09 avril 2006

Audiobook : Biology and human behavior

Biology and the human behavior
Robert Sapolsky
Stanford University
Ph.D., Rockefeller University

Lecture 1: The basic components

How a neuron works

100 000 000 000 neurons. Dendrites carry information thanks to a wave of depolarization running along the cell membrane.When the neuron gets excited the wave continues to move through the axon hillock. Some of our neurons have axons 3 feet long (60 feet long in a whale’s spinal cord). They are therefore expensive and vulnerable to all sorts of diseases. The wave then reaches the axon terminals, hooking to the dendrites of the next neuron.

Glial cells can form a myelin sheath by wrapping around the axon, which insulates it. The depolarization wave then moves faster along the axon. We are not born with these myelin sheaths, we develop them in our early childhood. Children start understanding language around 10 months of age when the corresponding part of the brain starts myelinating. Two to three months later, we myelinate the part of the cortex which generates language. The myelinating process goes on until age 30. In multiple sclerosis, the immune system starts damaging glial cells causing neurological damage.

Other cells communicate through electrical excitation or hormones, but neurons are the most elaborate mechanism and are used to get things going fast. They spend a lot of energy to separate ions on boths sides of their membrane in order to get a high signal-noise ratio – or high contrast – between the resting state and the excitatory state. However, the wave gets dampened as is moves along the dendrite, so that no single dendrite is able to generate a signal strong enough to pass through the axon hillock. Instead, many waves from several dendrites are required to get the axon excited. This is achieved through spatial or temporal integration until the axon hillock’s threshold is reached, at which point it generates an action potential. Unlike in the dendrite, the action potential does not decrement as it runs down the axon.

The average neuron has the ability to get input from 10,000 other neurons from its dendrites, and in turn sends its action terminals to 10,000 neurons. Our cortex can grow dendrites during our entire life, well into our 90’s and not only during childhood. The axon hillock’s threshold can also change over time, making it more jumpy for instance with a hormone such as testosterone.

Lecture 2: Neurochemistry

How two neurons communicate

The junction between an axon and a dendritic spine is called a synapse. However small this space is, the action potential cannot jump across the synapse filled with salt water. This is achieved by translating the electrical signal into a chemical one. The axon terminal contains synaptic vesicles filled with neurotransmitters. The vesicles are tied to the membrane by a little thread which collapses under electric excitation, causing the vesicle to merge into the membrane and release the neurotransmitter. The dendrite is covered by receptors behaving like locks fitted to a specific neurotransmitter which generates an excitation wave. Neurotransmitters can either be recycled into the axon terminal or degraded by enzymes sitting in the synapse and dumped out.

Not all neurotransmitters are excitatory: some are, and some others on the contrary are inhibitory and decrease the probability of triggering an action potential. In addition, their excitatory and inhibitory power varies between neurotransmitters making the integration process of the axon hillock very subtle. We have a limited number of neurotransmitters – typically a couple of hundreds – being used for various usages in different places of the nervous system, like an alphabet. The release of neurotransmitters into the synapse is a fast process which can occur as much as a hundred times a second. Due to their short lifetime, they are cheap chemical compounds with simple biosynthetic pathways, made out of common precursors. An important feature of neurotransmitters is that we are able to modifiy the nervous system by regulating their action through various chemicals.

Examples of neurotransmitters involved in various drugs:

  • Serotonine looks very much like a molecule found in LSD and mescalin. This molecule can fit into serotonine receptors and excite them, inducing hallucinations.
  • Curare can on the contrary fit into acetylcholine receptors and block them. Because acetylcholine is involved in the movement of our diaphragm, this causes death. Neuroleptics block dopamine receptors, and are used to improve schizophrenic and psychotic conditions.
  • Some drugs cause some neurotransmitters to be released in larger quantities. Amphetamines and cocaine cause dopamine to be released. Dopamine in a certain part of the brain is involved in feeling pleasure, but beyond a certain threshold its action in another part of the brain causes psychosis.
  • Certain drugs can destroy the vesicles of a given neurotransmitter, such as epinephrine (aka adrenaline), which plays a central role in short-term stress reaction and is involved in reducing high blood pressure.
  • If the breakdown and recycling of a neurotransmitter is slowed down, it will move from receptor to receptor and the signal can be amplified. This is the way Prozac acts on serotonine and norepinephrine synapses.
  • Other strategies include increasing the amount of precursors of a given neurotransmitter (L-Dopa for dopamine in Parkinson’s disease). One difficulty is to deliver the neurotransmitter in the right part of the brain.
  • Benzodiazepines are involved in reducing the feeling of anxiety and fear. Certain strains of rats have no benzodiazepine receptors and are heavily handicapped. We can therefore easily imagine that individuals vary in the number of receptors they have, and this will determine how much we tend to worry.

Lecture 3: Plasticity in the synapse

How learning works

In the early days, people believed that learning involved the creation of new neurons. This is not true and we now know that we stop making new neurons around the age of 4-5 and start losing them from then on. Another view was that we create new synapses, and although this occasionally happens it is not through this process that learning takes place. In fact, learning is achieved by the reinforcement of prexisting synapses. This plasticity takes place in specific regions of the brain such as the cortex. The hippocampus is the other main site involved in learning. Example of H.M. patient who had his hippocampus surgically removed for epilepsy.

If a synapse is excited over and over, this pathway’s dendrite eventually ends up generating a stronger response to a given signal and will remain so ever after. This process is called long-term potentiation (LTP) and is the core of learning. LTP involves a neurotransmitter called glutamate. It is one of the simplest chemicals, requiring no precursor, and is highly excitatory. It has two receptor classes with various excitability, one of which (NMDA) generates an explosive response only after repeated and sufficient excitation. This in turn causes Calcium to be released, which triggers the synthesis of more receptors, causes them to remain open a longer time, makes the dendritic membrane more excitable, and finally causes the synthesis of retrograde neurotransmitters in the post-synaptic neuron. The latter are gases (nitric oxyde and carbon monoxyde) which are able to flow into the synapse without the need for vesicles. When they reach the pre-synaptic neuron, they cause more glutamate to be released.

How do we ever forget anything? This can occur be reversing the above process, and happens for instance in severe depression. It is however difficult to know whether a memory is lost or simply more difficult to retrieve. Excess of glutamate can cause excitotoxicity, damaging the neuron. Because regulating glutamate uses up a lot of energy (oxygen and glucose), this happens when the brain receives not enough oxygen during a stroke. Glucose levels go down, and the hippocampus gets flooded with glutamate. Similarily, epileptic seizures use up so much energy that they cause memory loss. Monosodium glutamate is a synthetic version of glutamate used in food, and kept out of our brain by the blood-brain barrier. Since the latter is not effective in babies’ brain, MSG is banned in baby food. Aspartate is another neurotransmitter very close to glutamate, and we do not know whether high quantities of Aspartam can cause excitotoxic damage.

What are the factors, hormones, that can influence LTP? Ethanol disrupts LTP and causes blackout because no synapses are potentiated during a period of time, and can even kill neurons causing alcoholic dementia. Stress, by causing the release of adrenaline and glucocorticoids, has interesting effects on LTP. Up to moderate levels of stress – also called “stimulation” – these neurotransmitters improve LTP. This is why emotional events and high-stake school exams help us memorize things better. But high levels of stress cause to much of glucocorticoids to be released, decrease the efficacy of LTP, and get us distracted. Certain prescription drugs used in inflammatory or immune system diseases can cause such problems. When the post-synaptic neuron lacks energy (e.g. when we skip a meal), it releases a retrograde neurotransmitters to tell the pre-synaptic and modulate LTP.

Explicit or declarative memory is when we know that we know something (Kennedy was killed). On the contrary, procedural memory is about automatic, unconscious movements and actions (climbing stairs). In early stages of Alzheimer’s disease, the procedural memory is preserved, and a patient who used to be a professor of history can give a complete lecture although he does no know where he is or who you are. This is because Alzheimer’s disease first damages the hippocampus and declarative memory involves LTP and the hippocampus. Even without any specific disease, individuals differ in their number of receptors, glutamate levels, and therefore learn more or less easily.

Lecture 4: The dynamics of interacting neurons

Electrical excitation, neurochemistry, plasticity, now building models of larger groups of neurons. A simple model is that of a negative feedback where an axon has an inhibiting action on its originating neuron, shutting down the neuron after a burst of activity. This is a very common property used to sharpen the signal-to-noise ratio. Another feature links a sensory neuron to its immediate neighbours, inhibiting them, therefore sharpening sensory detection.

Around 1960, Hubel & Wiesel made a major discovery on how the cortex processes visual information. There is a point-to-point mapping from sensory receptors in the retinae to neurons forming a first layer in the visual cortex. These neurons “see” dots. In the second visual cortical layer, neurons get activated when a series of three “dot neurons” are activated in a straight line, they “see” lines. Finally, the third layer detects movements. But the hierarchy stops there, and there is no further layer. The reason is that this architecture requires an exponential number of neurons and cannot go on forever. No specific neuron will recognize your grandma’s face or Für Elise!

Instead, information is contained in patterns of neurons, and this feature is called associative memory. This can be used to retrieve memories through associations. To test Alzheimer’s disease, patients are typically asked “What was the name of the previous president of the US?”. Is this (declarative) memory gone or just impossible to retrieve? The patient is then provided additional informations: “It is a one-syllable name”, “His name is that of something you can encounter in a park”, and finally “Is is ‘tree’ or ‘shrub’ or ‘bush’?”. In such a disease the brain is not “turning into yogurt”, but rather into swiss cheese. In early stages, patients can sometimes fill the holes by making extensive use of associative processes.

Two interesting features appear in the sensory system. In one, an inhibiting neuron is associated with a sensory neuron, causing its excitatory state to stop after a short period of time. This causes sensations such as sharp pain, or epicritic pain. In the second, an excitatory neuron is associated with a sensory neuron, causing it to stay in an excitatory state for a long period of time. This causes dull, throbbing pain, or protopathic pain. Massage and rubbing can effectively stop protopathic pain because they stimulate inhibitory circuits of epicritic pain.

Lecture 5: The autonomic nervous system (ANS)

Read a dirty book and interesting things might happen in your body… How do our thoughts modify the functions of our body? The autonomous nervous system is that through which the brain influences involuntary functions such as blushing, goose flesh, pupillary contractions, orgasms, the immune system etc. This is located in the hypothalamus, far from the motor cortex commanding skeletal muscles. The ANS is a very distributed system influencing large numbers of distant parts of the body. It is split in two opposite parts:

- The sympathetic system releases adrenaline and noradrenaline in various areas of the body. Four F’s as in flight, fear, fright and sex (ha, ha!).

- The parasympathetic system is just the opposite, and releases acetylcholine for more vegetative functions such as sleep and digestion.

The heart is an organ that beats on its own, and all our brain does is telling it to speed up or slow down through the sympathetic/parasympathetic system. Taking a deep breath in case of stress will trigger a parasympathetic reflex in the intercostal muscles. The sympathetic system also acts on the digestive system, but with an inhibitory action to shut it down in case of emergency (dry mouth sensation). Research in this field helps understand the relationship between bacteria in our stomach, stress, and gastric ulcers.

How does the penis work? Erection is triggered by the parasympathetic system, but sexual activity will excite the sympathetic system more and more. At one point of high excitation, the parasympathetic system will let go and this causes ejaculation and subsequent lack of erection. Stress can have various effects. It can keep the parasympathetic system from working properly in the first place, causing stress-induced impotency. But when it does work, stress can cause the sympathetic systems to steps in too fast causing premature ejaculation. How do you tell the difference between organic and psychogenic impotency? Answer: male primates get an erection during R.E.M. sleep, which if it occurs eliminates the case of an organic cause. Postage stamp test: stick one on the penis before going to sleep!

The sympathetic system is used to speed up the heart rate in case of injury or cold. This kind of regulation involves a circuit going from peripheral sensors to the cortex and then through the hypothalamus and sympathetic system to a given organ. Just above the hypothalamus lies the limbic system, involved in emotions and mating, and containing the hippocampus. Most mammals are very sensitive to pheromones that carry all sorts of informations and will influence the ANS through the limbic system. Although humans respond much less to pheromones, it has been shown that “socially dominant” women will usually impose their menstrual cycle to others through such olfactory sensations.

The cortex can also influence the ANS directly. In the case of major depression, negative thoughts constantly stimulate the sympathetic system. Chronic stress can therefore be a predisposing factor of depression. Therefore, the depressive patient lying in bed with no energy is in fact fighting a constant battle in his head, with elevated sympathetic tone, increased levels of adrenalin and noradrenalin, high muscle tension, high metabolic expenditure. The cortex sends its information to the hypothalamus through a nervous pathway called the cingulum bundle. In very severe cases of depression, cutting it can provide relief!

Like the cortex and hippocampus, the ANS has its own plasticity. Over time, parachuting sportsmen can sharpen their sympathetic system to be triggered seconds before they jump. Through a different conditionning, sympathetic reactions can also take place in circumstances that remind of an accident. In biofeedback, this feature is used to train someone to consciously control their blood pressure and heart rate. Individuals differ in their sympathetic systems, and people more prone to stress, aggressiveness and depression are known to be at risk for cardiovascular diseases.

Lecture 6: Endocrinology I

Generating an endocrine signal

Apart from the hypothalamus, hormones are another way to influence every cell in the body. Hormones travel long distances, work slower than neurotransmitters (minutes to hours), can affect not only synapses but potentially any cell through the blood stream, activate genes and enzymes and a have a broad range of effects. In the neuro-endocrine flow, the hypothalamus regulates the pituitary gland which in turn regulates peripheral glands, all of these communications taking place through hormones. This was a surprise because the pituitary was long seen as the “master gland”, or possibly influenced by the hypothalamus through axons, and it was inimaginable that the brain itself could secrete hormones. In fact, the brain itself is the “master gland”. Even the heart can secrete a hormone called ANF when its muscles are stretched, causing the kidneys to produce urine in order to decrease blood pressure.

Like neurotransmitters, hormones are simple chemical compounds:

- Steroid hormones (oestrogens, androgens, glucocorticoids) are made from a single cheap precursor which is cholesterol (1% of it).

- Insulin and others are made from amino acids, and are therefore protein-derived.

- Often hormones are made of different combinations of the same precursors. Therefore, although the messengers are cheap, the receptors have to be very subtle to tell the difference between them.

- Somes hormones are a single amino acid, for instance glutamate or adrenaline and noradrenaline serving as hormones, or melatonine.

A common property is that the number of receptors increases/decreases when the quantity of hormones decreases/increases. This does not exactly cancel out, and creates a response with an inverse U pattern. This is how glucocorticoids can enhance LTP but long-term exposure or larger quantities will inhibit LTP.

The effect of stress on the male reproduction has been exposed. Surprisingly, females secrete a small amount of androgens coming from their adrenal glands. To allow the reproduction system to work, these are eliminated by fall cells containing an enzyme which can turn androgens into oestrogens (both steroid hormones, chemically close). When starving reduces the amount of fat, androgens build up and stop ovulation. This happens in anorexia and excessive exercice (running 50 miles per week and more). Again, exercise has an inverse U pattern.

Prolactin plays a central role in preventing ovulation, and this hormone is secreted by the pituitary during nursing, making nursing a natural contraceptive. For this to work, however, nursing must take place every hour for a very short period of time. This has been shown in Bushmen in Botswana where women give birth every 4 or 5 years although they have a correct diet and do not exercise to much. These women therefore have only a few periods in their entire life. We can speculate that letting the female reproductive system undergo 3 to 400 cycles during a lifetime is the cause for new diseases in western women.

Lecture 7: Endocrinology II

Hormonal effects on the brain

We have seen that the brain regulates hormones through the pituitary. The other way round, we will now discuss how hormones get into our brain and influence our behavior and mood. This field is called behavioral endocrinology:

- Glucocorticoids make our memory sensitive to moderate stress, helping us remember mainly important events.

- The lordotic reflex causes female rodents to arch their back, raise their tail and expose their genitals when pressed on their flanks. However, this reflex takes place only if the female has certain oestrogens in their blood meaning they are ovulating that day. The way oestrogens do this is by activating a gene which produce a neurotransmitter to make certain axon hillocks more excitable.

- Similarily, skin sensitivity on the genitals varies with androgens and oestrogens.

Testosterone is a hormone secreted by the testis and is closely related to aggressive behavior. Males tend to be more aggressive, with the exception of spotted hyenas in which females have higher male sex hormone levels than males. They display higher muscle mass and aggressiveness. How does this work? Stimulating the amygdala in the brain causes an aggressive outburst, and removing it greatly reduces it. The amygdala is very receptive to testosterone, a hormone which does not cause action potentiel in axon hillocks, but increases its frequency when it happens. However, studies show no correlation either in time or across the population between levels of testosterone and aggressiveness. Within its normal range, it therefore exacerbates existing patterns, but does not “cause” aggressiveness. Similarily, usual testosterone levels do not make a difference in sexual behavior and orientation. Outside usual levels, sexual interest will disappear when testosterone levels fall to zero.

The pancreas and gall bladder release all sorts of hormones. CCK is secreted at the end of digestion, and sends the hypothalamus a signal to make us feel satiety. Oestrogens and progesterone regulate events in the limbic systems, and what counts is not their absolute quantity but rather their ratio in regulating serotonin and adrenalin levels. In unipolar depression, people go from feeling ok to feeling depressed. In manic depression or bipolar depression, they go from feeling great to feeling depressed. Men and women have the same proportion of manic depression, but women get more unipolar depression, especially around the time of their periods, after giving birth or during menopause. Little is yet known on this subject. Similarily, violent crimes are more often committed during the premenstrual period by women suffering from premenstrual syndrome (PMS).

Although some diseases are easily understood by looking at how they correlate with hormone levels, it is also interesting to measure the effects of the number of receptors. In a certain disease, a girl can display an absence of puberty because she is in fact a boy with XY chromosomes and all standard male hormones except for lacking testosterone receptors. Because differenciation of female features into male features (genitals, beard, etc.) happens only if testosterone is able to act, these individuals display female characteristics. In another disease seen in the Dominican Republic, individuals have an enzyme imbalance which reduces the amount of testosterone signal going through the synapse. While they are kids, these males display female features, but as soon as they reach puberty and more testosterone is released, they start changing sex.

Lecture 8: A synthesis

The biology of who we are

The frontal cortex creates inhibitions preventing us to act asocially and saying out loud every nasty thought passing through our mind. Certain strokes and brain injuries in the frontal cortex can therefore change radically the individuals’ behavior. Similarily, Huntington’s disease is a hereditary disease causing uncontrolled movements of the limbs. In early stages of the disease, patients display disinhibited behavior close to those with frontal lesions. More generally, people with this kind of behavior in day to day life are said to be “frontal”.

We all have little superstitious rituals we need to satisfy. But some people have obsessive compulsive disorder and will open and close doors several times, wash their hands all the time, keep believing they left the gas open, etc. It is possible that anxiety causes them to undergo these rituals in order to make the world “less frightening”. There is a suggestion there is a genetic and neurochemical component to this disease, and modern imaging shows sustained high activity levels in the motor cortex.

In schizotypal personality disorder, patients are rather reclusive, tend to have flat emotions, with intense interest in science fiction and nonsensical new age pseudo science, and often very litteral interpretation of the Bible, capable of arguing that Elvis Presley might have been kidnapped by UFOs. They are often relatives of schizophrenics, adding to the idea that such diseases are genetic.

Epileptic seizures are caused by uncontrolled a release of action potential and can occur in various areas of the brain. Temporal lobe personality can be caused by epilepsy: people become humourless, tend to dislike new things and changes (neophobia), start writing a lot (hypergraphia) and take a very strong interest in religion and philosophy.

The implications of these discoveries are very disturbing, but we are beginning to have the tools to study the biology of many new personality disorders that were totally unknown fifty years ago. What will happen when we start saying things about political orientation, ability to have a stable relationship, and giving these people labels? “It is not me, it is this condition I have.” The comforting answer is that there is a biological continuum between full blown schizophrenia, schizotypal disorder, even milder conditions, and “normal” persons, therefore supporting the idea that our model of the brain effectively describes all of us and does not draw any kind of separation line.

Five years ago, Simon LeVay discovered that gay men had a structural difference in their brain. A certain part of their hypothalamus had a size closer to women than to straight men. Even if we assume that there is indeed a link between the size of this part of the brain and sexual orientation, and further that it is the cause of sexual orientation, what would we do with this information? The only answer is that we will have to become more open minded about what constitutes normality. Even if scientists end up explaining our personality, so what? Birds can be explained aerodynamically, and this does not keep us from being amazed by them. We do not have to chose between science and emotion! In addition, we are still barely scratching the surface of this subject, and it is unlikely that we will ever be able to explain everything.

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