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Cytoplasm (consisting of the cytosol, the cell fluid, and the organelles floating in it (mitochondria, Golgi, etc.))
the nucleus (the cell nucleus in the soma)
many dendrites (where they receive information from other cells through tens of thousands to millions of synapses) and
an axon (neurite) via which they send information to other cells.
While dendrites are at most a few hundred micrometers short, axons in humans can be between 0.1 millimeters and over a meter (or even up to 4 meters1] long. The axoplasm within the axon comprises more than 90 % of the cytosol. The axon hillock is the origin of the nerve cell’s electrical signal and connects the cell nucleus and axon. At the end of an axon are terminals that transmit the information from the presynaptic cell to postsynaptic cells via chemical synapses. The axonal synapses usually dock onto dendrites, sometimes onto somata and rarely also onto axons of other cells.
Axons can have a myelin sheath made of Schwann cells. This “insulates” the electrical conduction of the axon and causes a regular amplification of the electrical signal to be passed on by means of the lacing rings where the insulation is interrupted. The thicker the axon and the better it is coated (myelinated) by glial cells (oligodentrocytes in the brain, peripheral Schwann cells), the faster the electrical transmission (up to 120 meters / second).
If enough neurotransmitters dock to the excitatory receptors of a neuron and not enough to inhibitory receptors, an action potential is triggered. The neuron fires this as an electrical impulse via the axon to the active zones at the synapses, where vesicles fuse with the cell membrane and release neurotransmitters into the synaptic cleft.
Nerve cells can fire up to 500 times/second.
The human brain has around 100 billion nerve cells.
These are:2
glutamatergic - approx. 20,000,000,000 (20 billion) GABAergic - approx. 9,000,000,000 (8 billion)
serotonerg - approx. 250,000 dopaminergic - approx. 250,0002, 400,000 to 600,000 noradrenergic - approx. 30,000 to 50,000
Information is represented by the simultaneous firing of a particular group of nerve cells.
Unipolar, bipolar and multipolar neurons
In unipolar neurons, the axon is a branch of the dendrite. Unipolar neurons are mainly found in the nervous systems of non-vertebrates and in the autonomic nervous system of vertebrates.
Bipolar neurons have an oval soma from which the dendrite tree arises on one side and the axon on the other. Sensory cells are mostly bipolar neurons.
In multipolar neurons, a large number of dendrites and an axon arise from the soma. Most nerve cells in the brain are multipolar.
Sensory neurons, motor neurons, interneurons
Sensory neurons receive sensory signals (pressure, temperature, light, etc.) from the periphery and send them to the spinal cord.
Motor neurons transmit signals from the brain and spinal cord to muscles and glands Interneurons connect two other neurons to each other (which is what most neurons do).
Local interneurons connect nearby neurons and therefore have short axons; relay or projection interneurons transmit the signal to other brain regions and therefore have long axons.
All cells in the nervous system that are not neurons are called glial cells.
In the nervous system of vertebrates, there are 2 to 10 times as many glial cells as neurons. Glial cells do not send signals, but support nerve cells.
Astrocytes nourish the neurons via contacts with blood vessels. Astrocytes are significantly involved in fluid regulation in the brain and ensure that the potassium balance is maintained.
Astrocytes (astroglia) is the name of these cells in the central nervous system. (brain / spinal cord)
These cells are called mantle cells (satellite cells) if they occur in the body (peripherally).
Microglia are immune effector cells in the CNS. They only formally belong to the glial cell family. More precisely, they are cells of the mononuclear-phagocytic system.
Synapses are the junctions through which nerve cells communicate with each other.
There are
electrical synapses, which transmit electrical signals directly and therefore very quickly, but this is only possible to smaller neurons, and
chemical synapses in which the signal is mediated via neurotransmitters, which firstly enables modulating control and secondly amplification of the signal so that larger neurons can also be addressed.
While muscle cells are usually only excitatory controlled by a single motor neuron and each individual signal causes muscle activation, neurons in the brain are networked with each other in multiple and redundant ways, can be connected to each other in an excitatory or inhibitory manner and require the interaction of many signals (often 50 to 100) for activation.
Neurotransmitters are messenger substances that transmit information at chemical synapses between nerves. Examples are dopamine, noradrenaline, serotonin, acetylcholine, GABA and glutamate. The different neurotransmitters have different tasks in the brain and overlap in their effects.
The release of neurotransmitters at the synapses causes chemical stimulus transmission or blockade between neurons (nerve cells).
Other messenger substances, the hormones, slowly transmit their effect via the bloodstream to more distant target organs (e.g. adrenaline, cortisol, estradiol, insulin, testosterone, thyroxine, triiodothyronine).
Some substances act both as neurotransmitters and hormones (e.g. noradrenaline, serotonin, histamine) and some substances act both as neurotransmitters and hormones (e.g. noradrenaline, serotonin, histamine).
Neurotransmitters are synthesized in the cytosol of the cell nucleus, packaged in vesicles and transported via the microtubules through the axons to the nerve terminals where the transmitting synapses are located. The transport speed in the axons varies depending on the substance and is up to 5 µm/second = approx. 40 cm/day.3
The neurotransmitters are released from the nerve terminals into the synaptic cleft in response to an action potential by the vesicles connecting to the membrane. The synaptic cleft is between 20 and 40 nm wide.4
In the synaptic cleft, they dock onto postsynaptic receptors and thereby open ion channels, which can trigger a new action potential in the receiving cell.
The neurotransmitters then detach from the postsynaptic receptors and are reabsorbed into the transmitting cell in or at the edge of the synaptic cleft by presynaptic transporters. In the cell, they are either stored again in vesicles until the next release or metabolized by degrading enzymes (e.g. dopamine and noradrenaline by monoamine oxidase and COMT).
Neurotransmitters that are not reabsorbed diffuse into the extracellular space and from there can trigger D2 autoreceptors of the sending cell or receptors or transporters of other cells.
The purpose of chemical signal transmission by neurotransmitters is the filtering and modulation of signals and the possibility of amplifying the signal to be transmitted.
Inverted-U: Neurotransmitter levels that are too high or too low impair information transmission in catecholamines
Optimal information transmission requires optimal neurotransmitter levels - at least in the case of catecholamines (such as dopamine, noradrenaline, adrenaline). Both reduced and increased levels impair signal transmission. Optimal transmission of information between brain synapses requires an optimal level of the neurotransmitters involved. A neurotransmitter level that is too low leads to almost identical Consequences of the signal transmission disorder as a neurotransmitter level that is too high (inverted-U theory).56
The activity of the locus coeruleus (main source of cortical noradrenaline) shows an inverted-U relationship to task performance7
DRD1 activation has an inverted-U relationship with working memory performance89
The activity of the DA neurons in the VTA is in an inverted-U relationship to the performance of short-term memory10
There are around 500 different neurotransmitters in various neurotransmitter classes.
Soluble gases
Nitric oxide (NO)
Carbon monoxide (CO)
Hydrogen sulphide
Amines
Choline (quaternary amines)
Acetylcholine
Biogenic amines
(Classic) monoamines
Catecholamines:
Noradrenaline
Adrenalin
Dopamine
Indolamines
Serotonin
Melatonin
Imidazolamines
Histamine
Traceamine
Phenethylamines
Phenethylamine (PEA)
Tyramine
Indolamines
Tryptamine
Octopamine
Amino acids
Inhibitory amino acid transmitters
Gamma-amino-butyric acid (GABA)
Glycine
Β-alanine
Taurine
Excitatory amino acid transmitters
Glutamic acid (glutamate)
Aspartic acid (aspartate)
Cysteine
Homocysteine
Neuropeptides
Opioipeptides
Dynorphins
Dynorphin A
Dynorhin B
Α-Neoendorphin
Β-Neoendorphin
Endorphins
Somatostatin
Insulin
Glucagon
Α-Endopsychosin
Neurokinins / Tachykinins
Substance P (neurokinin 1)
Neurokinin A (substance K)
Neuropeptide K (neurokinin K)
Neuropeptide γ (neuropeptide gamma)
Neurokinin B
Hemokinin-1
Endokinin A, B, C and D
Enkephaline
Met-enkephalin
Leu-Enkephalin
Met-Arg-Phe-Enkephalin
Other neuropeptides
Oxytocin
Somatostatin
Vasopressin
Neuropeptide S
GHRH
Endocannabinoids
Anandamide
2-arachidonylglycerol
O-arachidonylethanolamide
Neurotransmitters pass on activating or inhibiting (inhibitory) information depending on the receptor to which they dock. Although dopamine and serotonin are predominantly involved in the transmission of inhibitory information, only the D2, D3 and D4 receptors are inhibitory (they inhibit the enzyme adenylyl cyclase), while the D1 and D5 receptors have an activating (excitatory) effect (they activate the enzyme adenylyl cyclase).
In ADHD, the transmission of information in the brain is primarily impaired in relation to the neurotransmitters dopamine and noradrenaline.
Receptors are docking sites for messenger substances. Depending on the receptor, a messenger substance can have an inhibiting or activating effect.
Ionotropic receptors
In these, the binding of a neurotransmitter directly causes the opening of an ion channel.
Metabotropic receptors
In these, the binding of a neurotransmitter causes the activation of messenger substances (second messengers), which in turn can address a number of transport channels.
All dopamine and noradrenaline receptors are metabotropic.
Excitatory and inhibitory receptors.
Receptors for one and the same neurotransmitter can have an excitatory (increasing the postsynaptic nerve voltage) and inhibitory (decreasing the postsynaptic nerve voltage) effect.
In contrast, neither the firing of neurons nor the type of neurotransmitter say anything about whether a signal should be activating (excitatory) or inhibiting (inhibitory).
Neurons transmit signals by triggering an action potential.
In their resting state, neurons contain an average voltage of 65 mV (between 45 and 90 mV depending on the cell type) lower than the extracellular space. This voltage difference is created by the so-called sodium-potassium pump (sodium-potassium ATPase, a membrane protein), which exchanges sodium ions from the inside of the cell for potassium ions from the extracellular space. Through potassium-permeable ion channels in the self-impermeable cell membrane, the potassium ions - following the concentration gradient - can slowly leave the cell again, leaving behind a non-neutralized negative charge on the inner cell membrane surface, which is usually around -65 mV.
At rest, the cells then contain around 1/10 as many sodium ions and 20 times as many potassium ions as extracellularly. The extracellular sodium and potassium ion level is maintained by the kidneys and the astrocytes. If sodium or calcium ions enter the cell, its voltage increases.
An action potential (a rapid voltage increase of +10 mV, e.g. from -65 to -55 mV) makes the cell membrane more permeable to sodium ions than to potassium ions. The resulting increased entry of sodium ions further increases the cell wall permeability for sodium ions, so that more and more sodium ions enter. This causes the negative voltage to drop abruptly and even briefly (for around 1 ms) turn positive to + 40 mV (“overshoot”). The action potential now travels at 1 to 100 meters/second along the axon to the terminals, where it opens ion channels.
The action potential is an all-or-nothing decision. If it is triggered, it always has full strength, regardless of whether the trigger threshold is only just exceeded or greatly exceeded.
The action potential remains constant over the entire distance in the axon. For this purpose, it is amplified at the Ranvier cords.
After the voltage maximum is reached, the return to the resting potential (repolarization) takes place through the closing of sodium channels and the opening of potassium channels.
The membrane voltage initially becomes even more negative than the original resting potential (hyperpolarization). The cell then returns to the starting point (resting potential).
After the triggering of an action potential, a neuron undergoes a pause, the refraction period.
Voltage increases (slowly or quickly) towards the threshold potential, e.g. from -70 mV to -50 mV (initial depolarization)
If incoming stimuli (after summation in the axon hillock) do not reach the threshold value, there is a temporary, reversible change in the membrane potential
Spread
Complete depolarization only occurs when the threshold potential is reached
Consequences:
The voltage-dependent sodium channels open and suddenly allow Na+ ions to flow from the extracellular space into the cytosol of the neuron
Meanwhile, the potassium channels are closed
A positive feedback mechanism even causes a charge reversal (“overshoot”) at the end.
Repolarization
Sodium channels begin to close again before the potential peak
The voltage-dependent potassium channels open, allowing K+ ions to flow from the cell interior into the extracellular space
The conductivity of the potassium channels reaches its maximum when almost all sodium channels are already inactivated
During repolarization, the potential moves back towards the resting potential, which leads to the closure of the potassium channels, while the sodium channels are slowly reactivated.
Hyperpolarization
Potassium channels close within 1 to 2 ms, and therefore more slowly than sodium channels
Meanwhile, the membrane potential drops below the actual resting potential (“hyperpolarization”)
Refractory period
after an action potential, the neuron is not excitable for a short time
until the sodium channels can be reactivated
Absolute refractory phase: Period shortly after overshoot, before repolarization is completed. Action potential cannot be triggered.
Relative refractory phase: threshold value for triggering an action potential is increased
While the action potential is always equally strong and is the only outgoing impulse of a neuron, there are two types of activating impulses:
the synaptic signal
the receptor signal.
Both are graduated in terms of strength.
Receptor signals are triggered by peripheral sensory stimuli, for example. A receptor signal corresponds in duration and strength to the intensity of the stimulus, but is relatively weak overall. It only reaches a few millimeters within the neuron. After one millimeter, it has already lost two thirds of its energy. If it reaches a Ranvier ring with sufficient strength within its range, its amplification effect triggers a complete action potential so that the sensory stimulus can reach the spinal cord.
Synaptic signals are triggered by neurotransmitter binding at receiving synapses on dendrites. Like the receptor signal, they are gradual depending on the number of activated receptors. Synaptic signals are summed at the axon hillock of the neuron. If the sum exceeds the threshold value, the action potential is triggered.
Even if an action potential is always equally strong, it can cause a gradual release of neurotransmitters due to the frequency and rate of its sequence and thus transmit signals of different strengths to the postsynaptically connected cells. If an action potential is only triggered once. The more frequently and quickly the action potential is triggered in succession, the greater the amount of transmitter release, which leads to a higher number of postsynaptically addressed receptors.
Around 600 km of blood vessels run through the human brain.
Blood vessels in the brain have special cells in their walls that prevent certain substances that are harmless in the body (peripheral) from interfering with the complex and sensitive processes of the brain (central) and prevent neurotransmitters and potassium from leaking from the extracellular cerebrospinal fluid into the blood.
Only fat-soluble substances with a molecular weight below 500 Da can diffuse through the blood-brain barrier, such as nicotine, alcohol, blood gases or narcotics such as halothane, but not ions or polar substances such as glucose. The latter are dependent on specific transport systems12
In the course of evolution, different areas of the brain have gradually developed, which we present below from old to new.
Fundamental to the areas of the human brain: Kandel, Shadlen (2021): The Brain and Behavior. In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.
each hemisphere is divided into 4 cerebral cortex lobes
frontal (PFC)
higher cognitive processes
Control of voluntary motor skills, attention, short-term memory tasks, motivation and planning
parietal (parietal lobe, parietal lobe, top)
somatosensory functions
visual control of movements and recognition of stimuli in the room
spatial thinking and “quasi-spatial” processes such as arithmetic and reading
Language processing
Interface between the sensory systems (especially the visual system) and the motor system for the calculation, execution and control of hand and eye movements.
occipital (back)
visual cortex (visual processing)
temporal (lateral lobe)
auditory cortex (acoustic processing)
Interpretation of information according to visual memory and language comprehension
9. Brain regions and functions - hardware and software¶
Although individual brain regions have preferred functions, there is no clear 1:1 allocation.
Simple reflexes are still controlled quite clearly by specific brain regions. The more complex a behavioral function is, the more the interaction of several brain regions is used - this is referred to as brain networks.
It helps an individual to survive if important functions can be controlled alternatively by different brain regions (redundancy). Functions that are lost (e.g. if a brain region is damaged by a stroke) can therefore be taken over by other brain regions (flexibility).
Without another brain region taking over the control of the impaired function, it would be possible to compensate for the deterioration or total loss of a function by shifting survival strategies to increased use of other abilities (behavioral change). However, it is much easier to maintain a behavior that has already been successfully learned by maintaining important functions because they are represented by more than just one brain region and only the control of the function has to be relearned.
This also explains the difficulties in attributing certain functional impairments to defects in specific brain regions. This applies in particular to mechanisms that do not represent a specific bodily function.
The problems associated with ADHD relate more to mechanisms for the long-term regulation of behavior and cannot be attributed to specific hardware defects in individual brain regions.
