP quickly. It also has direct effects, such as inducing smooth muscle relaxation in arterials. One function of this is if a muscle is low on energy, it releases adenosine, which causes the arteries to relax and expand, which increases the blood flow to the muscle, bringing more oxygen and nutrients.
Does this mean that one function of non REM sleep has to do with energy reserves in the brain? The brain uses energy differently than any other part of the brain. The brain can only use sugar as an energy source, which can be either glucose in the blood, or glucose that is stored in the brain as glycogen, which is stored in glial cells. So if a part of the brain becomes energy-challenged, it will need to dip into it's glycogen reserves, which increases release of adenosine, which brings on sleepiness and sleep. In experiments, injection of chemicals that mimic the action of adenosine bring on sleep with a high delta power, and chemicals that block adenosine from it's receptors promotes wakefulness. Caffeine is one of them.
The EEG pattern of REM sleep is very similar to the EEG of wakefulness. The activity of the cholinergic nucleii of the brain stem goes back up at the transition from non REM to REM sleep. A structure in the middle of the brain stem, called the pons, is critical for generating REM sleep. The nerves that control eye movement leave the brain at the level of the pons. The loss of cells in the pons from damage corresponds to a loss of REM sleep, especially the loss of cholinergic cells. Depending on the exact area of lesions in the pons, it is possible for some aspects of REM to be lost while others are maintained. This area of the pons has been called the Pontine Inhibitory Area (PIA). When cats were lesioned in the PIA, they made the transition to REM sleep but instead of the usual muscle atonia, they (appeared to be) acting out their dreams. Injecting a chemical into the pons that mimics acetylcholine induces REM sleep. The muscle atonia of sleep is induced by neurons that send signals down the spinal cord from the pons which release inhibitory neurotransmitters GABA and glycine onto the motor neurons in the spinal cord.
Delta power refers to the dominance of delta slow waves in the EEG of a sleeping person. The magnitude of delta power in the EEG is determined by the duration of prior wakefulness. Delta power seems to be a measure of sleep need. If we can understand the mechanisms behind these EEG changes, about the homeostatic drive to sleep, maybe we can understand the function of sleep. A function of sleep has to involve mechanisms at the cellular level. Organ function is a factor of the function of the cells that make up the organ. Likewise, the brain is made of neurons, and we need to understand their function in regards to sleep in order to understand sleep. Wakefulness is producing changes in the cells of the brain that is influencing their activity during sleep, and during sleep, those cellular changes are being reversed. Slow waves on an EEG are generated when whole groups of neurons fire together in a synchronized rhythmic pattern. We can then ask, what is happening at the cellular level that is making the neurons fire together?
A neuron is like a battery, it is negative on the inside and positive on the outside. The membrane of the neuron is like the insulation on a wire, it keeps the electrical charge from crossing it. There are small channels in the membrane that can be opened and closed, which are like the on/off switch of a flashlight, allowing electrical current to flow. In neurons the current is carried by charged chemical ions rather than electrons, such as in electrical currents. Channels in the membrane are specific to certain ions (i.e. calcium channels, potassium channels, etc). Sodium, potassium, and calcium ions are positively charged, while chloride is negatively charged. Channels can also be opened in several ways. When a channel is open a little bit, all the time, it's called a "weak channel". Voltage-gated channels are opened by a change in electrical charge across the membrane. Chemically gated channels are opened by a neurotransmitter.
There are also ion pumps in the cell membrane. Pumps require energy to exchange potassium ions for sodium ions. They move sodium out of the cell and potassium into the cell, so there is a higher concentration of potassium ions inside the neuron, and a higher concentration of sodium ions outside the neuron. Neurons have channels that leak potassium slowly, leaving behind an unbalanced negative charge.
Neurons turn on and off to send signals (called nerve impulses or action potentials), the way a flashlight can send signals by being turned on and off. The sodium channels are the switch that is used to turn them on or off. Sodium channels open, allowing sodium to rush into the cell, and the area around the gate becomes positively charged. This positive charge is the action potential, which then travels down the axon of the neuron to where it ends at another neuron and causes the release of a neurotransmitter. The voltage of a neuron is variable, and can be changed by the action of the various channels. And, the changes in voltage across the membrane influence the opening and closing of voltage gated channels. The sodium channel is a voltage gated channel. After sodium channels let sodium into the cell, potassium channels open to move potassium out of the cell, to reestablish the resting voltage. Anything that causes the resting potential of the membrane to be less negative will increase the sensitivity of the neuron and increase the likelihood that it will fire. Anything that makes the membrane potential more negative will decrease the chance of the neuron firing.
The neurotransmitters of the wake-promoting nucleii in the brain increase the sensitivity of the cortex, making it more excitable, and the neurons more likely to fire. These neuromodulators can be said to be raising the resting potential of these neurons (making them less negative). When you go to sleep, and the levels of those neuromodulators go down, the resting potential of the cortical neurons becomes more negative. They are less likely to fire when receiving input. The cortex is less activated so that a person can go to sleep, and becomes reactivated during REM sleep so that a person can dream.
Calcium channels are what allow the neurons to fire in waves to create delta waves. these calcium channels are called low-threshold voltage gated calcium channels. They can be activated at a much lower threshold than the sodium channel threshold. Once it opens, it becomes inactivated and closes until it is "de-inactivated", which essentially means that it can be turned on again by another stimulus. It cannot be turned back on- open again- until it is de-inactivated. When we are awake, these calcium channels are inactivated. They are de-inactivated when the membrane potential becomes very negative. An analogy of de-inactivation is that of a mousetrap, that needs to be reset once it has sprung. When these calcium gates open, calcium rushes into the cell, making the inside of the neuron more positive, which then allows the membrane to reach the voltage that opens the sodium channels, resulting in a burst of sodium action potentials. The calcium channels then inactivate and close, which makes the resting potential more negative, stops the sodium channels from firing, and if it becomes negative enough, will de-inactivate the calcium channels. This cyclical pattern is what causes the slow waves that are recorded in the EEG.
We can now ask what happens during sleep that causes the action potentials of the cortical neurons to become so negative that they de-inactivate the calcium channels, and what happens when we are awake that influences this process. At the onset of sleep, the withdrawal of the excitatory neuromodulators from the wakefulness promoting nucleii in the brain stem and the hypothalamus increases the negative resting potential of these neurons, but even if all of these neurotransmitters were removed, it would not result in a low enough resting negative potential to generate intense slow-wave activity. Chloride and potassium channels could increase the negativity of the resting potential. Chloride channels are the targets of benzodiazapines and GABA, the major inhibitory neurotransmitter. Chloride channels are also not enough to explain this, even if all of them were open, the membrane potential would still not be negative enough to de-inactivate the calcium channels.
This leaves potassium. The membrane potential that is low enough to stop the movement of potassium ions can cause efficient de-inactivation of the calcium channels. So something that occurs during wakefulness has to be able to open potassium channels during subsequent sleep. The chemical that can do this is adenosine, the same adenosine that is found in ATP, the molecule that stores energy from food in our bodies. Adenosine also acts as a neurotransmitter. One thing it can do is increase the leak of potassium through a special class of potassium channels. When cells are energy-challenged, they increase the production and release of adenosine through a metabolic process that makes more ATP out of ADP. Adenosine in circulation gets taken up by cells and converted back to ATP quickly. It also has direct effects, such as inducing smooth muscle relaxation in arterials. One function of this is if a muscle is low on energy, it releases adenosine, which causes the arteries to relax and expand, which increases the blood flow to the muscle, bringing more oxygen and nutrients.
Does this mean that one function of non REM sleep has to do with energy reserves in the brain? The brain uses energy differently than any other part of the brain. The brain can only use sugar as an energy source, which can be either glucose in the blood, or glucose that is stored in the brain as glycogen, which is stored in glial cells. So if a part of the brain becomes energy-challenged, it will need to dip into it's glycogen reserves, which increases release of adenosine, which brings on sleepiness and sleep. In experiments, injection of chemicals that mimic the action of adenosine bring on sleep with a high delta power, and chemicals that block adenosine from it's receptors promotes wakefulness. Caffeine is one of them.
The EEG pattern of REM sleep is very similar to the EEG of wakefulness. The activity of the cholinergic nucleii of the brain stem goes back up at the transition from non REM to REM sleep. A structure in the middle of the brain stem, called the pons, is critical for generating REM sleep. The nerves that control eye movement leave the brain at the level of the pons. The loss of cells in the pons from damage corresponds to a loss of REM sleep, especially the loss of cholinergic cells. Depending on the exact area of lesions in the pons, it is possible for some aspects of REM to be lost while others are maintained. This area of the pons has been called the Pontine Inhibitory Area (PIA). When cats were lesioned in the PIA, they made the transition to REM sleep but instead of the usual muscle atonia, they (appeared to be) acting out their dreams. Injecting a chemical into the pons that mimics acetylcholine induces REM sleep. The muscle atonia of sleep is induced by neurons that send signals down the spinal cord from the pons which release inhibitory neurotransmitters GABA and glycine onto the motor neurons in the spinal cord.
