Neurological Basics

Here, we will explain some basic concepts in neurology that will be helpful for further understanding.

For information on the basics of genes and heredity (genes, gene expression, DNA, RNA, nucleotides, proteins, amino acids), see Building blocks of heredity and behavior: genes, DNA, RNA, proteins, and more

1. Neurons¶

Neurons are nerve cells. They consist of

• Soma (the cell body itself, perikaryon)
• Cytoplasm (consisting of the cytosol, the cell fluid, and the organelles suspended within it (mitochondria, Golgi apparatus, etc.))
• the nucleus (the cell nucleus in the soma)
• numerous dendrites (through which they receive information from other cells via tens of thousands to millions of synapses) and
• an axon (neurite), through which they send information to other cells.

While dendrites are at most a few hundred micrometers long, axons in humans can range in length from 0.1 millimeters to over one meter (or even up to 4 meters)¹. The axoplasm within the axon accounts for more than 90% of the cytosol. The axon hillock is the origin of the nerve cell’s electrical signal and connects the cell nucleus to the axon. At the end of an axon are terminals that transmit information from the presynaptic cell to postsynaptic cells via chemical synapses. Axonal synapses typically connect to dendrites, occasionally to the cell body, and rarely to the axons of other cells.
Axons may have a myelin sheath formed by Schwann cells. This “insulates” the axon’s electrical conduction and, through the nodes of Ranvier—where the insulation is interrupted—causes a regular amplification of the electrical signal being transmitted. The thicker the axon, and the better it is sheathed (myelinated) by glial cells (oligodendrocytes in the brain, Schwann cells in the periphery), the faster the electrical transmission (up to 120 meters per second).

If enough neurotransmitters bind to a neuron’s excitatory receptors and few enough to its inhibitory receptors, an action potential is triggered. The neuron transmits this as an electrical impulse along 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 per second.

The human brain has approximately 100 billion nerve cells.
Of these:²
glutamatergic - approx. 20,000,000,000 (20 billion)
GABAergic - approx. 9,000,000,000 (8 billion)
serotonergic - approx. 250,000
dopaminergic - approx. 250,000², 400,000 to 600,000
noradrenergic - approx. 30,000 to 50,000

Contrary to earlier assumptions, neurons are not strictly limited to a single neurotransmitter. Many neurons take up and release several different neurotransmitters.³

Information is represented by the simultaneous (rhythmic) firing of a specific group of nerve cells.

(https://media.sketchfab.com/models/b7d5d0a1996a4eddaa44a631ebff6e4f/thumbnails/b9ccaa7964d4445c868b0ef519cbfb71/a53650d6fb914ac0a02986a2f86da90b.jpeg)
Schematic drawing of a nerve cell
[Nerve cell as a 3-D animation on DocCheck Flexikon]
Image of an axon

Basic text: Shadlen, Kandel (2021): Nerve Cells, Neural Circuity, and Behavior. In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.

Clusters of neurons are called nuclei in the CNS and ganglia in the PNS.

Neurogenesis is the formation of new neurons. The assumption, held until the end of the last millennium, that neurons could only form during the embryonic stage has been disproved.
The brains of adult rats generate up to 10,000 new neurons every day. Physical or mental activity increased this neurogenesis. Ethanol or cortisol (stress) reduced it or even led to apoptosis. These findings also apply to humans.
In mammals, neural stem cells are found in the hippocampus and the olfactory bulb. During the embryonic development of the brain, glial cells also function as stem cells.⁴

2. Glial cells¶

All cells in the nervous system that are not neurons are called glial cells.
The nervous system of vertebrates contains 2 to 10 times as many glial cells as neurons. According to recent studies, the ratio is 1 to 1⁵, or 2 glial cells for every 3 neurons.⁶
Glial cells do not send signals; instead, they support nerve cells.

2.1. Astrocytes (CNS) / Sheath cells (peripheral)¶

Star-shaped astrocytes are the largest glial cells. They supply neurons with nutrients via connections to blood vessels. Astrocytes play a key role in regulating fluid balance in the brain and help maintain potassium levels.
Astrocytes (astroglia) is the name given to these cells in the central nervous system. (Brain / spinal cord)
These cells are called mantle cells (satellite cells) when they occur in the body (peripherally).

Astrocytes and the factors they secrete (including thrombospondins 1 and 2, high endothelial venule protein (HEVIN), secreted acidic and cysteine-rich protein (SPARC), brain-derived neurotrophic factors (BDNF), transforming growth factor β (TGF-β), and γ-protocadherin) are essential for the formation of neurites and (particularly glutamatergic, but also GABAergic, cholinergic, and glycinergic) synapses in RGC neurons.⁷
ADHD is associated with changes in astrocytes:⁷

• Glutamate uptake by astrocytes via EAATs is impaired
  • this increases the number of excitatory synapses
• Activation of GABAB receptors in astrocytes upregulates TSP-1
  • this further increases the formation of excitatory synapses
• reduced lactate production in astrocytes
  • can impair the energy metabolism of neurons
• Dysfunction of astrocytes
  • compromise the integrity of the blood-brain barrier
• Increased cytokine release in reactive astrocytes
• Increased production of reactive oxygen species (ROS) in astrocytes
  • this increases oxidative stress and neuroinflammation

2.2. Oligodendrocytes (CNS) / Schwann cells (peripheral)¶

In the central nervous system, they form the myelin sheaths around axons. In the peripheral nervous system, these are called Schwann cells.
Oligodendrocytes form multiple myelin segments for several neurons, whereas Schwann cells form only one myelin segment between two Ranvier nodes.

2.3. Ependymal cells¶

They form a single-celled layer (the ependyma) in the ventricles of the central nervous system, which separates the cerebrospinal fluid (CSF) from the brain tissue.

2.4. Microglia¶

Microglia are immune effector cells in the central nervous system. They belong to the glial cell family only in a technical sense. More precisely, they are cells of the mononuclear phagocytic system.
They become active in response to disease or injury. They then multiply and engulf dead or dying neurons. Microglia can trigger inflammation.

Basic text: Stevens, Polleux, Barres (2021): The Cells of the Nervous System. In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.

3. Synapses¶

Synapses are the junctions through which nerve cells communicate with one another.
There are

• electrical synapses, which transmit electrical signals directly and therefore very quickly; however, this is only possible in smaller neurons, and
• chemical synapses, in which the signal is transmitted via neurotransmitters, which, first, allows for modulatory control and, second, amplifies the signal so that larger neurons can also be targeted.

While muscle cells are usually controlled excitatorily by a single motor neuron, and each individual signal causes muscle activation, neurons in the brain are interconnected in a complex and redundant manner; they can be connected in an excitatory or inhibitory manner and require the interaction of many signals (often 50 to 100).

For a fundamental discussion of this topic, see Yuste and Siegelbaum (2021): “Synaptic Integration in the Central Nervous System.” In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.

Symmetrical synapse (Type II synapse)⁸

• tends to have an inhibitory effect
  • mostly GABAergic
• flattened vesicles
• a less pronounced active zone
• a relatively narrow synaptic cleft
• the presynaptic and postsynaptic zones are approximately the same thickness
• usually near the soma (axodendritic, axosomatic, axoaxonal)

Asymmetric synapse (Type I synapse)⁸

• tends to have a stimulating effect
  • mostly glutamatergic
• round vesicles
• large active area
• synaptic cleft
• postsynaptic density
• If this is highly pronounced, it is referred to as an asymmetric synapse (also known as a Type I synapse)
• mostly axospinal

Tripartite Synapse (three-part synapse)⁹¹⁰
In addition to the two nerve cells (presynapse and postsynapse), astrocytes (a type of glial cell) are involved as a third active component:
Astrocytes use their fine processes to envelop the contact points of neurons and communicate with them in both directions: they take up neurotransmitters, release their own signaling molecules (gliatransmitters), and thereby regulate synaptic transmission and plasticity.

• Presynapse: Sends out chemical signals (neurotransmitters)
• Postsynapse: Receives the signals and transmits them
• Astrocyte: The surrounding glial cell that modulates the signal, supplies nutrients, and regulates the environment
  • Signal modulation through the amplification or attenuation of synaptic signals
  • Neurotransmitter buffering: uptake of neurotransmitters from the synaptic cleft
  • Energy metabolism: supplying neurons with lactate and regulating ion balance
  • Malfunctions in glial-neuronal communication may contribute to neuronal developmental disorders.¹¹

The previous three-part (tripartite) synapse model, which described interactions between presynaptic and postsynaptic neurons via perisynaptic astrocyte processes, has since been expanded into a four-part model.¹² In this model, microglia actively influence the formation, degradation, and efficacy of synapses through direct contact.¹³¹⁴
The concept of the “network synapse” integrates

• astrocyte processes
• perivascular microglia
• Endothelial cells
• Pericytes

4. Messenger substances: neurotransmitters, hormones¶

Neurotransmitters are chemical messengers that transmit information at chemical synapses between neurons. Examples include dopamine, norepinephrine, serotonin, acetylcholine, GABA, and glutamate. Different neurotransmitters have different functions in the brain, and their effects overlap.
When released at synapses, neurotransmitters facilitate or block the chemical transmission of signals between neurons (nerve cells).
Other signaling molecules, known as hormones, exert their effects slowly via the bloodstream on target organs located further away (e.g., adrenaline, cortisol, estradiol, insulin, testosterone, thyroxine, triiodothyronine).
Some substances act as both neurotransmitters and hormones (e.g., norepinephrine, serotonin, histamine). Some substances act as both neurotransmitters and hormones (e.g., norepinephrine, serotonin, histamine).

Neurotransmitters are typically synthesized in the cytosol of the cell nucleus, packaged into vesicles, and transported via the microtubules through the axons to the nerve terminals, where the presynaptic synapses are located. The transport speed in the axons varies depending on the substance and can reach up to 5 µm/second = approx. 40 cm/day.¹⁵ Some neurotransmitters are also synthesized only on demand at the axon terminals (e.g., endocannabinoids).
The release of neurotransmitters is triggered by an increase in intracellular Ca2+. The increase in intracellular Ca2+ is caused by depolarization of the presynaptic nerve terminals and an influx of Ca2+ through voltage-dependent Ca2+ channels (VDCCs).¹⁶
In response to the action potential, neurotransmitters are released from the nerve terminals into the synaptic cleft as the vesicles fuse with the membrane. The synaptic cleft is between 20 and 40 nm wide.¹⁷
In the synaptic cleft, they bind to postsynaptic receptors (and, in rare cases, “retrograde” to presynaptic receptors, such as endocannabinoids and nitric oxide) 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 sending cell by presynaptic transporters within or at the edge of the synaptic cleft. Within the cell, they are either stored again in vesicles until the next release or metabolized by degrading enzymes (e.g., dopamine and norepinephrine by monoamine oxidase and COMT).
Neurotransmitters that are not reabsorbed diffuse into the extracellular space, where they can bind to autoreceptors on the sending cell or to receptors or transporters on other cells.

The purpose of chemical signal transmission via neurotransmitters is to filter and modulate signals and to amplify the signal being transmitted.

Only the neurons that release a specific neurotransmitter contain all the proteins necessary for its synthesis.¹⁸

Depending on the receptor they bind to, neurotransmitters have an excitatory (activating) or inhibitory (suppressing) effect on the next neuron. Although dopamine and serotonin are primarily involved in transmitting inhibitory information, only the D2, D3, and D4 receptors are inhibitory (they inhibit the enzyme adenylate cyclase), while the D1 and D5 receptors have an activating (excitatory) effect (they activate the enzyme adenylate cyclase).

In ADHD, information transmission in the brain is primarily impaired in relation to the neurotransmitters dopamine and norepinephrine.

A detailed yet clear overview of neurotransmitter systems can be found in Hinghofer-Szalkay at physiologie.cc²⁵²⁶

5. Receptors¶

Receptors are binding sites for neurotransmitters. Depending on the receptor, a neurotransmitter can have an inhibitory or excitatory effect.

Ionotropic receptors
In these cases, the binding of a neurotransmitter directly causes an ion channel to open.

Metabotropic receptors
In these cases, the binding of a neurotransmitter triggers the activation of second messengers, which in turn can activate a number of transport channels.
All dopamine and norepinephrine receptors are metabotropic.

For a fundamental discussion of this topic, see Siegelbaum, Clapham, Marker (2021): “Modulation of Synaptic Transmission and Neuronal Excitability: Second Messengers.” In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.

Excitatory and inhibitory receptors.
Receptors for the same neurotransmitter can have both excitatory (increasing postsynaptic nerve activity) and inhibitory (decreasing postsynaptic nerve activity) effects.
However, neither the firing of neurons nor the type of neurotransmitter indicates whether a signal is intended to be activating (excitatory) or inhibiting (inhibitory).

5.1. Agonists and antagonists¶

Ligands are substances that bind to receptors.
Biased ligands are ligands that trigger signaling in receptors only through specific signaling pathways. G-protein-coupled receptors transmit their signal via various G-proteins (GTPases; 20 trimers and more than a hundred “small” G-proteins). Biased ligands trigger only individual G-protein signaling pathways.

Agonist: Binding to the receptor activates it and triggers the receptor signal.
Conventional agonist: increases the proportion of activated receptors.

Partial agonist: an agonist with low potency.
Some agonists act as partial agonists in one tissue and as full agonists in another.

Inverse agonist: Binds to a spontaneously active receptor and reduces its activity. Example: Antihistamines.
Spontaneously active receptors are those that send signals even in the absence of a stimulus.

Antagonist: binds to a receptor without exerting any effect itself. This prevents the receptor from being activated by other substances.
Antagonists, which block the effects of a substance that normally impairs cellular function, enhance cellular function.
Antagonists, which block the effects of a substance that normally enhances cellular function, reduce cellular function.

Reversible antagonist: Easily dissociates from the receptor after binding to it.
Irreversible antagonist: Does not dissociate from the receptor because it forms a stable, permanent, or nearly permanent chemical bond (e.g., through alkylation).
Pseudo-irreversible antagonist: dissociates slowly from its receptor.

Competitive antagonist: prevents an agonist from binding to the receptor.
Non-competitive antagonist: can bind to both the agonist and the antagonist simultaneously. Binding of the antagonist reduces or blocks the effect of the agonist.
Reversible competitive antagonist: The agonist and antagonist form short-lived bonds with the receptor. An equilibrium is established between the agonist and antagonist at the receptor.
An increase in the concentration of the agonist can overcome reversible competitive antagonism.
Example: The opioid receptor antagonist naloxone, when administered shortly before the agonist morphine, blocks the effect of the agonist morphine. Increasing the dose of the agonist morphine can overcome the competitive antagonism caused by naloxone.
Irreversible antagonism is a subtype of non-competitive antagonism.

Neutral antagonist: has the same affinity for both the active and inactive receptor states and does not interfere with the cell’s basal activity.

Agonist-antagonist: acts as both an agonist and an antagonist
Structural analogs of agonists often exhibit this property.
Example: Pentazocine activates opioid receptors while simultaneously blocking their activation by other opioids. As a result, pentazocine itself has an opioid-like effect, but it weakens the effects of other opioids as long as it remains bound to the receptors.

G protein-coupled receptors can adopt different conformational states depending on the ligand that binds to them.²⁷

5.2. Constitutive activity¶

A receptor does not always require an agonist to enter an active conformational state in which elevated baseline levels of intracellular signaling are maintained.
Many GPC receptors (e.g., CB1R) exhibit a high degree of constitutive activity.
The two-state model of receptor activation explains this:
Receptors exist in a state of equilibrium between the active and inactive states. An agonist stabilizes the active state, leading to activation; a neutral antagonist binds equally to both the active and inactive states; while an inverse agonist preferentially stabilizes the inactive state.

5.3. Allosteric modulators¶

Receptors can have different binding sites. Agonists (which activate the receptor) and antagonists (which inhibit the receptor) bind to the orthosteric binding site. At the allosteric binding site, modulators can bind, which can either increase or decrease the receptor’s effect if an agonist binds to it.
An allosteric modulator thus alters the effects of an orthosteric ligand (e.g., an agonist or inverse agonist) on a target protein (usually a receptor) by binding to a different (allosteric) binding site than the orthosteric agonist binding site. This causes a conformational change in the receptor protein, which alters the receptor affinity or the efficacy of the orthosteric ligand.

Positive allosteric modulator (PAM): enhances the effect of an agonist or inverse agonist.
Negative allosteric modulator (NAM): weakens the effect of an agonist or inverse agonist without exerting an effect itself.
Silent modulator (SAM): Binds to the allosteric binding site without affecting the action of agonists or inverse agonists.

Allosteric agonist: Activates a receptor in the absence of an orthosteric ligand by binding to an allosteric binding site
Ago-allosteric modulator: acts both as an allosteric agonist (activator) and as an allosteric modulator. Example: injectable barbiturates

On-target allosteric modulation: The modulator binds to the same protein as the orthosteric ligand
Off-target allosteric modulation: A modulator binds to a partner protein. Example: GPCR oligomers.

5.4. Downregulation, Upregulation, Desensitization¶

The receptors for dopamine, norepinephrine, cannabinoids, adenosine, serotonin, and opioids, among others, are members of the GPCR family. GPCRs often undergo dynamic changes in their activity.
A lack of agonists can lead to upregulation
A prolonged excess of agonists can lead to desensitization and downregulation.²⁸
Agonists can trigger time- and temperature-dependent endocytosis (internalization). During endocytosis, some receptor proteins are reintegrated into the cell membrane (recycling), while others are sorted out and degraded by lysosomes, which reduces the number of receptors.²⁹³⁰

Homologous Desensitization
The receptor that has bound a ligand is phosphorylated by a kinase (G-protein-coupled receptor kinase, GRK). This phosphorylation stabilizes the interaction between the receptor and arrestins. This prevents interaction with the G protein and interrupts signal transduction.

Heterologous desensitization
A receptor’s signaling pathway is interrupted or attenuated (regardless of ligand binding) due to the activation of other receptors on the cell surface. The activated receptors activate second messenger kinases (e.g., protein kinase A, protein kinase C), which phosphorylate not the activated receptor itself, but other receptors.

6. Action potential¶

Neurons transmit signals by generating an action potential.
At rest, neurons maintain an internal potential that is, on average, 65 mV lower than that of the extracellular space (ranging from 45 to 90 mV depending on the cell type). This voltage difference arises when the so-called sodium-potassium pump (sodium-potassium ATPase, a membrane protein) exchanges sodium ions from the cell interior for potassium ions from the extracellular space. Through potassium-permeable ion channels in the otherwise impermeable cell membrane, the potassium ions —following the concentration gradient—slowly leave the cell again, leaving behind a non-neutralized negative charge on the inner surface of the cell membrane, which is typically around -65 mV.
At rest, cells contain about one-tenth as many sodium ions and 20 times as many potassium ions as the extracellular space. Extracellular sodium and potassium ion levels are maintained by the kidneys and astrocytes. If sodium or calcium ions enter the cell, its voltage increases.
An action potential (a rapid rise in voltage 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 influx of sodium ions further increases the cell membrane’s permeability to sodium ions, allowing more and more sodium ions to enter. This causes the negative voltage to drop abruptly and even briefly (for about 1 ms) reverse to a positive value of +40 mV (“overshoot”). The action potential now travels along the axon at a speed of 1 to 100 meters per second to the terminals, where it opens ion channels.

The action potential is an all-or-nothing process. Once it is triggered, it always reaches its full intensity, regardless of whether the threshold is just barely exceeded or significantly exceeded.
The action potential remains constant throughout the axon. To achieve this, it is amplified at the nodes of Ranvier.

Once the peak voltage is reached, the cell returns to its resting potential (repolarization) as sodium channels close and potassium channels open.
In this process, the membrane potential initially becomes even more negative than the original resting potential (hyperpolarization). The cell then returns to its starting point (resting potential).
After firing an action potential, a neuron enters a resting phase known as the refractory period.

Phases of the action potential:³¹

• Initial phase
  • The voltage rises (slowly or quickly) toward 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, the result is only a temporary, reversible change in the membrane potential
• Spread
  • Complete depolarization occurs only and exclusively when the threshold potential is reached
  • Consequences:
    • The voltage-gated sodium channels open, allowing Na+ ions to flow rapidly from the extracellular space into the neuron’s cytosol
    • Meanwhile, the potassium channels are closed
    • A positive feedback mechanism ultimately even causes a charge reversal (“overshoot”).
• Repolarization
  • Sodium channels begin to close again even before the peak potential is reached
  • The voltage-gated potassium channels open, allowing K+ ions to flow from the interior of the cell into the extracellular space
  • The conductance of the potassium channels reaches its maximum when almost all sodium channels are already inactivated
  • During repolarization, the membrane potential returns toward the resting potential, causing the potassium channels to close while the sodium channels are slowly reactivated.
• Hyperpolarization
  • Potassium channels close within 1 to 2 ms, which is slower 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 period: The period shortly after overshoot, before repolarization is complete. Action potentials cannot be triggered.
  • Relative refractory period: The threshold for triggering an action potential is elevated

While the action potential is always of the same amplitude and is the only outgoing impulse from a neuron, there are two types of excitatory impulses:

• the synaptic signal
• the receptor signal.
  Both are graded by intensity.

Receptor signals are triggered, for example, by peripheral sensory stimuli. A receptor signal corresponds in duration and strength to the intensity of the stimulus, but is relatively weak overall. It travels only a few millimeters within the neuron. After traveling just one millimeter, it has already lost two-thirds of its energy. If it reaches a Ranvier node within its range with sufficient strength, the node’s amplifying effect triggers a full action potential, allowing the sensory stimulus to reach the spinal cord.

Synaptic signals are triggered by neurotransmitters binding to receptor synapses on dendrites. Like receptor signals, they are gradual in nature, depending on the number of activated receptors. Synaptic signals are summed at the neuron’s axon hillock. If the sum exceeds the threshold, the action potential is triggered.

Even though an action potential always has the same amplitude, the frequency and rate at which it occurs can result in a gradually varying release of neurotransmitters, thereby transmitting signals of varying strength to the postsynaptic cells. If an action potential is triggered only once. The more frequently and rapidly the action potential is triggered in succession, the greater the amount of neurotransmitter released, which leads to a higher number of postsynaptically targeted receptors.

For a fundamental discussion of this topic, see Koester and Siegelbaum (2021): “Membrane Potential and the Passive Electrical Properties of the Neuron.” In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science as well as Bean, Koester (2021): Propagated Signaling: The Action Potential. In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.

7. Blood-brain barrier¶

The human brain is crisscrossed by approximately 600 km of blood vessels.
Blood vessels in the brain have special cells in their walls that prevent certain substances—which are harmless in the body (peripherally)—from disrupting the complex and delicate processes of the brain (centrally), and that neurotransmitters and potassium leak from the extracellular brain fluid into the blood.
Only fat-soluble substances with a molecular weight below 500 Da can diffuse across the blood-brain barrier, such as nicotine, alcohol, blood gases, or anesthetics like halothane, but not ions or polar substances like glucose. The latter rely on specific transport systems that thus perform a regulatory and filtering function.³²

8. Synaptic plasticity: learning and unlearning¶

Synaptic plasticity refers to the brain’s ability to form new connections between neurons—which ultimately represent knowledge and experience—and to break them down again. Synaptic plasticity also involves increasing or decreasing the activity and stability of neural firing.
Different types of synaptic plasticity include:

• Short-term plasticity: changes in synaptic activity over a time scale ranging from milliseconds to seconds
• Long-term plasticity: changes in synaptic activity over hours, days, or longer
• Structural plasticity: Changes in the number and organization of synapses
• Functional plasticity: Changes in the release and modulation of neurotransmitters
• Presynaptic plasticity: Adaptive mechanisms for modulating synaptic transmission at the presynapse

8.1. Short-term plasticity¶

8.1.1. Depolarization induces disinhibition (DSI) or excitation (DSE)¶

Depolarization caused by strong activation (repeated action potentials or a step depolarization) induces a temporary suppression of inhibition (DSI) or excitation (DSE) in many neurons.³³
This inhibition suppression lasts for several dozen seconds.
Inhibitory synapses are more sensitive to depolarization-induced suppression of synaptic transmission than excitatory synapses.
DSE relies on a functional endocannabinoid transporter.³⁴

8.1.2. Metabotropic-induced suppression of inhibition (MSI) or excitation (MSE)¶

Metabotropic (via a metabolic process) inhibition (MSI) or excitation (MSE) are forms of synaptic short-term plasticity.³³

MSI and MSE are triggered by a variety of Gq/11-coupled GPCRs, including mGluR1, mGluR5, M1, M3, orexin A, CCKA, and α1-adrenergic receptors.

8.2. Long-term plasticity¶

8.2.1. Long-term potentiation (LTP)¶

Long-term potentiation (LTP) is a universal form of long-lasting strengthening of synaptic connections.
LTP can be caused by

• increased generation of action potentials
• improved communication between two cells
• Enlargement of synapses
• Emergence of new channels
• Increased release of neurotransmitters

8.2.2. Long-term depression (LTD)¶

Long-term depression (LTD) is a universal form of long-lasting reduction in synaptic connections that lasts from tens of minutes to several hours or longer.³⁵
Homosynaptic LTD: Affects only the synapse that is targeted by sustained low-frequency activity from the presynaptic neuron. It particularly affects glutamatergic synapses in the dorsal and ventral striatum.³³
Heterosynaptic LTD: also affects inactive neurons. The attenuation of the signal is controlled by an adjacent modulatory interneuron and does not depend on the activity of the presynaptic or postsynaptic neuron. For example, stimulation of the Schaffer collaterals in CA1 of the hippocampus causes a sustained reduction in GABAergic inhibition of CA1 pyramidal neurons.³³
Autaptic LTD: Autaptic neurons exhibit both endocannabinoid-mediated DSE and MSE. Autaptic LTD is CB1R-dependent, although it is induced not via the G(i/o) or G(s) proteins typically activated by CB1R, but via G(q) proteins.³⁵

8.2.3. Slow self-inhibition (SSI)¶

Slow self-inhibition (SSI) is a process that suppresses neuronal excitability. SSI occurs primarily in low-threshold spiking cortical interneurons and cerebellar basket cells, but also in some cortical principal cells.³³

9. The Nervous System - Structure and Regions¶

The nervous system consists of the central nervous system (CNS, the brain and spinal cord) and the peripheral nervous system (PNS, the rest of the body).

Over the course of evolution, various areas of the brain have gradually developed; we present them below in order from oldest to newest.
Fundamentals of the human brain: Kandel, Shadlen (2021): The Brain and Behavior. In: Kandel, Koester, Mack, Siegelbaum (2021): Principles of Neuronal Science.

9.1. Peripheral nervous system¶

The nerves of the peripheral nervous system originate from the spinal cord and the 12 pairs of cranial nerves.
The 12 cranial nerves are:

1. Olfactory nerve (transmits signals from the nose to the brain)
2. Optic nerve (transmits signals from the retina to the brain)
3. Oculomotor nerve (controls eye movements, the levator muscle, and the iris)
4. Trochlear nerve (controls the superior oblique muscle)
5. Trigeminal nerve (transmits sensory information from the face to the brain and innervates the masticatory muscles)
   5.1. Ophthalmic nerve
   5.2. Maxillary nerve
   5.3. Mandibular nerve
6. Abducens nerve (innervates the lateral eye muscle)
7. Facial nerve (controls the facial muscles and the stapedius muscle; mediates taste perception in the anterior two-thirds of the tongue; innervates all glands of the head except the parotid gland)
8. Vestibulocochlear nerve (transmits information from the cochlea and the vestibular system)
9. Glossopharyngeal nerve (Transmits signals from the back of the tongue to the brain; innervates the muscles of the pharynx [involved in swallowing]; innervates the parotid gland)
10. Vagus nerve (the main nerve of the parasympathetic nervous system; involved in the regulation of many internal organs)
11. Accessory nerve (supplies motor innervation to the trapezius muscle and the sternocleidomastoid muscle)
12. Hypoglossal nerve (controls tongue movement)

9.1.1. Somatic nervous system¶

The somatic nervous system (SNS) interacts with the external environment.
Afferent nerves transmit sensory signals—for example, from the skin, skeletal muscles, joints, eyes, and ears—to the central nervous system (triggering emotional responses)
Efferent nerves transmit motor signals from the CNS to the skeletal muscles (triggering motor responses).

9.1.2. Autonomic nervous system¶

The autonomic nervous system (ANS) regulates the body’s internal environment.
Afferent nerves transmit sensory signals from internal organs to the central nervous system (triggering emotional responses).
Efferent nerves (sympathetic and parasympathetic nervous systems) transmit motor signals from the central nervous system to the internal organs (triggering motor responses).
Every autonomic organ receives stimulating sympathetic and calming parasympathetic input. The ratio of sympathetic to parasympathetic input controls the organ’s activity.

For more details, see The autonomic nervous system: sympathetic / parasympathetic

9.1.2.1. Sympathetic nervous system¶

The sympathetic nerves extend from the thoracic and lumbar spine into the body.
switching (via synapses to other neurons) further away from the target organs.

Activate energy reserves in threatening situations (tension).

9.1.2.2. Parasympathetic nervous system¶

The parasympathetic nerves extend from the brain and the sacral (lower back)
(vertebral) regions of the spine.
Rewiring (via synapses to other neurons) near the target organs.

Conserve energy in calm situations (relaxation).

9.2. Central nervous system¶

9.2.1. Spinal cord¶

The spinal cord (medulla spinalis) receives and processes sensory and peripheral stimuli.

9.2.2. Brain¶

The brain is also called the encephalon.
It consists of various functionally separate parts that are connected to one another.

9.2.2.1. Brainstem¶

The embryonic hindbrain (metencephalon) develops into the pons and the cerebellum.
The hindbrain and brainstem together form the rhombencephalon.

The brainstem (truncus encephali) is the oldest part of the brain in evolutionary terms.

• processes and integrates incoming sensory input and outgoing motor information
• responsible for basic and reflexive control mechanisms
• the lowest part of the brain, directly adjacent to the spinal cord
• consisting of
  • Midbrain (mesencephalon)
  • Bridge (Pons)
  • Medulla oblongata (medulla; hindbrain; myelencephalon)
    • including the reticular formation (ascending reticular activating system)
      • consists of about 100 cores
        • Attention
        • Sleep
        • Exercise
        • Muscle tone
        • Reflexes
          • Heart
          • Circulation
          • Breathing
    • This is where the hemispheric nerve pathways cross
    • controls many automated processes such as
      • Heartbeat
      • Breathing
      • Metabolism
      • Reflex centers, e.g., for
        • Eyelid closure
        • Swallowing
        • Cough

The brainstem as a 3-D animation on dasGehirn.info
The midbrain as a 3-D animation on dasGehirn.info
The medulla oblongata as a 3-D animation on dasGehirn.info

9.2.2.2. Cerebellum¶

Distinguishes between the two hemispheres
Responsible for

• Balance
• Movements
• Motor coordination
• unconscious learning
  • Language acquisition
  • social learning

The cerebellum as a 3-D animation on dasGehirn.info

9.2.2.4. Diencephalon¶

The diencephalon is involved in

• Sleep-wake regulation (see ARAS, pain perception, temperature regulation).

The diencephalon consists of:

Thalamus (upper part)

• transmits sensory and motor signals to and from the cerebrum
• collects all information from the sensory organs and transmits it
• consists mainly of gray matter

hypothalamus

• regulates numerous physical and mental processes
• is regulated partly by the nervous system via the autonomic nervous system and partly by hormones via the bloodstream
• connected to the pituitary gland

The hypothalamus and pituitary gland serve as the central link between the endocrine and nervous systems.

Subthalamus (central thalamus)

• consisting of
  • Subthalamic nucleus
  • Pallidum (not to be confused with the globus pallidus)
• Control of gross motor skills

Epithalamus

• consisting of
  • Pineal gland (epiphysis, corpus pineale, glandula pinealis)
  • Subcommissural organ (Organum subcommissurale)
  • Commissura habenularum
  • Posterior commissure (epithalamic commissure)
  • Habenae (reins)
  • Prefrontal area

The diencephalon as a 3-D animation on dasGehirn.info.

9.2.2.5. Cerebrum (Cortex cerebri, Cerebrum, Telencephalon)¶

Parts of the cerebrum include:

Cerebral cortex (Cortex cerebri)³⁶

• The outer layer of the cerebrum
• 2–4 mm thick
• tightly folded (like a cloth in a glass)
• just under a quarter of a square meter
• contains approximately 16–³⁷ s or 19 billion (in women) to 23 billion in men³⁸(ca. 20 % des gesamten Gehirns)
• Cell layers according to their developmental age³⁹
  • Allocortex (older; e.g., hippocampus): 3 layers. From the outside in:
    • Archicortex
      • Molecular layer (Lamina molecularis)
      • Pyramid cell layer (lamina pyramidalis)
      • polymorphic layer (lamina multiformis)
    • Paleocortex
      • three to five cell layers
      • primarily processes smell and taste
  • Mesocortex
    • An intermediate form between the allocortex and the isocortex
    • three to six layers
    • is located in the insula, cingulate gyrus, and parahippocampal gyrus
  • Isocortex (the more recent part, neocortex; 90% of the human cortex): 6 layers. From the outside in:
    • Molecular layer (Lamina molecularis)
    • Outer granular layer (Lamina granularis externa)
    • Outer pyramidal cell layer (Lamina pyramidalis externa)
    • Inner granular layer (lamina granularis interna)
    • Inner pyramidal cell layer (lamina pyramidalis interna)
    • polymorphic layer (lamina multiformis)
• is divided into two hemispheres
  • Each hemisphere is divided into four cerebral lobes
    • frontal (PFC)
      • higher-order cognitive processes
      • Assessment of voluntary motor skills, attention, short-term memory tasks, motivation, and planning
    • parietal (parietal lobe, top)
      • somatosensory functions
      • visual control of movements and detection of stimuli in the environment
      • spatial reasoning and “quasi-spatial” processes such as arithmetic and reading
      • Natural language processing
      • The interface between the sensory systems (particularly 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 (temporal lobe)
      • auditory cortex (acoustic processing)
      • Interpretation of information based on visual memory and language comprehension

The cerebral cortex as a 3-D animation on dasGehirn.info

Corpus callosum (corpus callosum)

• thick nerve bundle
• connects the two hemispheres

The corpus callosum as a 3-D animation on dasGehirn.info

Cingulate gyrus

• lies dorsal to the corpus callosum
• Emotion
• Sensation of pain
• Cognition

Insula

• Emotion
• Homeostasis
• Sense of taste

The Insula as a 3-D animation on dasGehirn.info

basal ganglia

• consisting of
  • dorsal striatum
    • Caudate nucleus
    • Inner capsule (in adulthood)
    • Putamen
  • Globus pallidus (not to be confused with pallidum)
    • Together with the pars reticularis of the substantia nigra, it forms the primary origin of the basal ganglia
• regulates
  • Movement execution
  • implicit memory
    • motor learning
    • Habit-based learning

The basal ganglia as a 3-D animation on dasGehirn.info

Hippocampus

• regulates explicit memory
  • Memories of people, places, things, and events

The hippocampus as a 3-D animation on dasGehirn.info

Amygdala

• coordinates the autonomic and endocrine responses to emotional states
• including fear memory (a component of implicit memory)

The Amygdala as a 3-D animation on dasGehirn.info.

From an anatomical perspective, further distinctions can be made:

White matter

• the myelinated nerve fibers
• run beneath the bark

Gray matter

• Clusters of nerve cell bodies
  • pink in the living brain
  • gray in a dead brain

The limbic system as a 3-D animation on dasGehirn.info

9.2.3. Connectome¶

The connectome is the totality of neural connections between different (brain) structures.

10. Brain Regions and Functions - Hardware and Software¶

Although individual brain regions have specific functions, there is no clear one-to-one correspondence.
Simple reflexes are still quite clearly controlled by specific regions of the brain. The more complex a behavioral function is, the more it relies on the interaction of multiple brain regions—this is referred to as brain networks.
It helps an individual survive when important functions can be controlled by different regions of the brain (redundancy). This means that functions that are lost (e.g., when a region of the brain is damaged by a stroke) can be taken over by other regions of the brain (flexibility).
Without another region of the brain taking over control of the impaired function, it would indeed be possible to compensate for the deterioration or total loss of a function by shifting survival strategies toward increased use of other abilities (behavioral change). However, it is much easier to maintain a behavior that has already been successfully learned, as important functions can be sustained because they are represented by more than just one brain region, and only the control of the function needs to be relearned.

This also explains why it is difficult to attribute certain functional impairments to defects in specific regions of the brain. This is particularly true of mechanisms that do not represent a specific bodily function.
The problems associated with ADHD tend to involve mechanisms for the long-term regulation of behavior and cannot be attributed to specific structural defects in individual brain regions.

11. Cognition and emotion, thoughts and feelings¶

An analytical understanding of the environment helps us form a conceptual model of it. This allows us to visualize in our minds—and store in our memory—not only the elements that make up the environment, but also the mechanisms by which these elements interact and influence one another.
Thanks to our ability to think abstractly and simplify (by grouping elements with shared characteristics and distilling interaction mechanisms into common rules), we can store far more information and make predictions about possible connections that we have not yet personally experienced in specific, individual instances. This means it is not necessary to have seen every existing species of snake once in order to recognize it. It is sufficient to know the characteristics of snakes (elongated, no legs, often found in forests or fields, usually on the ground) to recognize even unknown snakes as such. Similarly, it is sufficient to know the venomous nature of some of them to be able to infer a risk from a snake species one has never seen before.

Cognition and analysis are processed in the brain by its most recently evolved region, the prefrontal cortex (PFC). Its analytical view of the world can perhaps be compared to looking through a microscope. This view reveals a vast amount of detail, allowing for far more conclusions than would be possible without this magnification.
However, such a detailed view is of very limited use when it comes to managing one’s own behavior. Trying to manage one’s entire life through constant analysis would be far too time-consuming. There would be far too much data to evaluate all at once. As valuable as a microscope is for examining details, it would be overwhelming to use it to examine all the information—for example, during a social evening at a bar—all at once.

If the PFC were to control all actions on its own, it would be completely overwhelmed. To avoid this, we store cognitively learned information (knowledge) and actions performed consciously (under the control of the PFC) as automatic responses. To form a habit, an action generally needs to be practiced for 4 to 6 weeks. Through practice and automation, control of the action is transferred from the PFC to other, posterior brain regions. Once a habit is formed and an action is automated, the PFC can devote itself to other tasks and generate new knowledge.
However, automatic responses and habits are not entirely beyond our control. Controlling them, however, is far less complex and detailed. This control mechanism is our emotions. Emotions react very quickly, but also very roughly. Emotions subconsciously steer the individual toward safe areas.
When emotions intensify—for example, because something particularly pleasant or troubling happens—they become palpable. Feelings (the physical sensation of emotions) signal these emotions to our conscious mind, thereby creating the opportunity for cognitive influence.
The better these automatic responses are trained, and the more conscious corrections and refinements they have undergone, the better they can meet the demands placed on the individual. People who have devoted many years to a particular area of life, who have practiced extensively, and who have repeatedly subjected the results of their emotion-driven (hypothetical or actual) actions repeatedly scrutinized under the microscope of the PFC and made corrections to improve the results, possess highly trained automatic responses in this area—a sharpened intuition. Specialists in demanding professions (doctors, technicians, lawyers, mathematicians) are well acquainted with having to assess something and feeling: “According to the known rules, this should work this way. But something isn’t right here…”, without being able to immediately explain what it is. Only after some cognitive, analytical engagement with the matter do they realize what particularity is at play that requires a deviation from the general rules.

Automation is the consequence of densely formed synaptic connections. Cells that fire together, wire together. This synchronized firing is initially controlled by the brain. If it continues long enough, the active brain neurons form connections with one another, so that they require less cognitive guidance to fire together.
The formation of synaptic connections between neurons and their synchronized firing is facilitated by LTP (long-term potentiation). LTP represents the neural correlate of learning. LTD (long-term depression), on the other hand, helps us break habits and stop automatic behaviors (roughly speaking: forgetting)—by weakening connections between neurons and inhibiting their synchronized firing.

12. Conditioning¶

12.1. Classical conditioning¶

Along with an unconditioned stimulus (e.g., food) that triggers an unconditioned response (e.g., salivation), a neutral (essentially irrelevant) stimulus (e.g., the ringing of a bell) is repeatedly presented.
Through classical conditioning, the neutral stimulus is associated with the unconditioned response, so that after a few repetitions, the neutral stimulus (bell) triggers the previously unconditioned response (salivation), thereby becoming a conditioned response (here: Pavlovian reflex).

Conditioning generally requires:

• frequent repetitions
• Simultaneity of the unconditioned and neutral stimuli (temporal contiguity)

Exceptions include, for example: conditioned taste aversion, conditioned defensive burying

12.2. Operant conditioning¶

Reinforcement (through pleasant stimuli) or extinction (through unpleasant stimuli) of a randomly occurring action (e.g., pressing a button)

12.3. Conditioned taste aversion¶

It is important for living beings to avoid food that is indigestible, toxic, or disease-causing,
Many living organisms are neophobic, meaning they avoid new experiences in order to minimize risks.
Rodents only taste small amounts of unfamiliar foods. If they become ill afterward, they will avoid those foods in the future, even if the illness was not directly caused by the food. A single experience or conditioning is sufficient for this to occur.
In humans, for example, nausea caused by chemotherapy or excessive alcohol consumption can lead to an aversion to foods previously consumed.⁶

12.4. Conditioned defensive burrowing¶

Objects that startle rodents with mild shocks trigger a reflex in them to bury the object.
Example: A tube that protrudes from the wall just above the litter-covered floor and causes fear with a burst of air or a foul odor is covered with a pile of litter.

13. Imaging techniques¶

13.1. Computed Tomography (CT)¶

A CT scan is an X-ray-based imaging technique. It is fast, widely used, and helpful in cases of acute bleeding or head injuries.

13.2. Magnetic Resonance Imaging (MRI)¶

Structural MRI uses magnetic fields and radio waves to image soft tissues. It offers high resolution and involves no radiation exposure.

Specialized MRI techniques include:

• Diffusion-weighted MRI (DWI)
  • identifies pathways along which water molecules diffuse more quickly
  • This occurs primarily along nerve pathways (bundles of axons)
• Perfusion MRI
• Magnetic resonance angiography (MRA)
• Tractography (DTI)

13.3. Functional MRI (fMRI)¶

fMRI measures changes in blood oxygen levels (the BOLD signal), typically to visualize areas of the brain that are active during tasks such as speech, movement, or planning actions.
Low temporal resolution of 2 to 3 seconds, making it very imprecise in neurological terms.

13.4. Functional near-infrared spectroscopy (fNIRS)¶

Other names for NIRS: Near-Infrared Imaging (NIRI), Diffuse Optical Imaging (DOI), Diffuse Optical Tomography (DOT), Near-Infrared Tomography (NIT), Near-Infrared Neuroimaging (NIN), Event-Related Optical Signals (EROS).

fNIRS is similar to fMRI, but it is an optical imaging technique. fNIRS measures blood oxygen levels in the brain through the skull.
Infrared light (between 600 and 1000 nm) penetrates biological tissue relatively well. Since oxygenated and deoxygenated hemoglobin have specific absorption spectra in the same spectral range, fNIRS can measure changes in the concentration of oxygenated and deoxygenated blood in specific brain regions and use this to map the activity of these brain regions.
Although its temporal and spatial resolution is lower than that of an EEG, it is free from interference caused by cables.

13.5. Positron Emission Tomography (PET)¶

PET uses radioactively labeled substances (tracers) to visualize metabolic activity, particularly in the diagnosis of tumors, dementia, or Alzheimer’s disease.

13.6. Single-Photon Emission Computed Tomography (SPECT)¶

SPECT is a nuclear medicine imaging technique that can produce three-dimensional images of functional metabolic processes in organs. After a radiolabeled tracer is administered, its distribution in the body is detected using a rotating gamma camera and processed into cross-sectional images.

13.7. SPECT-CT¶

SPECT-CT complements SPECT by fusing functional SPECT images with anatomical CT images, thereby improving the accuracy of localization.

13.8. Ultrasound (Sonography)¶

High-frequency sound waves are used to create a non-invasive image based on the different ways sound is reflected by various types of tissue and bone.

13.9. Angiography (digital subtraction angiography, DSA)¶

DSA is an invasive procedure that involves the administration of contrast dye.

The gold standard for imaging blood vessels (e.g., in cases of aneurysms or stenosis).

13.10. Myelography¶

Myelography is an X-ray examination of the spinal cord that uses contrast agents injected into the subarachnoid space. It has largely been replaced by MRI.

14. Physiological measurement methods¶

14.1. Electrocardiography (ECG)¶

Measurement and recording of the sum vector of the electrical activity of cardiac muscle fibers.

14.2. Electroencephalography (EEG)¶

An EEG measures the brain’s overall electrical activity using electrodes attached to the scalp.
In addition, there are also invasive EEG procedures, but these are relevant only in specific cases and in research.

14.3. Magnetoencephalography (MEG)¶

MEG measures changes in the magnetic fields on the scalp. These changes reflect patterns of neural activity near the surface of the skull.
The spatial resolution is higher than that of an EEG.
Imaging of subcortical activity is more reliable than that of an EEG.
Unfortunately, MEG is very expensive and has limited applications due to the need for patients to remain motionless.

14.4. Electromyography (EMG)¶

EMG is the standard method for measuring muscle tension.

14.5. Electrooculography (EOG)¶

Measurement of eye movements and changes in the resting potential of the retina. Displayed in the form of an electrooculogram.
During jerky horizontal eye movements, electrical voltage fluctuations can be recorded from the skin to the right and left of the eye. The magnitude of these potential fluctuations, or their increase during the transition from a 12-minute dark adaptation to a bright environment, reflects the function of certain retinal layers, particularly the pigment epithelium.

15. Pharmacological measurement methods¶

15.1. Immunocytochemistry¶

Using specially engineered antibodies that react only to specific individual neuropeptides and are conjugated with dyes or radioactive tracers, it is possible to locate the relevant neuropeptides in the brain.
Since only those neurons that produce a neurotransmitter also contain the enzymes required for its synthesis, antibodies specific to neurotransmitter-related enzymes can be used to label the respective neurons; for example, noradrenergic neurons can be labeled using antibodies against dopamine-beta-hydroxylase, which converts dopamine to norepinephrine.⁶

15.2. In situ hybridization¶

All peptides and proteins are synthesized on messenger RNA (mRNA) strands based on nucleotide base sequences. The nucleotide base sequences of many neuroproteins are known, so hybrid mRNA strands with complementary base sequences can be artificially produced.
In in situ hybridization, hybrid RNA strands with a base sequence complementary to the mRNA that synthesizes the target neuroprotein are labeled with a dye or a radioactive tracer. In brain sections, the introduced labeled hybrid RNA strands bind to the complementary mRNA strands, thereby marking the location of the neurons that synthesize the target protein.

15.3. Chemical lesion¶

Some substances are toxic only to very specific neurons. For example, the neurotoxin 6-OHDA (6-hydroxydopamine) is taken up only by noradrenergic and dopaminergic neurons, allowing for the selective chemical destruction of these neurons. The axons of other neurons that pass through the affected area remain unharmed.

15.4. 2-Deoxyglucose¶

2-Deoxyglucose (2-DG) has a chemical structure similar to that of glucose. Active neurons therefore absorb more 2-DG than inactive neurons, without being able to metabolize it, causing 2-DG to accumulate within them. When 2-DG is radioactively labeled, it can be used to identify neurons that are active in specific contexts (behavioral tasks).

16. Genetic engineering¶

16.1. Gene knockout¶

In gene knockout, individual genes are completely deactivated through gene targeting. To do this, genetically modified embryonic stem cells are introduced into the germline.

16.2. Gene knock-in¶

In gene editing, a new or modified DNA sequence is inserted into the genome by introducing manipulated embryonic stem cells into the germline.
This allows genes to be inserted or replaced with other gene variants.

16.3. Gene editing¶

CRISPR/Cas9 (CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; Cas: CRISPR-associated) is a molecular biology technique that allows DNA to be precisely cut and modified. Using CRISPR/Cas, genes can be inserted, removed, or silenced, and nucleotides within a gene can be altered. The epigenome can also be modified.

16.4. Optogenetics¶

Targeted depolarization and polarization of neurons using opsins. Opsins (channelrhodopsins) are ion channels that open in response to light.

17. Methods of taking medication¶

Pharmacological substances (medications) can be administered in many different ways:⁴⁰

• enteral (through the digestive tract)
• parenteral (outside the digestive tract)
  • avoid the first-pass effect of hepatic metabolism, which frequently occurs with oral administration
    • therefore generally result in higher bioavailability
  • avoid unpredictable effects associated with enteral absorption processes
• oral (by mouth)
• directly into the stomach (nasogastric tube)
• intravenously (into a blood vessel)
• epicutaneous (on the skin)
• intradermal (into the skin)
• subcutaneous (under the skin)
• transdermal (through the skin, e.g., patches)
• intramuscular (into the muscle)
• transcorneal (on the eye)
• intraocular (or into the eye)
• intracerebral (into the brain)
• epidural (into the space surrounding the dura mater)
• intrathecal (into the space surrounding the distal spinal cord);
• intraosseous (into the bone marrow cavity)
• intranasal (sprayed into the nose for absorption through the nasal mucosa or the lungs)
• intratracheal (into the lungs via direct tracheal instillation or inhalation)

Different routes of administration each have their own impact on the drug’s effects, as the rate of absorption and the metabolism of substances can depend on the method of administration.

18. Experimental setups for animal testing¶

The following models describe typical experimental setups for rodents.

18.1. Open Field¶

The test animals are placed in a spacious, empty chamber.
Anxious behavior correlates with

• lack of exercise
• spends a lot of time near the edges or walls
• Avoid the center of the room
• rare rearing
• infrequent grooming
• increased output (bolus delivery)

18.2. Elevated Plus Maze¶

A maze 50 cm above the ground with four arms arranged in the shape of a plus sign. Two of the arms have side walls; the other two do not.
Anxious defensive behavior correlates with

• the time spent in the closed, protective arms compared to the time spent in the open arms

18.3. Morris Water Maze¶

The Morris water maze is a tank filled with cloudy water that is deep enough that rodents must swim in it. Just below the water’s surface, there is a platform that is invisible through the murky water; its location within the tank can be changed.
Rodents are placed in the water and must swim until they find the platform. On subsequent trials, they find the platform more quickly, as long as it remains in the same spot,
The experimental setup is designed to measure orientation ability.

18.4. Radial-arm labyrinth¶

A radial arm maze consists of eight or more identical-looking arms that radiate outward in a circle from the starting position at equal intervals. Food can be placed at the ends of the arms.
In rodents, their spatial orientation and memory are tested with respect to empty or cleared-out arms that they have already visited. Rotating the maze can make spatial orientation more difficult.

19. Neuropsychological tests and what they measure¶

Variable41	Assignment/Test	What is measured is measured
N-back score	EN-Back task	Working memory
List Sorting	Toolbox List Sorting Working Memory Test	Working memory, information processing
Flanker-Cost Effect	Toolbox Flanker Task	Attention, Inhibition
Flanker	Toolbox Flanker Task	Attention, inhibition of automatic responses
Image	Toolbox image sequence memory test	Episodic memory, sequencing
Card Sorting	Toolbox Dimensional Change Card Sorting Task	Executive Functions
Sample	Toolbox Sample Comparison Processing Speed Test	Information Processing
SST Score	The Stop-Signal Task	Reaction Inhibition
Picture Vocabulary	Toolbox Picture Vocabulary Activity	Language