Chapters 2 & 3

Signals Across The Synapse

While transmission of a signal along an axon is electrical, transmission between neurons is chemical. The chemicals used to signal are known as neurotransmitters, and the neuron synthesizes them in the axon terminals.

Neurotransmitters

There are about a hundred chemicals that are either confirmed or suspected neurotransmitters. Most fall into the following categories:

• Amino acids
• Modified amino acids/monoamines
• Includes serotonin, dopamine, norepinephrine, ephinephrine
• Neuropeptides, which are chains of amino acids
• Includes endorphins
• Purines
• Gases

    Neurons make most neurotransmitters by modifying amino acids. For example, catecholamines, which includes dopamine, epinephrine, and norepinephrine, are made by attaching a catechol group to an amine group. These three all come from phenylanine. Serotonin comes from tryptophan (found in soy). We get these amino acids from our diet. Neurons keep supplies of neurotransmitters in the axon terminal after synthesis.

The Neurotransmitter Release Process

1. When an action potential reaches a terminal, it triggers the entrance of calcium into the cell through voltage-gated channels. 
2. This causes exocytosis, or bursts of releases of neurotransmitters into the synapse. 
3. The neurotransmitters bind to receptors on the postsynaptic cell. 
4. Different postsynaptic cells have different responses. 
5. The receptors release the neurotransmitters after the response is triggered. 
6. Neurotransmitters can be taken back into the presynaptic neuron (reuptake), or may be left outside both cells and diffuse away. 

Most neurons release two or more neurotransmitters per action potential. Sometimes they’re both released immediately, and sometimes one is released fast and another one more slowly. Sometimes different transmitters are released from different terminals. 
Systems of neurons are also flexible, and neurons can change their transmitters over time. For example, some release one in winter and one in summer. These changes also require changes in the receptors of postsynaptic neurons.

The Postsynaptic Process

Signaling over a synapse is not really binary. Different neurotransmitters can produce different effects because receptors on the postsynaptic cell cause different effects when they bind with a neurotransmitter. 

    In an ionotropic effect, the receptor opens a transmitter-gated channel. Glutamate is the most common neurotransmitter for excitatory ionotropic synapses, while GABA is the most common neurotransmitter for inhibitory ionotropic synapses.

In a metabotropic effect, the neurotransmitters, most commonly dopamine, norepinephrine, and serotonin, initiate a sequence of metabolic reactions.

1. Neurotransmitter binds to receptor.
2. Receptor bends, detaching the G protein it’s holding on the inside of the postsynaptic cell.
3. The G protein activates a “second messenger,” which acts like a neurotransmitter but inside the cell.
4. The second messenger might open/close a channel, but it also does things like turning on a gene in the nucleus.

Basically, ionotropic synapses are for communicating information quickly through the brain and between the brain and other parts of the body. Metabotropic synapses are for longer-lasting effects. Vision relies on more ionotropic synapses, and taste relies on more metabotropic synapses. Arousal, attention, pleasure, and emotions are also the function of metabotropic synapses. These effects take longer to arise but last longer.

Neuropeptides

Neuropeptides are synthesized in the cell body, and are released mostly by dendrites. This is in contrast to typical neurotransmitters, which are synthesized in and released from the axon terminals.
They are released only as the result of repeated depolarization. Neuropeptide release from one cell triggers the release of the same neuropeptide from other cells’ dendrites. Neuropeptides are released rarely, but when they are released, substantial amounts are released, and they diffuse more widely, affecting a large region of neurons. Many of them alter gene activity.
They are involved in hunger, thirst, and long-term behavior and experience changes, and are sometimes called neuromodulators.

Receptors

There are several different types of receptors in the brain for each neurotransmitter. Sometimes drugs can target one kind of receptor to attempt a specific effect, rather than trying to alter the general levels of a given neurotransmitter.
But it’s complicated, because sometimes receptors have different effects in different parts of the brain, and sometimes they even have different effects in different people. There is some proof that there are genetic variations in synaptic proteins that affect behaviors like anxiety and sleep.

Reuptake

The reuptake process varies for different neurotransmitters. Acetylcholine is broken down and recycled, while erotonin and the catecholamines are taken back through transporter proteins in a process called reuptake. Any remaining neurotransmitters are broken down by the COMT enzyme.

    Neuropeptides are not inactivated. They just diffuse away.

Electrical Synapses

Electrical synapses are the exception, but they do exist. Electrical transmission is faster than chemical, and so certain functions requiring synchronicity, like rhythmic breathing, are controlled by electric synapses. Many animals also have electric synapses to help with rapid escape.
Electrical synapses work by direct contact between neurons, lining up ion channels so that sodium and other ions can flow out of the ion channel in the presynaptic neuron right into an ion channel in the postsynaptic neuron, and therefore into the cell. The action potential essentially travels from one neuron to the next and keeps going.

Structure of the Brain

    The brains consists of three parts: the hindbrain, the midbrain, and the forebrain. 

    The hindbrain consists of the cerebellum, which is involved in movement, “feeling” time, and some aspects of learning and conditioning; and the medulla and pons, which control heart rate, breathing, vital functions via the cranial nerves.

The forebrain consists of two hemispheres, which receive sensory information from the body and control muscles. Each hemisphere mostly receives input from and controls the contralateral/opposite side of the body. The outer portion of the forebrain is the cerebral cortex. Underneath the cerebral cortex are other structures, including the thalamus, basal ganglia, and limbic system. 

    The thalamus processes sensory information and sends it up to the cerebral cortex, except for smell, which goes through the olfactory bulb to the cerebral cortex. The thalamus consists of “nuclei,” which each process information from one sense’s system. The cerebral cortex also sends information back to the thalamus, which can prolong or focus attention on a particular sensory stimulus. The basal ganglia are related to movement, and also connect motivation and emotion to change the force behind actions. They’re also related to learning and habits.

    The limbic system consists of several structures that are related to motivation and emotion. Specifically, eating, drinking, sexual activity, anxiety, and aggression have all been linked to it. 

    The structures of the limbic system include the olfactory bulb, which is incolved in smell; the hypothalamus, which controls eating, drinking, temperature control, reproductive behavior; the hippocampus, which is critical for memory; and the amygdala, which is a big part of how we evaluate emotions, and fear in particular.

The Cerebral Cortex

The parts of the cerebral cortex include gray matter, which consists of cell bodies and dendrites on the outer surface of the forebrain, and their axons extending inward, which are called white matter.

The cerebral cortex contains six laminae in humans. Laminae are layers of cell bodies that lie parallel to the cortex surface. Between the laminae are layers of fibers. Across the cortex, laminae differ in thickness and may even be missing in some areas. Two notable layers are:

• Layer IV: Tain site for incoming sensory information. It receives axons from the sensory nuclei of the thalamus. It's thickest over the visual, auditory, and somatosensory cortices. 
• Layer V: The main source of motor output, which sends long axons to the spinal cord.

Multiform layer: In two parts, VIa and VIb, both made of spindle cells.

Axons of the cortex are organized into "columns" perpendicular to the laminae. Cells within a column have similar properties, meaning they respond to the same kind of stimuli at similar locations. The cell bodies of the axons from each column of the brain rest in the different layers of the laminae according to their function. 

Lobes of the Cerebral Cortex 

   The central sulcus is a deep groove in the cortex surface. Behind it is the parietal lobe, which monitors the positions of the body, including where your eyes are looking and the tilt of the body.  It includes the postcentral gyrus, also known as the primary somatosensory cortex. It takes in touch and pressure sensations from different parts of the body. The parietal lobe is also responsible for other spatial information and numerical information. Our numerical senses and our sense of space are very related.

The occipital lobe processes visual information, including in dreams. The temporal lobe processes auditory information, but it also contributes to vision perception, including movement and facial perception. Hallucinations often are related to activity here, rather than in the occipital lobe. Damage to the temporal lobe also seems to impact either the ability to recognize or to fear threats (Klüver-Bucy syndrome).

The frontal lobe includes the primary motor cortex on the other side of the central sulcus. It controls the motor function of different body parts. The frontal lobe also includes the prefrontal cortex, which has three major regions. The posterior portion deals mostly with movement. The middle deals with working memory, cognitive control, and emotional reactions. The anterior (front-most) part is for decision-making.

Integration

The binding problem, or the large-scale integration problem, is the question of how different parts of the brain work together. How do smell, vision, taste, and touch combine to create the experience of eating? These senses activate different parts of the cerebral cortex. And how do they connect to something like previous memories? 

The Brain and the Use of Drugs

    Drugs can operate by inhibiting receptors, or resemble a neurotransmitter and bind to the receptor, triggering its effect. Many hallucinogenic drugs like LSD resemble serotonin, and simulate the effects of serotonin but for longer durations than normal. The hallucination effect comes because brain areas that don’t normally communicate much get connected. Nicotine binds to acetylcholine receptors on neurons that trigger the release of dopamine. Dopamine is associated with reward, so the use of nicotine is “rewarding.” This makes it addictive.

    Cannabinoids work a bit differently, simulating “reverse transmitters,” which provide negative feedback from a postsynaptic cell to a presynaptic cell, stopping further release. They decrease both excitatory and inhibitory messages.

    Amphetamine and cocaine are stimulant drugs which inhibit reuptake transporters for dopamine, serotonin, and norepinephrine. A side effect of preventing reuptake, especially to the degree of amphetamine and cocaine, is that neurotransmitters build up outside of neurons, triggering COMT to come break them down. Because it takes a while for neurons to build their store of neurotransmitters back up, this can cause depression-like withdrawal.

   To a lesser degree, many antidepressants and drugs like Ritalin work the same way, by inhibiting reuptake. SSRIs are selective serotonin reuptake inhibitors, and they were among the first medical antidepressants prescribed to patients with depression and other mental illnesses. They block transporters from taking serotonin back into the axon terminals as easily, leading to more serotonin in the system. While there is more serotonin in the brain within hours of a patient taking the medication, studies show that it often takes a few weeks for patients to show improvement in symptoms. This suggests that depression is not a simple serotonin deficiency, and improved symptoms are the result of a domino effect in the brain that is only started by SSRIs, but may involve other changes. There are also studies that suggest that SSRIs are only minimally more effective than placebo, or only work in the most severe cases of depression. However, for now, SSRIs continue to be the first medication tried for many patients with depression.

Opioids simulate epinephrine, but binds to epinephrine receptors strongly, and for much longer periods of time. The body responds to increased levels of opioids by decreasing the number of epinephrine receptors and increasing the number of receptors for its opposite, noradrenaline. This helps the body cope with the effects that a lack of noradrenaline can have on the body, which includes problems with breathing and heart rate. But because of the body’s changes, stopping opioid use can cause severe illness, even lasting for weeks, as the body is too sensitive to noradrenaline and opioids are no longer blocking its presence in the body. The body does adjust eventually. But if a person starts using opioids again after a break, perhaps to stop the feelings of illness that accompany withdrawal, their body may be too sensitive to opioids again to handle their old normal dosage. This is what frequently leads to accidental overdoses.

Rehabilitation centers which require people to be completely clean before starting can be difficult for people to attend and stay in, both because of the strength of their withdrawals and because they cannot afford to take time off from work for the length of time of recovery. Recovering from addiction is also complicated by the fact that many of the people who struggle with opioid addiction have other mental health issues, often predating their use of opioids. Medications to help people safely decrease their dosage over time, in combination with behavior therapy, can help people decrease their dependency on opioids and recover their mental and physical health.