Stanford’s Robert Sapolsky On Depression

Published on May 25, 2014 (edited for improved sound: noise and stereo issues, and miscellaneous parts taken out) Stanford Professor Robert Sapolsky, posits that depression is the most damaging disease that you can experience. Right now it is the number four cause of disability in the US and it is becoming more common. Sapolsky states […]

Published on May 25, 2014
(edited for improved sound: noise and stereo issues, and miscellaneous parts taken out)

Stanford Professor Robert Sapolsky, posits that depression is the most damaging disease that you can experience. Right now it is the number four cause of disability in the US and it is becoming more common. Sapolsky states that depression is as real of a biological disease as is diabetes.


Neurotransmitters

The neurotransmitter serotonin is involved in regulating many important physiological (body-oriented) functions, including sleep, aggression, eating, sexual behavior, and mood. Serotonin is produced by serotonergic neurons. Current research suggests that a decrease in the production of serotonin by these neurons can cause depression in some people, and more specifically, a mood state that can cause some people to feel suicidal.

In the 1960s, the “catecholamine hypothesis” was a popular explanation for why people developed depression. This hypothesis suggested that a deficiency of the neurotransmitter norepinephrine (also known as noradrenaline) in certain areas of the brain was responsible for creating depressed mood. More recent research suggests that there is indeed a subset of depressed people who have low levels of norepinephrine. For example, autopsy studies show that people who have experienced multiple depressive episodes have fewer norepinephrinergic neurons than people who have no depressive history. However, research results also tell us that not all people experience mood changes in response to decreased norepinephrine levels. Some people who are depressed actually show hyperactivity within the neurons that produce norepinephrine. More current studies suggest that in some people, low levels of serotonin trigger a drop in norepinephrine levels, which then leads to depression.

Another line of research has investigated linkages between stress, depression, and norepinephrine. Norepinephrine helps our bodies to recognize and respond to stressful situations. Researchers suggest that people who are vulnerable to depression may have a norepinephrinergic system that doesn’t handle the effects of stress very efficiently.

The neurotransmitter dopamine is also linked to depression. Dopamine plays an important role in regulating our drive to seek out rewards, as well as our ability to obtain a sense of pleasure. Low dopamine levels may in part explain why depressed people don’t derive the same sense of pleasure out of activities or people that they did before becoming depressed.

Monoamine neurotransmitters

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and thethyroid hormones by the action of aromatic amino acid decarboxylase enzymes. Monoaminergic systems, i.e., the networks of neurons that […]

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, tryptophan, and thethyroid hormones by the action of aromatic amino acid decarboxylase enzymes. Monoaminergic systems, i.e., the networks of neurons that utilize monoamine neurotransmitters, are involved in the regulation of cognitive processes such as emotion, arousal, and certain types of memory. It has been found that monoamine neurotransmitters play an important role in the secretion and production of neurotrophin-3 by astrocytes, a chemical which maintains neuron integrity and provides neurons with trophic support.[1] Drugs used to increase (or reduce) the effect of monoamine are sometimes used to treat patients with psychiatric disorders, including depression, anxiety, and schizophrenia.[2]

neurotransmitter molecules

Chemical synapses are biological junctions through which neurons signal to each other and to non-neuronal cells such as those inmuscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and […]

Chemical synapses are biological junctions through which neurons signal to each other and to non-neuronal cells such as those inmuscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

At a chemical synapse, one neuron releases neurotransmitter molecules into a small space (the synaptic cleft) that is adjacent to another neuron. The neurotransmitters are kept within small sacs called vesicles, and are released into the synaptic cleft by exocytosis. These molecules then bind to receptors on the postsynaptic cell’s side of the synaptic cleft. Finally, the neurotransmitters must be cleared from the synapse through one of several potential mechanisms including enzymatic degradation or re-uptake by specific transporters either on the presynaptic cell or possibly by neuroglia to terminate the action of the transmitter.

The adult human brain is estimated to contain from 1014 to 5 × 1014 (100–500 trillion) synapses.[1] Every cubic millimeter of cerebral cortex contains roughly a billion (short scale, i.e. 109) of them.[2]

The word “synapse” comes from “synaptein”, which Sir Charles Scott Sherrington and colleagues coined from the Greek “syn-” (“together”) and “haptein” (“to clasp”). Chemical synapses are not the only type of biological synapse: electrical and immunological synapses also exist. Without a qualifier, however, “synapse” commonly means chemical synapse.

Synaptic transmission can be changed by previous activity. These changes are called synaptic plasticity and may result in either a decrease in the efficacy of the synapse, called depression, or an increase in efficacy, called potentiation. These changes can either be long-term or short-term. Forms of short-term plasticity include synaptic fatigue or depression and synaptic augmentation. Forms of long-term plasticity include long-term depression and long-term potentiation. Synaptic plasticity can be either homosynaptic (occurring at a single synapse) or heterosynaptic (occurring at multiple synapses).

Neurotransmitters also known as chemical messengers, are endogenous chemicals that enableneurotransmission. They transmit signals across a chemical synapse, such as a neuromuscular junction, from one neuron (nerve cell) to another “target” neuron, muscle cell, or gland cell.[1] Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available from the diet and only require a small number of biosynthetic steps to convert them. Neurotransmitters play a major role in shaping everyday life and functions. Their exact numbers are unknown but more than 100 chemical messengers have been identified.[2]

There are four main criteria for identifying neurotransmitters:

  1. The chemical must be synthesized in the neuron or otherwise be present in it.
  2. When the neuron is active, the chemical must be released and produce a response in some target.
  3. The same response must be obtained when the chemical is experimentally placed on the target.
  4. A mechanism must exist for removing the chemical from its site of activation after its work is done.

However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term “neurotransmitter” can be applied to chemicals that:

  • Carry messages between neurons via influence on the postsynaptic membrane.
  • Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
  • Communicate by sending reverse-direction messages that have an impact on the release or reuptake of transmitters.

The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify either the location of either the transmitter substances themselves, or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, one neuron may release more than one transmitter from its synaptic terminal.[7] Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.[8]

There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes.

Major neurotransmitters:

In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are “co-released” along with a small-molecule transmitter. Nevertheless, in some cases a peptide is the primary transmitter at a synapse. ?-endorphin is a relatively well known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.

Single ions (such as synaptically released zinc) are also considered neurotransmitters by some,[10] as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S).[11] The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.[4] The next most prevalent is Gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

Here are a few examples of important neurotransmitter actions:

Toxoplasma gondii

A food-borne parasite that infects domestic cats can get inside the human brain by commandeering special cells of the immune system which it uses as a Trojan horse to enter the central nervous system, a study has found. Scientists believe they have finally discovered the mechanism that allows Toxoplasma gondii – a single-celled parasite – […]

A food-borne parasite that infects domestic cats can get inside the human brain by commandeering special cells of the immune system which it uses as a Trojan horse to enter the central nervous system, a study has found.


Scientists believe they have finally discovered the mechanism that allows Toxoplasma gondii – a single-celled parasite – to pass from the human gut to the brain where it may cause behavioural changes.
Researchers have shown that the parasite can infect the dendritic white blood cells of the immune system causing them to secrete a chemical neurotransmitter that allows the infected cells, and the parasite, to cross the natural barrier protecting the brain.
Toxoplasma gondii can live in many different species but it can only complete its life cycle in cats, which secrete the parasite in their faeces. Studies have shown that toxoplasma affects the behaviour of rats and mice, making them more likely to be eaten by cats, thereby completing parasite’s complex life-cycle.
Latest figures released in September by the Food Standards Agency show about 1,000 people a day in Britain – 350,000 a year – are being infected with toxoplasma, probably from either direct contact with cats or by eating poorly-cooked meat or vegetables.
Up to 40 per cent of the British population are believed to be infected with toxoplasma and although the vast majority show no apparent symptoms, there is a risk to unborn children if their mothers become infected for the first time during pregnancy.
However, recent studies have also suggested that toxoplasma may be a trigger for psychological disturbances in humans, including schizophrenia, although the research has fallen well short of showing a cause-and-effect.
Antonio Barragan of Sweden’s Centre for Infectious Diseases at the Karolinksa Institute in Stockholm said that when infected with toxoplasma human dendritic cells, which are not part of the central nervous system, begin to secrete a neurotransmitter called GABA which is normally produced by brain cells.
“For toxoplasma to make cells in the immune defence to secrete GABA was as surprising as it was unexpected…This was unknown before. It means that the parasite had the capacity potentially to manipulate the central nervous system,” Dr Barragan said.
The study, published in the on-line journal Plos Pathogens, used human dendritic cells growing in a test tube, but it also showed that infected dendritic cells pass more easily than uninfected cells into the brains of laboratory mice.
“We’ve shown that it happens in human dendritic cells taken from healthy donors and also proved that the same thing happens in the mouse model. It shows that the parasite is using dendritic cells as a sort of Trojan horse to transport itself from the human gut to the brain,” Dr Barragan said.
“We’ve not looked at behaviour changes in people infected with toxoplasma, as that’s been dealt with by previous studies. Instead, we’ve shown for the first time how the parasite behaves in the body of its host, by which I mean how it enters the brain and manipulates the host by taking over the brain’s neurotransmitters,” he said.
GABA, or gamma aminobutyric acid, is involved, among other things, in inhibiting the sense of fear and anxiety. Rats and mice infected with toxoplasma show little fear of cats and Dr Barragan suggested that infected dendritic cells may continue to stimulate the production of GABA once the cells have entered the brain.
However, other scientists have shown that toxoplasma is capable of producing another nerve substance called L-dopa which is a chemical precursor to the dopamine neurotransmitter, which may be another route to altering mammalian behaviour.
“Many neuropsychiatric disorders implicate a dysregulation of several neurotransmitters. If one is affected, this may affect the others, or the balance between neurotransmitters. How GABA specifically acts in the equation is a question for the future,” Dr Barragan said.
Scientists emphasised that the jury is still out on whether toxoplasma is capable of influencing the behaviour or mental state of infected people given the preliminary nature of the studies showing a tentative link between the parasite and human behaviour.
“We believe that this knowledge may be important for the further understanding of complex interactions in some major public health issues that modern science still hasn’t been able to explain fully,” Dr Barragan said.
“At the same time, it’s important to emphasise that humans have lived with this parasite for many millennia, so today’s carriers of toxoplasma need not be particularly worried,” he said.