Information

35.2: How Neurons Communicate - Biology


Skills to Develop

  • Describe the basis of the resting membrane potential
  • Explain the stages of an action potential and how action potentials are propagated
  • Explain the similarities and differences between chemical and electrical synapses
  • Describe long-term potentiation and long-term depression

All functions performed by the nervous system—from a simple motor reflex to more advanced functions like making a memory or a decision—require neurons to communicate with one another. While humans use words and body language to communicate, neurons use electrical and chemical signals. Just like a person in a committee, one neuron usually receives and synthesizes messages from multiple other neurons before “making the decision” to send the message on to other neurons.

Nerve Impulse Transmission within a Neuron

For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or ‘resting’ membrane charge.

Neuronal Charged Membranes

The lipid bilayer membrane that surrounds a neuron is impermeable to charged molecules or ions. To enter or exit the neuron, ions must pass through special proteins called ion channels that span the membrane. Ion channels have different configurations: open, closed, and inactive, as illustrated in Figure (PageIndex{1}). Some ion channels need to be activated in order to open and allow ions to pass into or out of the cell. These ion channels are sensitive to the environment and can change their shape accordingly. Ion channels that change their structure in response to voltage changes are called voltage-gated ion channels. Voltage-gated ion channels regulate the relative concentrations of different ions inside and outside the cell. The difference in total charge between the inside and outside of the cell is called the membrane potential.

Link to Learning

This video discusses the basis of the resting membrane potential.

Resting Membrane Potential

A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential; it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell, as shown in the table below. The difference in the number of positively charged potassium ions (K+) inside and outside the cell dominates the resting membrane potential (Figure (PageIndex{2})). When the membrane is at rest, K+ ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient. However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps brings two K+ ions into the cell while removing three Na+ ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid. It should be noted that calcium ions (Cl) tend to accumulate outside of the cell because they are repelled by negatively-charged proteins within the cytoplasm.

Table (PageIndex{1}): Ion Concentration Inside and Outside Neurons. The resting membrane potential is a result of different concentrations inside and outside the cell.

IonExtracellular concentration (mM)Intracellular concentration (mM)Ratio outside/inside
Na+1451212
K+41550.026
Cl−120430
Organic anions (A−)100

Action Potential

A neuron can receive input from other neurons and, if this input is strong enough, send the signal to downstream neurons. Transmission of a signal between neurons is generally carried by a chemical called a neurotransmitter. Transmission of a signal within a neuron (from dendrite to axon terminal) is carried by a brief reversal of the resting membrane potential called an action potential. When neurotransmitter molecules bind to receptors located on a neuron’s dendrites, ion channels open. At excitatory synapses, this opening allows positive ions to enter the neuron and results in depolarization of the membrane—a decrease in the difference in voltage between the inside and outside of the neuron. A stimulus from a sensory cell or another neuron depolarizes the target neuron to its threshold potential (-55 mV). Na+ channels in the axon hillock open, allowing positive ions to enter the cell (Figure (PageIndex{3}) and Figure (PageIndex{4})). Once the sodium channels open, the neuron completely depolarizes to a membrane potential of about +40 mV. Action potentials are considered an "all-or nothing" event, in that, once the threshold potential is reached, the neuron always completely depolarizes. Once depolarization is complete, the cell must now "reset" its membrane voltage back to the resting potential. To accomplish this, the Na+ channels close and cannot be opened. This begins the neuron's refractory period, in which it cannot produce another action potential because its sodium channels will not open. At the same time, voltage-gated K+ channels open, allowing K+ to leave the cell. As K+ ions leave the cell, the membrane potential once again becomes negative. The diffusion of K+ out of the cell actually hyperpolarizes the cell, in that the membrane potential becomes more negative than the cell's normal resting potential. At this point, the sodium channels will return to their resting state, meaning they are ready to open again if the membrane potential again exceeds the threshold potential. Eventually the extra K+ ions diffuse out of the cell through the potassium leakage channels, bringing the cell from its hyperpolarized state, back to its resting membrane potential.

Art Connection

Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K+ through voltage-gated K+ channels. Which part of the action potential would you expect potassium channels to affect?

Link to Learning

This video presents an overview of action potential.

Myelin and the Propagation of the Action Potential

For an action potential to communicate information to another neuron, it must travel along the axon and reach the axon terminals where it can initiate neurotransmitter release. The speed of conduction of an action potential along an axon is influenced by both the diameter of the axon and the axon’s resistance to current leak. Myelin acts as an insulator that prevents current from leaving the axon; this increases the speed of action potential conduction. In demyelinating diseases like multiple sclerosis, action potential conduction slows because current leaks from previously insulated axon areas. The nodes of Ranvier, illustrated in Figure (PageIndex{5}) are gaps in the myelin sheath along the axon. These unmyelinated spaces are about one micrometer long and contain voltage gated Na+ and K+ channels. Flow of ions through these channels, particularly the Na+ channels, regenerates the action potential over and over again along the axon. This ‘jumping’ of the action potential from one node to the next is called saltatory conduction. If nodes of Ranvier were not present along an axon, the action potential would propagate very slowly since Na+ and K+ channels would have to continuously regenerate action potentials at every point along the axon instead of at specific points. Nodes of Ranvier also save energy for the neuron since the channels only need to be present at the nodes and not along the entire axon.

Synaptic Transmission

The synapse or “gap” is the place where information is transmitted from one neuron to another. Synapses usually form between axon terminals and dendritic spines, but this is not universally true. There are also axon-to-axon, dendrite-to-dendrite, and axon-to-cell body synapses. The neuron transmitting the signal is called the presynaptic neuron, and the neuron receiving the signal is called the postsynaptic neuron. Note that these designations are relative to a particular synapse—most neurons are both presynaptic and postsynaptic. There are two types of synapses: chemical and electrical.

Chemical Synapse

When an action potential reaches the axon terminal it depolarizes the membrane and opens voltage-gated Na+ channels. Na+ ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated Ca2+ channels to open. Calcium ions entering the cell initiate a signaling cascade that causes small membrane-bound vesicles, called synaptic vesicles, containing neurotransmitter molecules to fuse with the presynaptic membrane. Synaptic vesicles are shown in Figure (PageIndex{6}), which is an image from a scanning electron microscope.

Fusion of a vesicle with the presynaptic membrane causes neurotransmitter to be released into the synaptic cleft, the extracellular space between the presynaptic and postsynaptic membranes, as illustrated in Figure (PageIndex{7}). The neurotransmitter diffuses across the synaptic cleft and binds to receptor proteins on the postsynaptic membrane.

The binding of a specific neurotransmitter causes particular ion channels, in this case ligand-gated channels, on the postsynaptic membrane to open. Neurotransmitters can either have excitatory or inhibitory effects on the postsynaptic membrane, as detailed in the table below. For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na+ channels to open. Na+ enters the postsynaptic cell and causes the postsynaptic membrane to depolarize. This depolarization is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. Release of neurotransmitter at inhibitory synapses causes inhibitory postsynaptic potentials (IPSPs), a hyperpolarization of the presynaptic membrane. For example, when the neurotransmitter GABA (gamma-aminobutyric acid) is released from a presynaptic neuron, it binds to and opens Cl- channels. Cl- ions enter the cell and hyperpolarizes the membrane, making the neuron less likely to fire an action potential.

Once neurotransmission has occurred, the neurotransmitter must be removed from the synaptic cleft so the postsynaptic membrane can “reset” and be ready to receive another signal. This can be accomplished in three ways: the neurotransmitter can diffuse away from the synaptic cleft, it can be degraded by enzymes in the synaptic cleft, or it can be recycled (sometimes called reuptake) by the presynaptic neuron. Several drugs act at this step of neurotransmission. For example, some drugs that are given to Alzheimer’s patients work by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine. This inhibition of the enzyme essentially increases neurotransmission at synapses that release acetylcholine. Once released, the acetylcholine stays in the cleft and can continually bind and unbind to postsynaptic receptors.

Table (PageIndex{2}): Neurotransmitter Function and Location
NeurotransmitterExampleLocation
AcetylcholineCNS and/or PNS
Biogenic amineDopamine, serotonin, norepinephrineCNS and/or PNS
Amino acidGlycine, glutamate, aspartate, gamma aminobutyric acidCNS
NeuropeptideSubstance P, endorphinsCNS and/or PNS

Electrical Synapse

While electrical synapses are fewer in number than chemical synapses, they are found in all nervous systems and play important and unique roles. The mode of neurotransmission in electrical synapses is quite different from that in chemical synapses. In an electrical synapse, the presynaptic and postsynaptic membranes are very close together and are actually physically connected by channel proteins forming gap junctions. Gap junctions allow current to pass directly from one cell to the next. In addition to the ions that carry this current, other molecules, such as ATP, can diffuse through the large gap junction pores.

There are key differences between chemical and electrical synapses. Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is unidirectional. Signaling in electrical synapses, in contrast, is virtually instantaneous (which is important for synapses involved in key reflexes), and some electrical synapses are bidirectional. Electrical synapses are also more reliable as they are less likely to be blocked, and they are important for synchronizing the electrical activity of a group of neurons. For example, electrical synapses in the thalamus are thought to regulate slow-wave sleep, and disruption of these synapses can cause seizures.

Signal Summation

Sometimes a single EPSP is strong enough to induce an action potential in the postsynaptic neuron, but often multiple presynaptic inputs must create EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential. This process is called summation and occurs at the axon hillock, as illustrated in Figure (PageIndex{8}). Additionally, one neuron often has inputs from many presynaptic neurons—some excitatory and some inhibitory—so IPSPs can cancel out EPSPs and vice versa. It is the net change in postsynaptic membrane voltage that determines whether the postsynaptic cell has reached its threshold of excitation needed to fire an action potential. Together, synaptic summation and the threshold for excitation act as a filter so that random “noise” in the system is not transmitted as important information.

Everyday Connection: Brain-computer interface

Amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s Disease) is a neurological disease characterized by the degeneration of the motor neurons that control voluntary movements. The disease begins with muscle weakening and lack of coordination and eventually destroys the neurons that control speech, breathing, and swallowing; in the end, the disease can lead to paralysis. At that point, patients require assistance from machines to be able to breathe and to communicate. Several special technologies have been developed to allow “locked-in” patients to communicate with the rest of the world. One technology, for example, allows patients to type out sentences by twitching their cheek. These sentences can then be read aloud by a computer.

A relatively new line of research for helping paralyzed patients, including those with ALS, to communicate and retain a degree of self-sufficiency is called brain-computer interface (BCI) technology and is illustrated in Figure (PageIndex{9}). This technology sounds like something out of science fiction: it allows paralyzed patients to control a computer using only their thoughts. There are several forms of BCI. Some forms use EEG recordings from electrodes taped onto the skull. These recordings contain information from large populations of neurons that can be decoded by a computer. Other forms of BCI require the implantation of an array of electrodes smaller than a postage stamp in the arm and hand area of the motor cortex. This form of BCI, while more invasive, is very powerful as each electrode can record actual action potentials from one or more neurons. These signals are then sent to a computer, which has been trained to decode the signal and feed it to a tool—such as a cursor on a computer screen. This means that a patient with ALS can use e-mail, read the Internet, and communicate with others by thinking of moving his or her hand or arm (even though the paralyzed patient cannot make that bodily movement). Recent advances have allowed a paralyzed locked-in patient who suffered a stroke 15 years ago to control a robotic arm and even to feed herself coffee using BCI technology.

Despite the amazing advancements in BCI technology, it also has limitations. The technology can require many hours of training and long periods of intense concentration for the patient; it can also require brain surgery to implant the devices.

Link to Learning

Watch this video in which a paralyzed woman use a brain-controlled robotic arm to bring a drink to her mouth, among other images of brain-computer interface technology in action.

​​​​​Synaptic Plasticity

Synapses are not static structures. They can be weakened or strengthened. They can be broken, and new synapses can be made. Synaptic plasticity allows for these changes, which are all needed for a functioning nervous system. In fact, synaptic plasticity is the basis of learning and memory. Two processes in particular, long-term potentiation (LTP) and long-term depression (LTD) are important forms of synaptic plasticity that occur in synapses in the hippocampus, a brain region that is involved in storing memories.

Long-term Potentiation (LTP)

Long-term potentiation (LTP) is a persistent strengthening of a synaptic connection. LTP is based on the Hebbian principle: cells that fire together wire together. There are various mechanisms, none fully understood, behind the synaptic strengthening seen with LTP. One known mechanism involves a type of postsynaptic glutamate receptor, called NMDA (N-Methyl-D-aspartate) receptors, shown in Figure 35.2.10. These receptors are normally blocked by magnesium ions; however, when the postsynaptic neuron is depolarized by multiple presynaptic inputs in quick succession (either from one neuron or multiple neurons), the magnesium ions are forced out allowing Ca ions to pass into the postsynaptic cell. Next, Ca2+ ions entering the cell initiate a signaling cascade that causes a different type of glutamate receptor, called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, to be inserted into the postsynaptic membrane, since activated AMPA receptors allow positive ions to enter the cell. So, the next time glutamate is released from the presynaptic membrane, it will have a larger excitatory effect (EPSP) on the postsynaptic cell because the binding of glutamate to these AMPA receptors will allow more positive ions into the cell. The insertion of additional AMPA receptors strengthens the synapse and means that the postsynaptic neuron is more likely to fire in response to presynaptic neurotransmitter release. Some drugs of abuse co-opt the LTP pathway, and this synaptic strengthening can lead to addiction.

Long-term Depression (LTD)

Long-term depression (LTD) is essentially the reverse of LTP: it is a long-term weakening of a synaptic connection. One mechanism known to cause LTD also involves AMPA receptors. In this situation, calcium that enters through NMDA receptors initiates a different signaling cascade, which results in the removal of AMPA receptors from the postsynaptic membrane, as illustrated in Figure (PageIndex{10}). The decrease in AMPA receptors in the membrane makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron. While it may seem counterintuitive, LTD may be just as important for learning and memory as LTP. The weakening and pruning of unused synapses allows for unimportant connections to be lost and makes the synapses that have undergone LTP that much stronger by comparison.

Summary

Neurons have charged membranes because there are different concentrations of ions inside and outside of the cell. Voltage-gated ion channels control the movement of ions into and out of a neuron. When a neuronal membrane is depolarized to at least the threshold of excitation, an action potential is fired. The action potential is then propagated along a myelinated axon to the axon terminals. In a chemical synapse, the action potential causes release of neurotransmitter molecules into the synaptic cleft. Through binding to postsynaptic receptors, the neurotransmitter can cause excitatory or inhibitory postsynaptic potentials by depolarizing or hyperpolarizing, respectively, the postsynaptic membrane. In electrical synapses, the action potential is directly communicated to the postsynaptic cell through gap junctions—large channel proteins that connect the pre-and postsynaptic membranes. Synapses are not static structures and can be strengthened and weakened. Two mechanisms of synaptic plasticity are long-term potentiation and long-term depression.

Art Connections

[link] Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K+ through voltage-gated K+ channels. Which part of the action potential would you expect potassium channels to affect?

[link] Potassium channel blockers slow the repolarization phase, but have no effect on depolarization.

Glossary

action potential
self-propagating momentary change in the electrical potential of a neuron (or muscle) membrane
depolarization
change in the membrane potential to a less negative value
excitatory postsynaptic potential (EPSP)
depolarization of a postsynaptic membrane caused by neurotransmitter molecules released from a presynaptic cell
hyperpolarization
change in the membrane potential to a more negative value
inhibitory postsynaptic potential (IPSP)
hyperpolarization of a postsynaptic membrane caused by neurotransmitter molecules released from a presynaptic cell
long-term depression (LTD)
prolonged decrease in synaptic coupling between a pre- and postsynaptic cell
long-term potentiation (LTP)
prolonged increase in synaptic coupling between a pre-and postsynaptic cell
membrane potential
difference in electrical potential between the inside and outside of a cell
refractory period
period after an action potential when it is more difficult or impossible for an action potential to be fired; caused by inactivation of sodium channels and activation of additional potassium channels of the membrane
saltatory conduction
“jumping” of an action potential along an axon from one node of Ranvier to the next
summation
process of multiple presynaptic inputs creating EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential
synaptic cleft
space between the presynaptic and postsynaptic membranes
synaptic vesicle
spherical structure that contains a neurotransmitter
threshold of excitation
level of depolarization needed for an action potential to fire

16.2 How Neurons Communicate

All functions performed by the nervous system—from a simple motor reflex to more advanced functions like making a memory or a decision—require neurons to communicate with one another. While humans use words and body language to communicate, neurons use electrical and chemical signals. Just like a person in a committee, one neuron usually receives and synthesizes messages from multiple other neurons before “making the decision” to send the message on to other neurons.


Nerve Impulse Transmission within a Neuron

For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or ‘resting’ membrane charge.


183 How Neurons Communicate

By the end of this section, you will be able to do the following:

  • Describe the basis of the resting membrane potential
  • Explain the stages of an action potential and how action potentials are propagated
  • Explain the similarities and differences between chemical and electrical synapses
  • Describe long-term potentiation and long-term depression

All functions performed by the nervous system—from a simple motor reflex to more advanced functions like making a memory or a decision—require neurons to communicate with one another. While humans use words and body language to communicate, neurons use electrical and chemical signals. Just like a person in a committee, one neuron usually receives and synthesizes messages from multiple other neurons before “making the decision” to send the message on to other neurons.

Nerve Impulse Transmission within a Neuron

For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or ‘resting’ membrane charge.

Neuronal Charged Membranes

The lipid bilayer membrane that surrounds a neuron is impermeable to charged molecules or ions. To enter or exit the neuron, ions must pass through special proteins called ion channels that span the membrane. Ion channels have different configurations: open, closed, and inactive, as illustrated in (Figure). Some ion channels need to be activated in order to open and allow ions to pass into or out of the cell. These ion channels are sensitive to the environment and can change their shape accordingly. Ion channels that change their structure in response to voltage changes are called voltage-gated ion channels. Voltage-gated ion channels regulate the relative concentrations of different ions inside and outside the cell. The difference in total charge between the inside and outside of the cell is called the membrane potential .


This video discusses the basis of the resting membrane potential.

Resting Membrane Potential

A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell, as shown in (Figure). The difference in the number of positively charged potassium ions (K + ) inside and outside the cell dominates the resting membrane potential ((Figure)). When the membrane is at rest, K + ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient. However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps brings two K + ions into the cell while removing three Na + ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid. It should be noted that chloride ions (Cl – ) tend to accumulate outside of the cell because they are repelled by negatively-charged proteins within the cytoplasm.

The resting membrane potential is a result of different concentrations inside and outside the cell.
Ion Concentration Inside and Outside Neurons
Ion Extracellular concentration (mM) Intracellular concentration (mM) Ratio outside/inside
Na + 145 12 12
K+ 4 155 0.026
Cl − 120 4 30
Organic anions (A−) 100


Action Potential

A neuron can receive input from other neurons and, if this input is strong enough, send the signal to downstream neurons. Transmission of a signal between neurons is generally carried by a chemical called a neurotransmitter. Transmission of a signal within a neuron (from dendrite to axon terminal) is carried by a brief reversal of the resting membrane potential called an action potential . When neurotransmitter molecules bind to receptors located on a neuron’s dendrites, ion channels open. At excitatory synapses, this opening allows positive ions to enter the neuron and results in depolarization of the membrane—a decrease in the difference in voltage between the inside and outside of the neuron. A stimulus from a sensory cell or another neuron depolarizes the target neuron to its threshold potential (-55 mV). Na + channels in the axon hillock open, allowing positive ions to enter the cell ((Figure) and (Figure)). Once the sodium channels open, the neuron completely depolarizes to a membrane potential of about +40 mV. Action potentials are considered an “all-or nothing” event, in that, once the threshold potential is reached, the neuron always completely depolarizes. Once depolarization is complete, the cell must now “reset” its membrane voltage back to the resting potential. To accomplish this, the Na + channels close and cannot be opened. This begins the neuron’s refractory period , in which it cannot produce another action potential because its sodium channels will not open. At the same time, voltage-gated K + channels open, allowing K + to leave the cell. As K + ions leave the cell, the membrane potential once again becomes negative. The diffusion of K + out of the cell actually hyperpolarizes the cell, in that the membrane potential becomes more negative than the cell’s normal resting potential. At this point, the sodium channels will return to their resting state, meaning they are ready to open again if the membrane potential again exceeds the threshold potential. Eventually the extra K + ions diffuse out of the cell through the potassium leakage channels, bringing the cell from its hyperpolarized state, back to its resting membrane potential.


Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K + through voltage-gated K + channels. Which part of the action potential would you expect potassium channels to affect?


This video presents an overview of action potential.

Myelin and the Propagation of the Action Potential

For an action potential to communicate information to another neuron, it must travel along the axon and reach the axon terminals where it can initiate neurotransmitter release. The speed of conduction of an action potential along an axon is influenced by both the diameter of the axon and the axon’s resistance to current leak. Myelin acts as an insulator that prevents current from leaving the axon this increases the speed of action potential conduction. In demyelinating diseases like multiple sclerosis, action potential conduction slows because current leaks from previously insulated axon areas. The nodes of Ranvier, illustrated in (Figure) are gaps in the myelin sheath along the axon. These unmyelinated spaces are about one micrometer long and contain voltage-gated Na + and K + channels. Flow of ions through these channels, particularly the Na + channels, regenerates the action potential over and over again along the axon. This ‘jumping’ of the action potential from one node to the next is called saltatory conduction . If nodes of Ranvier were not present along an axon, the action potential would propagate very slowly since Na + and K + channels would have to continuously regenerate action potentials at every point along the axon instead of at specific points. Nodes of Ranvier also save energy for the neuron since the channels only need to be present at the nodes and not along the entire axon.


Synaptic Transmission

The synapse or “gap” is the place where information is transmitted from one neuron to another. Synapses usually form between axon terminals and dendritic spines, but this is not universally true. There are also axon-to-axon, dendrite-to-dendrite, and axon-to-cell body synapses. The neuron transmitting the signal is called the presynaptic neuron, and the neuron receiving the signal is called the postsynaptic neuron. Note that these designations are relative to a particular synapse—most neurons are both presynaptic and postsynaptic. There are two types of synapses: chemical and electrical.

Chemical Synapse

When an action potential reaches the axon terminal it depolarizes the membrane and opens voltage-gated Na + channels. Na + ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated Ca 2+ channels to open. Calcium ions entering the cell initiate a signaling cascade that causes small membrane-bound vesicles, called synaptic vesicles , containing neurotransmitter molecules to fuse with the presynaptic membrane. Synaptic vesicles are shown in (Figure), which is an image from a scanning electron microscope.


Fusion of a vesicle with the presynaptic membrane causes neurotransmitter to be released into the synaptic cleft , the extracellular space between the presynaptic and postsynaptic membranes, as illustrated in (Figure). The neurotransmitter diffuses across the synaptic cleft and binds to receptor proteins on the postsynaptic membrane.


The binding of a specific neurotransmitter causes particular ion channels, in this case ligand-gated channels, on the postsynaptic membrane to open. Neurotransmitters can either have excitatory or inhibitory effects on the postsynaptic membrane, as detailed in (Figure). For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na + channels to open. Na + enters the postsynaptic cell and causes the postsynaptic membrane to depolarize. This depolarization is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. Release of neurotransmitter at inhibitory synapses causes inhibitory postsynaptic potentials (IPSPs) , a hyperpolarization of the presynaptic membrane. For example, when the neurotransmitter GABA (gamma-aminobutyric acid) is released from a presynaptic neuron, it binds to and opens Cl – channels. Cl – ions enter the cell and hyperpolarizes the membrane, making the neuron less likely to fire an action potential.

Once neurotransmission has occurred, the neurotransmitter must be removed from the synaptic cleft so the postsynaptic membrane can “reset” and be ready to receive another signal. This can be accomplished in three ways: the neurotransmitter can diffuse away from the synaptic cleft, it can be degraded by enzymes in the synaptic cleft, or it can be recycled (sometimes called reuptake) by the presynaptic neuron. Several drugs act at this step of neurotransmission. For example, some drugs that are given to Alzheimer’s patients work by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine. This inhibition of the enzyme essentially increases neurotransmission at synapses that release acetylcholine. Once released, the acetylcholine stays in the cleft and can continually bind and unbind to postsynaptic receptors.

Neurotransmitter Function and Location
Neurotransmitter Example Location
Acetylcholine CNS and/or PNS
Biogenic amine Dopamine, serotonin, norepinephrine CNS and/or PNS
Amino acid Glycine, glutamate, aspartate, gamma aminobutyric acid CNS
Neuropeptide Substance P, endorphins CNS and/or PNS

Electrical Synapse

While electrical synapses are fewer in number than chemical synapses, they are found in all nervous systems and play important and unique roles. The mode of neurotransmission in electrical synapses is quite different from that in chemical synapses. In an electrical synapse, the presynaptic and postsynaptic membranes are very close together and are actually physically connected by channel proteins forming gap junctions. Gap junctions allow current to pass directly from one cell to the next. In addition to the ions that carry this current, other molecules, such as ATP, can diffuse through the large gap junction pores.

There are key differences between chemical and electrical synapses. Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is unidirectional. Signaling in electrical synapses, in contrast, is virtually instantaneous (which is important for synapses involved in key reflexes), and some electrical synapses are bidirectional. Electrical synapses are also more reliable as they are less likely to be blocked, and they are important for synchronizing the electrical activity of a group of neurons. For example, electrical synapses in the thalamus are thought to regulate slow-wave sleep, and disruption of these synapses can cause seizures.

Signal Summation

Sometimes a single EPSP is strong enough to induce an action potential in the postsynaptic neuron, but often multiple presynaptic inputs must create EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential. This process is called summation and occurs at the axon hillock, as illustrated in (Figure). Additionally, one neuron often has inputs from many presynaptic neurons—some excitatory and some inhibitory—so IPSPs can cancel out EPSPs and vice versa. It is the net change in postsynaptic membrane voltage that determines whether the postsynaptic cell has reached its threshold of excitation needed to fire an action potential. Together, synaptic summation and the threshold for excitation act as a filter so that random “noise” in the system is not transmitted as important information.


Brain-computer interface
Amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s Disease) is a neurological disease characterized by the degeneration of the motor neurons that control voluntary movements. The disease begins with muscle weakening and lack of coordination and eventually destroys the neurons that control speech, breathing, and swallowing in the end, the disease can lead to paralysis. At that point, patients require assistance from machines to be able to breathe and to communicate. Several special technologies have been developed to allow “locked-in” patients to communicate with the rest of the world. One technology, for example, allows patients to type out sentences by twitching their cheek. These sentences can then be read aloud by a computer.

A relatively new line of research for helping paralyzed patients, including those with ALS, to communicate and retain a degree of self-sufficiency is called brain-computer interface (BCI) technology and is illustrated in (Figure). This technology sounds like something out of science fiction: it allows paralyzed patients to control a computer using only their thoughts. There are several forms of BCI. Some forms use EEG recordings from electrodes taped onto the skull. These recordings contain information from large populations of neurons that can be decoded by a computer. Other forms of BCI require the implantation of an array of electrodes smaller than a postage stamp in the arm and hand area of the motor cortex. This form of BCI, while more invasive, is very powerful as each electrode can record actual action potentials from one or more neurons. These signals are then sent to a computer, which has been trained to decode the signal and feed it to a tool—such as a cursor on a computer screen. This means that a patient with ALS can use e-mail, read the Internet, and communicate with others by thinking of moving his or her hand or arm (even though the paralyzed patient cannot make that bodily movement). Recent advances have allowed a paralyzed locked-in patient who suffered a stroke 15 years ago to control a robotic arm and even to feed herself coffee using BCI technology.

Despite the amazing advancements in BCI technology, it also has limitations. The technology can require many hours of training and long periods of intense concentration for the patient it can also require brain surgery to implant the devices.


Watch this video in which a paralyzed woman uses a brain-controlled robotic arm to bring a drink to her mouth, among other images of brain-computer interface technology in action.

Synaptic Plasticity

Synapses are not static structures. They can be weakened or strengthened. They can be broken, and new synapses can be made. Synaptic plasticity allows for these changes, which are all needed for a functioning nervous system. In fact, synaptic plasticity is the basis of learning and memory. Two processes in particular, long-term potentiation (LTP) and long-term depression (LTD) are important forms of synaptic plasticity that occur in synapses in the hippocampus, a brain region that is involved in storing memories.

Long-term Potentiation (LTP)

Long-term potentiation (LTP) is a persistent strengthening of a synaptic connection. LTP is based on the Hebbian principle: cells that fire together wire together. There are various mechanisms, none fully understood, behind the synaptic strengthening seen with LTP. One known mechanism involves a type of postsynaptic glutamate receptor, called NMDA (N-Methyl-D-aspartate) receptors, shown in (Figure). These receptors are normally blocked by magnesium ions however, when the postsynaptic neuron is depolarized by multiple presynaptic inputs in quick succession (either from one neuron or multiple neurons), the magnesium ions are forced out allowing Ca ions to pass into the postsynaptic cell. Next, Ca 2+ ions entering the cell initiate a signaling cascade that causes a different type of glutamate receptor, called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, to be inserted into the postsynaptic membrane, since activated AMPA receptors allow positive ions to enter the cell. So, the next time glutamate is released from the presynaptic membrane, it will have a larger excitatory effect (EPSP) on the postsynaptic cell because the binding of glutamate to these AMPA receptors will allow more positive ions into the cell. The insertion of additional AMPA receptors strengthens the synapse and means that the postsynaptic neuron is more likely to fire in response to presynaptic neurotransmitter release. Some drugs of abuse co-opt the LTP pathway, and this synaptic strengthening can lead to addiction.

Long-term Depression (LTD)

Long-term depression (LTD) is essentially the reverse of LTP: it is a long-term weakening of a synaptic connection. One mechanism known to cause LTD also involves AMPA receptors. In this situation, calcium that enters through NMDA receptors initiates a different signaling cascade, which results in the removal of AMPA receptors from the postsynaptic membrane, as illustrated in (Figure). The decrease in AMPA receptors in the membrane makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron. While it may seem counterintuitive, LTD may be just as important for learning and memory as LTP. The weakening and pruning of unused synapses allows for unimportant connections to be lost and makes the synapses that have undergone LTP that much stronger by comparison.


Section Summary

Neurons have charged membranes because there are different concentrations of ions inside and outside of the cell. Voltage-gated ion channels control the movement of ions into and out of a neuron. When a neuronal membrane is depolarized to at least the threshold of excitation, an action potential is fired. The action potential is then propagated along a myelinated axon to the axon terminals. In a chemical synapse, the action potential causes release of neurotransmitter molecules into the synaptic cleft. Through binding to postsynaptic receptors, the neurotransmitter can cause excitatory or inhibitory postsynaptic potentials by depolarizing or hyperpolarizing, respectively, the postsynaptic membrane. In electrical synapses, the action potential is directly communicated to the postsynaptic cell through gap junctions—large channel proteins that connect the pre-and postsynaptic membranes. Synapses are not static structures and can be strengthened and weakened. Two mechanisms of synaptic plasticity are long-term potentiation and long-term depression.

Visual Connection Questions

(Figure) Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K+ through voltage-gated K+ channels. Which part of the action potential would you expect potassium channels to affect?

(Figure) Potassium channel blockers slow the repolarization phase, but have no effect on depolarization.

Review Questions

For a neuron to fire an action potential, its membrane must reach ________.

  1. hyperpolarization
  2. the threshold of excitation
  3. the refractory period
  4. inhibitory postsynaptic potential

After an action potential, the opening of additional voltage-gated ________ channels and the inactivation of sodium channels, cause the membrane to return to its resting membrane potential.

What is the term for protein channels that connect two neurons at an electrical synapse?

  1. synaptic vesicles
  2. voltage-gated ion channels
  3. gap junction protein
  4. sodium-potassium exchange pumps

Which of the following molecules is not involved in the maintenance of the resting membrane potential?

Critical Thinking Questions

How does myelin aid propagation of an action potential along an axon? How do the nodes of Ranvier help this process?

Myelin prevents the leak of current from the axon. Nodes of Ranvier allow the action potential to be regenerated at specific points along the axon. They also save energy for the cell since voltage-gated ion channels and sodium-potassium transporters are not needed along myelinated portions of the axon.

What are the main steps in chemical neurotransmission?

An action potential travels along an axon until it depolarizes the membrane at an axon terminal. Depolarization of the membrane causes voltage-gated Ca 2+ channels to open and Ca 2+ to enter the cell. The intracellular calcium influx causes synaptic vesicles containing neurotransmitter to fuse with the presynaptic membrane. The neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane. Depending on the specific neurotransmitter and postsynaptic receptor, this action can cause positive (excitatory postsynaptic potential) or negative (inhibitory postsynaptic potential) ions to enter the cell.

Describe how long-term potentiation can lead to a nicotine addiction.

Long-term potentiation describes the process whereby exposure to a stimulus increases the likelihood that a neuron will depolarize in response to that stimulus in the future. Nicotine exposure causes long-term potentiation of neurons in the amygdala, and activates reward centers of the brain. As nicotine exposure continues, long-term potentiation reinforces the activation of the reward pathways in response to nicotine consumption.

Glossary


A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell, as shown in Table 16.1. The difference in the number of positively charged potassium ions (K + ) inside and outside the cell dominates the resting membrane potential (Figure 16.10). When the membrane is at rest, K + ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient. However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps brings two K + ions into the cell while removing three Na + ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid. It should be noted that calcium ions (Cl – ) tend to accumulate outside of the cell because they are repelled by negatively-charged proteins within the cytoplasm.

Table 16 .1. The resting membrane potential is a result of different concentrations inside and outside the cell.
Ion Concentration Inside and Outside Neurons
Ion Extracellular concentration (mM) Intracellular concentration (mM) Ratio outside/inside
Na + 145 12 12
K+ 4 155 0.026
Cl − 120 4 30
Organic anions (A−) 100

Figure 16.10.
The (a) resting membrane potential is a result of different concentrations of Na+ and K+ ions inside and outside the cell. A nerve impulse causes Na+ to enter the cell, resulting in (b) depolarization. At the peak action potential, K+ channels open and the cell becomes (c) hyperpolarized.

Chemical signaling operates over a broad range of distances

Animals use chemical signaling over a very broad range of spatial scales ( FIGURE 35.2 ). In this concept we have discussed chemical signaling on two spatial scales— the two different scales of distance seen in nervous signaling and in endocrine signaling. However, chemical signaling also takes place on even shorter and even longer scales of distance.

Many chemical signals diffuse from cell to cell in a tissue without entering the blood. Two such types of signals are paracrines and autocrines. Paracrines are chemicals that are secreted by one cell and affect the functions of other, neighboring cells in a tissue by binding to receptors in or on the neighboring cells (see Figure 35.2A ). Autocrines are chemicals that are secreted by a cell into the surrounding intercellular fluids and then diffuse to receptors on that very same cell and affect its functions (see Figure 5.10 ).

Neurotransmitters and hormones work at intermediate distances. Neurotransmitters resemble paracrines in that they move just short distances from cell to cell by diffusion, because only the width of a synaptic cleft separates a presynaptic neuron from its target cell. However, the secretion of neurotransmitters is controlled from farther away by electrical signals that travel the length of the presynaptic cell (see Figure 35.2B ). Hormones are carried to the farthest reaches of an animal’s body by the circulation of the blood (see Figure 35.2C ).

Pheromones are chemical signals that an individual animal releases into its external environment and that exert specific effects (e.g., behavioral effects) on other individuals of the same species (see Figure 35.2D ). Some pheromones travel hundreds of meters before reaching their targets.

CHECKpoint CONCEPT 35.1

  • Why is endocrine control described as slow and broadcast?
  • Why is it correct to say that both nervous and endocrine control depend on chemical signaling?
  • If all cells in the body are bathed by a hormone, why are some affected while others are not?

Now that we’ve compared and contrasted the nervous and endocrine systems, let’s turn our spotlight on the endocrine system.


Sensory Neurons vs. Motor Neurons

To put it simply, sensory neurons are for “feeling,” and motor neurons are for “doing.”

Motor neurons are efferent (meaning they carry information out towards the periphery from the central nervous system). In contrast, sensory neurons are efferent (they carry information in towards the central nervous system from the periphery).

Motor neurons tend to have a multipolar morphology, with a single axon and many dendrites. However, sensory neurons are usually pseudounipolar. Additionally, motor neurons have short dendrites and long axons, whereas sensory neurons have long dendrites and short axons.

The two neurons also have profound functional differences. Whereas in motor neurons, the new nerve impulse is generated in the neuron of the motor cortex of the brain, in the sensory neurons, the new signal is generated in the peripheral nervous system.


Sources

IQWiG health information is written with the aim of helping people understand the advantages and disadvantages of the main treatment options and health care services.

Because IQWiG is a German institute, some of the information provided here is specific to the German health care system. The suitability of any of the described options in an individual case can be determined by talking to a doctor. We do not offer individual consultations.

Our information is based on the results of good-quality studies. It is written by a team of health care professionals, scientists and editors, and reviewed by external experts. You can find a detailed description of how our health information is produced and updated in our methods.


Neurons are suspended, as you say, in an extracellular matrix. Brain tissues are a little bit more specific. Here I quote a few summaries from literature to answer and give your a perspective on your basic question. In bold I highlight important statements which differentiate the brain's ECM from the ECM found elsewhere in the body.

Barros, Franco & Müller, 2011: An astonishing number of extracellular matrix glycoproteins are expressed in dynamic patterns in the developing and adult nervous system. Neural stem cells, neurons, and glia express receptors that mediate interactions with specific extracellular matrix molecules. Functional studies in vitro and genetic studies in mice have provided evidence that the extracellular matrix affects virtually all aspects of nervous system development and function. Here we will summarize recent findings that have shed light on the specific functions of defined extracellular matrix molecules on such diverse processes as neural stem cell differentiation, neuronal migration, the formation of axonal tracts, and the maturation and function of synapses in the peripheral and central nervous system.

Ruoslahti, 1996: The extracellular matrix of the adult brain tissue has a unique composition. The striking feature of this matrix is the prominence of lecticans, proteoglycans that contain a lectin domain and a hyaluronic acid-binding domain. Hyaluronic acid and tenascin family adhesive/anti-adhesive proteins are also abundant. Matrix proteins common in other tissues are nearly absent in adult brain. The brain extracellular matrix appears to have trophic effects on neuronal cells and affect neurite outgrowth. The unique composition of this matrix may be responsible for the resistance of brain tissue toward invasion by tumors of non-neuronal origin.

Dityatev et al. 2010: The extracellular matrix (ECM) of the central nervous system is well recognized as a migration and diffusion barrier that allows for the trapping and presentation of growth factors to their receptors at the cell surface. Recent data highlight the importance of ECM molecules as synaptic and perisynaptic scaffolds that direct the clustering of neurotransmitter receptors in the postsynaptic compartment and that present barriers to reduce the lateral diffusion of membrane proteins away from synapses. The ECM also contributes to the migration and differentiation of stem cells in the neurogenic niche and organizes the polarized localization of ion channels and transporters at contacts between astrocytic processes and blood vessels. Thus, the ECM contributes to functional compartmentalization in the brain.


Part 2: Cracking the Circuits for Olfaction: Odors, Neurons, Genes and Behavior

00:00:00.00 Hi, I'm Cori Bargmann,
00:00:03.25 from the Rockefeller University in New York,
00:00:05.29 and the Howard Hughes Medical Institute.
00:00:08.02 And I'm going to talk today about work that we've been doing to try to crack circuits for olfaction,
00:00:13.27 to understand how you go from odors to neurons to genes to behavior.
00:00:19.24 Now, I'm going to talk about this in the context not of the noble human brain,
00:00:24.20 but of the noble brain of the nematode worm, Caenorhabditis elegans.
00:00:28.20 Why would we study a simple animal instead of studying humans?
00:00:31.29 The reason is that the human brain is almost unimaginably complex:
00:00:36.14 it has billions of neurons that are connected to each other by trillions of synapses.
00:00:42.03 By contrast, the nervous system of the nematode worm C. elegans has only 302 neurons
00:00:47.27 that are connected by 7000 synapses, and another 600 or so gap junctions.
00:00:54.15 Now, this much simpler nervous system nonetheless shares many components with the nervous system of a human.
00:01:01.19 So whereas humans have about 25,000 genes,
00:01:04.09 worms have about 20,000 genes,
00:01:06.09 many or which are shared between the species.
00:01:08.20 And when we look at the properties of the nervous system,
00:01:11.01 we find that many features of the nervous system are similar,
00:01:14.22 that worms use similar neurotransmitters, channels, and developmental genes, as humans.
00:01:20.07 Therefore, we think that some of the principles that underlie the function of the brain
00:01:24.08 and the function of brain circuits in behavior will also be similar between simpler animals like the worm
00:01:30.06 and complex animals like ourselves.
00:01:34.17 Now, with C. elegans, we also have, from the work of John White and his colleagues,
00:01:39.06 knowledge of how those 302 neurons communicate with each other, through a wiring diagram.
00:01:45.05 This wiring diagram contains only 6000 or 7000 connections,
00:01:48.26 but that's still too many, as you can see in this illustration,
00:01:52.24 to really understand the flow of information.
00:01:55.05 We need to directly test what the connections do,
00:01:57.28 we need to test what the neurons do, in order to understand behavior.
00:02:03.28 And the way that we try to understand behavior is using the behavior of the entire animal,
00:02:10.29 the functions of individual genes, and the functions of neurons,
00:02:14.18 and relate those to each other vertically, from the level of molecules
00:02:18.23 to the level of the entire organism.
00:02:21.07 Now, the starting point for this set of studies will be the fact that worms respond to odors
00:02:27.15 with robust behavioral responses,
00:02:29.24 that pose a set of questions we can ask about how behavior is generated.
00:02:33.24 So, if you put a lot of worms down in an environment where there's no odor,
00:02:36.27 they'll scatter around.
00:02:38.24 But if you them in an environment where there's a good odor on one side,
00:02:41.25 they'll quickly move to the source of that good odor and accumulate there.
00:02:46.29 Conversely, if you put them in an environment with a bad odor,
00:02:49.06 they'll go as far from it as they possibly can.
00:02:51.25 So we can see attraction, repulsion, or neutral responses in the behavior of the animal.
00:02:57.21 We can then ask: What parts of the worm brain are required for these different kinds of behaviors?
00:03:04.15 And we can ask this question through different kinds of approaches,
00:03:08.22 either loss-of-function approaches or gain-of-function approaches,
00:03:12.01 and both of those converge on the same answer,
00:03:15.03 which is that specific neurons detect odors and initiate behaviors in the animal,
00:03:20.20 and that the neurons that do this are reliably similar from worm to worm.
00:03:25.23 So, one way to determine that is to eliminate the functions of single neurons,
00:03:29.27 which we can do by killing them with a laser microbeam,
00:03:32.13 and when we do that, for example, for this neuron shown here in blue, the AWC neuron,
00:03:37.13 we find that the animals become defective in their ability to chemotax
00:03:40.26 to certain attractive odors and to search for food.
00:03:44.15 Now, if we kill the neuron right next to AWC, this red neuron, ASH,
00:03:48.20 there's no defect in odor chemotaxis and food search.
00:03:51.14 But now instead, there's a defect in nociception
00:03:55.16 and escape behavior that is triggered by noxious compounds that the worm hates.
00:04:00.20 So this tells us these neurons are required for different behaviors.
00:04:04.08 We can complement this loss-of-function analysis by gain-of-function analysis,
00:04:08.19 where we activate these neurons artificially and ask what behaviors the animal generates.
00:04:14.15 And the method that's used to do that currently in neuroscience
00:04:18.07 is to use a molecule called channelrhodopsin.
00:04:21.03 It's a light-activated ion channel from a unicellular organism.
00:04:25.23 The gene for channelrhodopsin can be introduced into different neurons in different animals,
00:04:30.25 and it will then make those neurons responsive to light,
00:04:33.15 so that when you shine light on them, the neurons become active.
00:04:36.15 You can then ask, in this gain-of-function configuration,
00:04:39.20 what happens when you activate one of these neurons?
00:04:42.26 And so for, example, as is shown in this movie here, when you activate the ASH
00:04:47.24 nociceptive neuron that mediates escape behaviors simply by turning a light on
00:04:52.26 and activating channelrhodopsin, the worm generates a reversal.
00:04:57.01 This is an escape behavior associated with a change of direction
00:05:00.16 that's exactly like what would happen if ASH detected one of its normal,
00:05:05.04 noxious stimuli that would also direct an escape behavior.
00:05:09.12 And so we can say here that ASH is both necessary and sufficient for generating escape behaviors.
00:05:18.13 Now, explaining escape behavior is pretty straightforward.
00:05:22.17 Escape behavior is deterministic
00:05:24.26 that means that, when a worm encounters a noxious substance,
00:05:28.09 as illustrated by this series of panels, every worm generates a reliable response
00:05:33.09 to that noxious substance, in a way that's quite predictable,
00:05:37.08 where it will back up, turn away, and move in a new direction.
00:05:41.04 But when we try to understand chemotaxis behavior, we see that it has different properties.
00:05:46.01 It's a probabilistic behavior,
00:05:48.08 and what I mean by that is that,
00:05:49.29 while all of the worms will eventually reach the odor,
00:05:53.12 they get to the odor by what seems to be an unpredictable path.
00:05:57.00 Every worm seems to follow a different path to reach the odor source.
00:06:01.09 How can we explain this more complex trajectory,
00:06:04.21 which doesn't look like the reflex or deterministic action?
00:06:07.26 What we need is some kind of a model that would explain
00:06:11.00 how animals can approach an odor.
00:06:13.29 And in fact, exactly such a model was developed by Shawn Lockery and colleagues,
00:06:19.05 and what they showed was that worms approach the odor using a strategy
00:06:24.01 called a "biased random walk," which is the same strategy that bacteria use
00:06:29.06 to detect attractive chemicals in their environment.
00:06:32.12 A biased random walk occurs through a fascinating strategy where
00:06:37.19 animals don't point their nose straight up toward the odor like a weather vane
00:06:42.11 instead, they simply move through their environment,
00:06:45.17 waiting to see whether conditions are changing, and if so,
00:06:51.05 whether they're getting better or worse.
00:06:53.18 And what the animals do is that they turn, changing directions,
00:06:56.29 at some constant rate in constant conditions.
00:06:59.25 But if conditions get better, if the odor increases,
00:07:05.23 then they make fewer turns.
00:07:08.04 If the conditions get worse, if the odor decreases,
00:07:11.12 they make more turns.
00:07:12.27 And the effect of this, is that animals will move in a good direction
00:07:17.00 where odors are increasing for a longer period of time,
00:07:21.04 and they'll move in a bad direction where odors are decreasing
00:07:24.00 for shorter periods of time.
00:07:25.20 And eventually, just changing direction at random,
00:07:28.15 this will lead them to accumulate at the odor through what appears to be a
00:07:32.13 more-or-less random path.
00:07:34.14 So the key feature of this strategy is that the animals aren't detecting the absolute levels of odors,
00:07:40.01 they're detecting the change in an odor level.
00:07:42.27 are things getting better or are things getting worse?
00:07:46.03 They're looking at the change in concentration over time.
00:07:51.05 So, we would like to test this model.
00:07:53.14 How do you go about testing a model like this, about odor concentrations over time?
00:07:58.20 The way you have to test this model is to generate a temporal gradient,
00:08:03.12 an odor environment that changes only over time and not over space,
00:08:08.12 to test the predictions of this particular quantitative model.
00:08:12.13 And the way that this can be done is by generating small chambers
00:08:16.11 in which animals can be exposed to odors flowing past them rapidly,
00:08:20.13 and then examine for their different kinds of behavioral responses.
00:08:24.07 And a chamber to carry out this task was designed by Dirk Albrecht.
00:08:30.05 So, what Dirk did was to find a small environment in which he could provide pulses of odors
00:08:35.20 at a known concentration at a known schedule,
00:08:38.10 and examine the responses of the worms in these environments.
00:08:41.23 And as is seen in the movie here, when you watch worms moving through this chamber,
00:08:46.02 sometimes they move in straight lines, and sometimes they change directions,
00:08:49.11 generating different kinds of turns.
00:08:51.28 Now, this light color here are worms in the absence of an odor.
00:08:55.12 Some of them are turning, some of them are moving in straight lines.
00:08:58.07 When the dark color appears, that will signal the appearance of an attractive odor.
00:09:02.25 When the light colors appears, the odor will disappear.
00:09:05.25 And what you should be able to see is that,
00:09:07.17 when the odor appears, the worms move in long, straight lines,
00:09:11.08 and when the odor disappears, they turn, they change direction.
00:09:15.02 Again, attractive odor. long, straight lines.
00:09:18.28 Disappearance. turning.
00:09:21.13 This is exactly the behavior that is predicted in the biased random walk model:
00:09:26.22 An increase of turning when conditions are getting worse.
00:09:30.14 So here we can see that at a visual level.
00:09:33.05 But in order to understand behaviors, we need to quantify those behaviors,
00:09:37.08 not just look at them qualitatively.
00:09:40.16 And to do that, we can use methods to automatically analyze the turning behaviors
00:09:45.08 using computers to monitor the position of worms over time.
00:09:49.04 We can then assign to each of the worms a description of what it's doing at any particular time:
00:09:54.23 Is it moving forward, here in gray?
00:09:57.02 Is it pausing or reversing, here in black?
00:09:59.24 Or is it generating different kinds of turns, called pirouettes, here in red?
00:10:04.17 This analysis can be done for many hundreds of animals over different kinds of stimulus protocols,
00:10:10.20 leading to the kinds of data shown here, where animals are exposed to pulses of odors in blue,
00:10:17.25 and odor being removed (replaced by buffer) in white.
00:10:21.25 And then here, hundreds of animals are monitored for their behavior in response
00:10:26.04 to that sequence of odor and buffer pulses.
00:10:29.04 Now what you should be able to see is that there's a lot of red and black material in the presence of buffer,
00:10:34.26 but much less when odor is present.
00:10:38.04 These hundreds of traces can then be quantified to generate the one trace underneath,
00:10:42.29 which shows the probability of turning under different conditions.
00:10:47.12 And what you can see is that, when odor is present, as it is here,
00:10:51.08 the probability of turning is quite low, but it's not zero.
00:10:55.04 And when odor is removed, as is shown here,
00:10:57.17 the probability of turning shoots up, but it doesn't go up to 100%.
00:11:02.03 it eventually returns again to the basal probability of turning.
00:11:06.11 So from this we can say a couple of different things:
00:11:08.29 We can confirm the biased random walk model, we can say that, yes,
00:11:12.14 turning rates do change based on odor history,
00:11:16.01 whether odor has been added or removed.
00:11:19.02 And we can also notice that this is indeed a probabilistic behavior,
00:11:23.29 that the probability of turning changes, but it's never 0%, and it's never 100%.
00:11:29.19 To understand behavior, we have to think quantitatively and statistically
00:11:33.28 about what animals are doing at any given time.
00:11:39.17 So, using these kinds of assays and simpler assay that resemble these,
00:11:44.09 it's been possible to map out neurons that are required for odor chemotaxis and food search.
00:11:50.18 I told you that the AWC neuron, an olfactory neuron, is required for odor detection.
00:11:55.23 AWC forms synapses onto three different classes of interneurons,
00:12:00.16 neurons that collect information from a variety of sensory neurons,
00:12:04.23 and these neurons are connected to each other and with a fourth neuron.
00:12:09.04 All four of these neurons, that are one synapse away from the AWC neuron,
00:12:13.26 regulate turning probabilities.
00:12:16.15 Two of them, shown in blue,
00:12:18.15 act to increase the rate of turning when odor is removed, and two of them, show in red,
00:12:24.09 act to decrease the the rate of turning.
00:12:26.14 So they're both positive and negative signals in this circuit that are mediating odor information.
00:12:32.27 Now, once a turn is being generated,
00:12:36.08 the worm has to decide what kind of turn it's going to be.
00:12:39.00 The neurons shown here in gray at the bottom of the slide
00:12:42.02 are neurons that help interpret this turning frequency information and
00:12:45.19 turn it into different kinds of output motor behaviors.
00:12:48.22 I won't talk about those further in this talk.
00:12:51.02 I'll just concentrate on the first step:
00:12:53.08 How is the problem of detecting odor transformed through the neurons
00:12:57.11 that collect this information from the sensory neuron, to regulate turning rates?
00:13:04.28 So, one way to answer that question is to start to get a dynamic picture
00:13:09.18 of what the neurons are doing in response to odors.
00:13:13.10 We want to visualize what's happening in these neurons.
00:13:16.21 So what are the tools we can use to understand when neurons are active?
00:13:20.25 In C. elegans, one of the tools we like to use are genetically encoded calcium indicators.
00:13:27.23 These are fluorescent proteins based on the "green fluorescent protein"
00:13:32.05 that include within them a calcium-binding protein "calmodulin,"
00:13:35.29 as well as a peptide that will bind to calmodulin when calcium is present.
00:13:40.25 Through genetic engineering and biochemical studies,
00:13:43.13 Junichi Nakai and others have generated versions of these proteins that increase fluorescence
00:13:49.06 when they are bound to calcium, and are less fluorescent when they are not bound to calcium.
00:13:53.28 This is useful to us because calcium is a good reporter of when a neuron is active.
00:13:59.20 When neurons are depolarized, they open voltage-gated calcium channels,
00:14:04.07 leading to an increase of calcium within the cell.
00:14:07.03 And therefore, an increase in fluorescence of a protein associated with
00:14:11.07 an increase of calcium will tell you when a neuron is depolarized.
00:14:16.04 To monitor a specific neuron,
00:14:17.27 we then take advantage of the powerful transgenic tools in C. elegans
00:14:22.04 to express this genetically encoded fluorescent protein
00:14:25.02 only in a single kind of neuron of interest,
00:14:27.23 in this case, in the AWC neuron, to ask when that neuron is active.
00:14:35.20 Now there's a third component required to monitor the activity of these neurons,
00:14:39.22 and that is that we need to be able to hold the worm still and
00:14:42.29 deliver odors in precise patterns while monitoring the fluorescence intensity of the AWC neuron.
00:14:50.05 We do that by borrowing a technology back from the engineering,
00:14:54.05 from the silicon chip, industry, into biology, called microfabrication.
00:14:58.23 And we build special worm traps that are worm dimension,
00:15:02.21 that enable us to hold a worm in an optically transparent environment,
00:15:07.23 while restraining it in three dimensions, and then flowing different kinds of fluids
00:15:11.20 past the nose of the worm while monitoring fluorescence intensity.
00:15:15.12 This microfluidic chamber then permits us to combine the genetic tools
00:15:20.00 with chemical tools to monitor neural activity.
00:15:25.13 And that's exactly what's happening in this image here.
00:15:28.17 So this is a single AWC neuron expressing a genetically encoded calcium indicator,
00:15:33.20 and you will see when the movie starts, the neuron starts with a yellow level of fluorescence
00:15:39.05 and a relatively low level of fluorescence in the process of the neuron.
00:15:42.26 Ten seconds into the movie, a switch in odor stimuli will occur, and the neuron will become brighter.
00:15:49.22 The brighter color, the more intense color, the larger white color in the cell body of the neuron over here,
00:15:54.21 all reflect the fact that calcium has gone up, and the neuron has become active.
00:15:59.17 So, indeed, we can see that the AWC neuron responds to odors by changing its activity.
00:16:06.23 But it responds in a way that we did not expect,
00:16:10.06 because the AWC neurons are not activated when odors are presented to the worm.
00:16:15.26 In fact, when we look at the fluorescence intensity and graph it in the presence of odor,
00:16:20.05 it is, if anything, a little less intense than it would have been in the absence of odor.
00:16:26.27 Instead, the AWC neurons become active when odor is removed.
00:16:31.21 This leads to a large increase in the fluorescence intensity,
00:16:34.21 indicating depolarization and the presence of calcium.
00:16:38.08 So these neurons seem to work in reverse.
00:16:41.13 They are inhibited by odors, their natural stimuli.
00:16:44.28 They are active when odors are removed.
00:16:47.24 And I just want to remind you that the worm has to generate a behavior when odor is removed.
00:16:53.02 When odor is removed, the worm is going to start turning.
00:16:56.00 So the activity of the neuron is correlated with the behavioral output, not with the input stimulus.
00:17:05.18 So we can now say something about this first neuron that interacts with odors.
00:17:10.25 How does it communicate with the target neurons that then convert this information into behavior?
00:17:17.10 The way that we study this is by studying the process of synaptic transmission.
00:17:21.15 Neurons connect to each other at specialized structures called synapses,
00:17:25.08 where a presynaptic neuron, the upstream neuron, in this case AWC,
00:17:29.28 will release vesicles filled with a neurotransmitter, and these neurotransmitters
00:17:33.24 will interact with receptors on the postsynaptic neuron, here shown in gray.
00:17:39.01 One kind of neurotransmitter that neurons release is glutamate, an amino acid,
00:17:45.25 and glutamate is packaged into special synaptic vesicles by a molecule called the
00:17:49.25 "vesicular glutamate transporter," or EAT-4 in C. elegans.
00:17:54.25 We can use this EAT-4 molecule to probe the action of synapses in the AWC neuron.
00:18:02.27 We can do that by using mutants in EAT-4 to inactivate the transporter
00:18:07.26 and therefore the ability of AWC to release glutamate.
00:18:11.19 And we can ask then,
00:18:13.09 what kinds of behavior can the animal generate in the absence of this glutamate transmitter?
00:18:18.15 And remember that turning is a reflection of the response to odor removal,
00:18:23.22 an important component of chemotaxis behavior, and that we can quantify this.
00:18:26.27 So a high level here of "1" is a high level of turning.
00:18:31.13 In red here is an eat-4 mutant.
00:18:33.15 The eat-4 mutant does not turn efficiently when odor is removed,
00:18:37.21 indicating to us that glutamate is required as a neurotransmitter for this turning behavior.
00:18:43.04 And when we restore EAT-4 just in the AWC neurons using a specific transgene,
00:18:48.22 we restore most of the turning behavior.
00:18:51.01 And so we can say that glutamate from AWC promotes turning.
00:18:57.25 So we now have insight into the first step of how AWC communicates with its target:
00:19:03.10 It uses EAT-4 to package glutamate into vesicles, it releases glutamate,
00:19:08.06 and this must then act on target neurons.
00:19:10.23 How does it communicate with the target neurons?
00:19:12.26 How does it communicate with these three different neurons with which it forms connections?
00:19:17.00 Well, it has to do that through glutamate receptors,
00:19:20.04 proteins that are expressed on the target neurons that enable them to detect the released glutamate.
00:19:25.11 And we found that there are two classes of glutamate receptors
00:19:28.22 that are important for this particular behavior.
00:19:31.29 There's a glutamate-gated cation channel it's an excitatory receptor called GLR-1.
00:19:38.01 And there's also a glutamate-gated chloride channel,
00:19:41.05 an anion channel that is an inhibitory receptor called GLC-3.
00:19:45.14 These two glutamate receptors,
00:19:47.11 which can generate two different kinds of responses in target neurons,
00:19:50.20 are important for AWC's communcation with its targets.
00:19:56.26 We can demonstrate that both through quantitative behavioral assays
00:20:02.18 and through direct observation of the activity of target neurons,
00:20:06.18 which we do using genetically encoded calcium indicators.
00:20:10.15 Now, instead of expressing them in AWC, we express them in downstream neurons,
00:20:15.24 such as AIB.
00:20:17.18 AIB is one of the neurons that receives synapses from AWC,
00:20:21.16 and we see that AIB, like AWC, responds to odor removal by an increase in calcium.
00:20:29.06 This response disappears if the AWC neuron is killed,
00:20:33.21 and it also disappears in an animal that lacks the glutamate receptor GLR-1.
00:20:38.17 GLR-1 is required in AIB for AIB to sense the glutamate signal from AWC.
00:20:46.09 This excitatory glutamate receptor transmits an excitatory signal from sensory neuron to interneuron.
00:20:56.03 Next, we looked at the AIA and AIY interneurons.
00:21:01.09 These neurons also respond to odors,
00:21:04.05 but these neurons respond oppositely to AWC.
00:21:08.12 AIA and AIY respond with an increase in calcium to odor addition,
00:21:13.22 there's been a change in the sign of the signal between the sensory neuron and the interneuron.
00:21:18.21 They don't respond to odor removal.
00:21:21.19 Now this response to odor addition still requires AWC,
00:21:25.19 and it requires a glutamate receptor.
00:21:28.04 It requires GLC-3, the glutamate-gated chloride channel.
00:21:32.21 This inhibitory receptor serves to transmit a signal from an excited AWC
00:21:38.18 into a signal that will inhibit the downstream neurons,
00:21:42.06 so the downstream neurons AIA and AIY respond oppositely
00:21:47.00 to odors than the upstream neuron AWC.
00:21:52.24 So putting this information together, here on the left,
00:21:56.09 we can assemble a C. elegans odor circuit.
00:21:59.26 We can say that attractive odors inhibit the AWC olfactory neurons,
00:22:04.16 that the AWC olfactory neurons now release glutamate
00:22:08.03 onto two classes of downstream neurons through two classes of receptors.
00:22:12.16 They excite one class of neurons, the AIB neurons,
00:22:15.25 through an excitatory glutamate receptor.
00:22:18.14 They inhibit other classes of neurons, AIA and AIY neurons,
00:22:22.17 through an inhibitory glutamate receptor.
00:22:25.15 By splitting the information in this way,
00:22:27.15 the AWC neurons have now transformed information into two streams:
00:22:32.00 One signals the appearance of odor, an "odor ON" response
00:22:35.17 the second stream signals the disappearance of odor, an "odor OFF" response.
00:22:40.26 Remarkably, when we examine this circuit,
00:22:43.12 it looks similar to another sensory circuit that's been well characterized,
00:22:47.14 and that is the circuit that is used to collect light in the vertebrate retina,
00:22:51.18 in your own eye.
00:22:53.14 So in your eye, light is collected by the rod and cone photoreceptors.
00:22:58.15 Rods and cones are active in the dark
00:23:00.29 they are inhibited by light, their natural stimulus,
00:23:04.03 just as AWC neurons are inhibited by odors.
00:23:08.12 Rods and cones release glutamate to communicate with their targets,
00:23:12.04 and they have two major classes of target neurons.
00:23:14.28 The target neurons are called bipolar cells.
00:23:17.24 One connection is through an excitatory glutamate receptor, and therefore,
00:23:22.24 these neurons have the same pattern of activity as the photoreceptors.
00:23:27.01 They're what are called "OFF" bipolar cells they signal when lights go off.
00:23:31.26 The other class of neurons are connected through inhibitory glutamate receptors.
00:23:36.01 Therefore, these neurons are called "ON" bipolar cells they signal when lights come on.
00:23:43.05 So comparing these different neural circuits,
00:23:45.19 we can say that in a worm olfactory system and in a vertebrate visual system,
00:23:50.23 some of the same principles are used to process sensory information.
00:23:55.02 Differential signaling of the appearance and the disappearance of a stimulus,
00:23:59.16 differential signaling through different classes of glutamate receptors,
00:24:03.01 to split information through different circuits.
00:24:05.22 This kind of insight helps convince us that there may be principles
00:24:09.10 for neural circuits that apply across different systems,
00:24:12.16 that will help us understand information processing.
00:24:16.01 What I've told you is that AWC communicates with three downstream neurons,
00:24:20.19 using glutamate to send complex information about the input stimulus
00:24:24.25 to different downstream sets.
00:24:28.23 In addition, AWC has another way of communicating with its targets,
00:24:33.04 because AWC doesn't just release glutamate,
00:24:35.23 it releases a second transmitter, a neuropeptide neurotransmitter called NLP-1.
00:24:41.15 NLP-1 is related to neuropeptides called buccalin in other animals,
00:24:46.02 and NLP-1 signals through a G protein-coupled receptor, called NPR-11.
00:24:52.04 NPR-11 is expressed on some of the downstream neurons from AWC,
00:24:57.18 but not all, including the AIA neurons.
00:25:01.09 So glutamate is released from AWC onto several neurons, and in addition,
00:25:05.29 a neuropeptide is released from AWC onto a subset of those neurons.
00:25:12.29 What is the function of NLP-1?
00:25:15.18 We can ask that by examining animals that are mutant for the NLP-1 neuropeptide
00:25:21.00 or mutant for its receptor,
00:25:22.27 and then comparing their behaviors to the behaviors of wild-type animals.
00:25:27.13 And what we find is that the function of NLP-1 is to antagonize
00:25:32.17 the glutamate signal from the same AWC neuron.
00:25:36.17 So, this is illustrated here in the quantitative turning behaviors that measure AWC output.
00:25:42.11 So a wild-type animal, shown here in white,
00:25:44.29 will turn about once a minute in response to odor removal.
00:25:48.22 These turns are absolutely dependent on the glutamate signal from AWC.
00:25:52.29 There are simply no turns when AWC glutamate is absent, as shown by this mutant.
00:26:00.06 But when we look at the nlp-1 mutant, we see that there are turns.
00:26:03.25 In fact, there are more turns than there would be in a wild-type animal.
00:26:07.21 So AWC is both sending a signal to stimulate turning (the glutamate signal),
00:26:12.20 and it's sending a second signal that inhibits turning (the NLP-1 signal).
00:26:17.23 It's limiting its own output by generating these two antagonistic signals.
00:26:24.08 We next asked how this signal interacts with the circuit
00:26:29.12 to affect the activity of different neurons.
00:26:32.20 And here there was a large surprise.
00:26:35.14 So we examined the nlp-1 mutant, and mutants in its receptor NPR-11,
00:26:40.17 to see where activity in the circuit was changed compared to the activity of wild-type animals.
00:26:45.25 We saw changes in the activity of the neurons not just in downstream target neurons
00:26:51.16 we saw changes in AWC itself.
00:26:54.23 The olfactory neuron responds differently to odors
00:26:58.01 depending on the activity of this peptide system.
00:27:01.21 So we can see this here in calcium imaging experiments showing
00:27:05.08 the response of AWC neurons to odor removal.
00:27:08.23 In wild-type, they show a sharp, short response.
00:27:12.06 In animals that lack the NLP-1 peptide or its receptors,
00:27:16.27 we instead see a longer-lasting response and repeated responses,
00:27:20.21 indicating that the AWC neuron is staying active for longer after odor has been removed.
00:27:28.17 Now, AWC is releasing this signal, the receptor for this signal in on a downstream neuron.
00:27:34.23 How does that information come back to AWC?
00:27:38.15 The answer is that the downstream neuron releases another signal, a feedback signal,
00:27:44.20 that is an insulin-like peptide, that returns to the AWC neuron to modify its activity.
00:27:50.26 So, a signal from AWC talks to a target neuron,
00:27:54.07 the target neuron then sends a signal back to AWC,
00:27:57.13 and again, the use of that signal limits the activity of the AWC neuron.
00:28:02.12 The feedback keeps AWC from generating these longer
00:28:06.03 or repetitive responses to odor removal.
00:28:11.29 So, it seems curious that a neuron would be generating
00:28:14.21 both positive and negative responses.
00:28:16.29 What could be the purpose of generating a negative feedback signal?
00:28:21.13 To understand this, you should understand that,
00:28:24.02 in animals, odor preference is modified by its experience with odor.
00:28:28.10 And this can be illustrated in a variety of ways,
00:28:31.15 but one simple way is that, when animals are exposed to odor in the absence of food,
00:28:35.25 they slowly adapt to the odor, so that they are no longer attracted to it.
00:28:40.15 This causes animals to prefer new odors,
00:28:43.18 or odors that have been paired with food,
00:28:45.14 to odors that have been seen in the absence of food,
00:28:49.02 and it represents an obvious good behavioral strategy for finding odors
00:28:53.11 that might be predictive of food in the future.
00:28:56.00 This can be quantified here, where the attraction to odor, shown here in black,
00:28:59.22 drops after 60 minutes of seeing an odor without food,
00:29:03.04 and drops even further after two hours of seeing the odor without food.
00:29:09.03 This change in the odor-dependent activity requires the neuropeptide feedback loop
00:29:16.10 that limits AWC activity.
00:29:19.06 If you remove either NLP-1 or its receptor NPR-11
00:29:24.13 or the feedback signal INS-1 that converts that information back to AWC,
00:29:29.19 then animals that have been exposed to odor, adapted animals, as shown here,
00:29:34.05 continue to respond to odor even after a long time of pairing of odor at the absence of food,
00:29:40.07 where wild-type animals would lose their response.
00:29:44.09 Adaptation requires the function of NLP-1 in the AWC neurons
00:29:49.22 and the function of NPR-11 and of INS-1 (the feedback signal) in the AIA neurons.
00:29:56.04 And so we can map this particular negative feedback signal to a particular
00:30:01.09 negative feedback that must occur to drive a useful olfactory behavior:
00:30:06.10 olfactory adaptation.
00:30:09.14 The activity of this feedback loop is observed not only at the behavioral level,
00:30:13.23 but also at the level of neuronal responses,
00:30:17.01 because when we examine the activity of AWC neurons after a long time of exposure to high odor,
00:30:23.06 as shown here in black, they simply stop responding to the odor
00:30:27.17 if the odor was present in the absence of food.
00:30:30.26 And this suppression of their response is defective in animals
00:30:36.05 that lack the neuropeptide feedback signal, as shown here in red,
00:30:39.29 which continue to respond to the odor even when it no longer predicts the presence of food.
00:30:50.07 So the conclusion of this part of the talk is that neuropeptide feedback,
00:30:55.04 superimposed on the basic function of the circuit, shapes sensory dynamics:
00:31:01.06 That sensory neurons like AWC respond to odors not in one way,
00:31:05.17 but in different ways depending on the activity of a feedback circuit
00:31:09.20 that if that feedback circuit is lost, the sensory neurons respond for longer and with multiple stimuli
00:31:16.14 that if the feedback circuit is present, they respond with a short stimulus
00:31:20.07 and that if the feedback circuit is strongly activated through olfactory adaptation,
00:31:24.25 the sensory neurons stop responding,
00:31:26.23 allowing the animals to suppress the response to that odor, and to respond to new odors.
00:31:34.08 And the conclusion of this talk is that circuits change over time, that circuits are not fixed,
00:31:41.09 that they actively shape and transform sensory information.
00:31:45.05 They don't just passively receive that information.
00:31:48.03 And furthermore, circuits change their own properties
00:31:51.05 based on sensory information in real time.
00:31:55.12 This process, this dynamic and active interpretation of information,
00:32:00.18 allows circuits to perform complex computations and calculations.
00:32:05.14 If you take just what I told you about this small circuit of just a few C. elegans neurons,
00:32:11.06 you can realize that, if you multiply that by the billions of neurons in a human brain,
00:32:15.21 it can start to explain why a human brain can generate an
00:32:19.17 infinite number of perceptions, memories, and behaviors.
00:32:23.18 Thank you.

  • Part 1: Genes, the Brain and Behavior