unit 6 - beginning of exam 2

Question 1

why study the ANS, endocrine, and immune systems in pharmacology?

Answer 1

The condition of the body affects brain function and in turn psychological processes
Hormones, immune factors and autonomic afferents act on the brain
Autonomic-, immune-, and hormone- related drugs are valuable tools for the analysis of CNS function and of behavioral mechanisms
Many principles related to neurobiology and drug action in the CNS have resulted from studying the ANS and hormone systems

Question 2

Claude Bernard

Answer 2

a French physiologist. He has been called “one of the greatest of all men of science”. He was one of the first to suggest the use of blind experiments to ensure the objectivity of his physiological observations. He originated the term milieu intérieur, and the necessity of maintaining the internal environment as a condition for life.

Question 3

Walter Bradford Cannon

Answer 3

American physiologist, professor and chairman of the Department of Physiology at Harvard. He coined the term “fight or flight” response and was the first to introduce the term stress into the study of physiology and pathophysiology. Importantly, Cannon expanded Claude Bernard’s concept of maintaining the internal environment by calling it “homeostasis”. He popularized his theories in his book The Wisdom of the Body, first published in 1932.

Question 4

homeostasis

Answer 4

“The presence of a nearly fixed proportion of water in the interior milieu, a condition of free life”
“The coordinated physiological processes which maintain most of the steady states in the organisms are so complex to living beings.. That I have suggested special designation for these states, homeostasis. The word does not imply something set and immoblae, a stagnation. It means a condition which may vary, but which is relatively constant
Homeostasis means to regulate the internal environment of the body so that it remains stable and relatively constant.

Question 5

maintaining internal environment in the face of damage and stressors

Answer 5

This is a list of body variables that are regulated to stay fairly constant. There are challenges and insults to the body that must be dealt with (loss of body water from working in a hot environment, loss of blood from a wound, loss of body water from diarrhea or vomiting when you are sick, etc.). The body defends these variables through actions of the autonomic nervous system, endocrine system, immune system, and through homeostatic behaviors and responses to stress,.

Question 6

internal defense systems

Answer 6

ANS, endocrine system, immune system

Question 7

behavioral defenses

Answer 7

homeostatic behaviors, fight/flight

Question 8

physiological mechanisms to maintain consistency of body temp.

Answer 8

Some of the primary ways our body gains (left) and conserves and loses (right) heat and their neural control. In addition, behavior also plays an important role in thermoregulation. For example, we can move from a cool to a warm environment (or vice versa), put on a sweater, exercise, or adjust the thermostat to exert a behavioral control on heat generation, conservation, or loss. The dependent variable, that is the physiological endpoint that is to be maintained, is commonly referred to as being regulated, or the regulated variable. This regulation is achieved by activating one or more control mechanisms. For example in the above, body temperature is regulated by activating control systems such as increased thyroid activity/thyroid hormone, metabolism of brown fat, perspiration, fanning oneself, etc

Question 9

an important regulatory mechanism in a self regulating system

Answer 9

sensory feedback in a negative feedback loop

Question 10

in a negative feedback loop

Answer 10

increased output from the system inhibits future production by the system

Question 11

negative feedback loop

Question 12

sensory feedback

Question 13

theories of homeostasis

Answer 13

Physiologists have applied engineering control theory to the analysis of complex homeostatic systems in order to understand them better and to identify and quantify key variables
A system is a collection of components arranged and interconnected in a specific wy so that there is an identified output for a known input
One approach to understanding the function of control mechanisms is to examine the effects of varying strength of a challenge on the response of a system
Physiologists have applied engineering control theory to the analysis of complex homeostatic systems in order to understand them better and to identify and quantify key variables.
One approach to understanding the nature of control mechanisms is to examine the progressive complexity of control that can be exerted on a system.
A system is a collection of components arranged and interconnected in a specific way so that there is an identified output for a known input.

Question 14

addition-subtraction symbol

Answer 14

For instance, let x represent the rate of intake of salt in the solid food eaten each day, y the intake of salt in liquids drunk each day, and z the rate of loss of salt in the urine each day. Then the net rate of change of salt in the body will be x + y – z, as indicated by the arrow.

Question 15

the multiplication symbol

Answer 15

The figure illustrates multiplication of three quantities, x, y, and z, to give xyz. For example, assume that three separate factors are affecting arterial pressure and that these factors multiply each other. Thus, the sympathetic nervous system might be causing x effect to elevate arterial pressure; a hormone secreted by one of the endocrine glands might be causing y effect to elevate arterial pressure; and hemorrhage might be causing z effect to decrease arterial pressure. The net effect would be xyz.

Question 16

multiplication by a constant factor

Answer 16

The figure illustrates multiplication by a constant factor. Assume that x is the concentration of sodium in the extracellular fluids and K is the volume of extracellular fluid; the total quantity of sodium in the extracellular fluid would then be Kx.

Question 17

division symbol

Answer 17

The figure shows the value x divided by the value y to give x/y. For example, if x is the total quantity of sodium in the extracellular fluid and y is the extracellular fluid volume, then the output of this block, x/y, is the concentration of sodium in the extracellular fluid.

Question 18

the integration (or accumulation) symbol)

Answer 18

Many functions of the body depend upon slow accumulation of some factor. If the rate of change of a hormone in the body is represented by the differential term, dA/dt, the output of the block is the quantity of the hormone that has accumulated in the body at any given time, t. The symbol in this block is called the integration symbol, or, in other words, the rate dA/dt is integrated to give A. If dA/dt is positive, the quantity of the hormone in the body will be increasing, whereas if dA/dt is negative, the quantity of aldosterone in the body will be decreasing.

Question 19

other types of mathematical functions

Answer 19

Other types of mathematical functions in which x is shown in each example to enter a block and y to exit from the block. Each block means that y is related to x in accordance with the function inside the box. This mathematical (often empirically determinable) relationship between an input and an output is called the transfer function. In some cases this function is represented graphically or by an algebraic equation. The figure illustrates four inputs and one output, showing that three of the inputs add to each other and the other multiples the first three.

Question 20

behavior and maintaining homeostasis

Answer 20

In some species behavior is the most important mechanism for controlling body temperature.
Endotherms, so-called warm-blooded animals, are those that maintain a constant body temperature independent of the environment, largely by generating internal heat.
Ectotherms, so-called cold-blooded animals are those whose regulation of body temperature depends on external sources, such as sunlight or a heated rock surface.

Question 21

homeostatic behaviors

Answer 21

temp. regulation, body fluid balance - water intake, and salt ingestion, food intake

Question 22

ANS and the target organs it serves

Answer 22

The autonomic nervous system and the target organs and functions served by the sympathetic and parasympathetic branches.
- The divisions of the autonomic nervous system INNERVATE (send nerves to) the many (but not all) of the SAME ORGANS.
- In cases of organs with dual innervation, this is how the two divisions can have, essentially, opposing effects on physiological responses. The cell bodies of the two divisions originate from different locations, however.
- The cell bodies of the sympathetic division originate from the middle regions of spinal cord (thoracolumbar).
The cell bodies of the parasympathetic division originate from the brainstem and lower spinal cord. Note that the parasympathetic divisions has two origins (craniosacral).

Question 23

the sympathetic chain of the sympathetic nervous system

Answer 23

composed of two kinds of neurons connected in series called preganglionic and postganglionic neurons, where the ganglia are locations of the postganglionic cells. The locations of the ganglia are different for the two divisions.
- ganglia are located just lateral to the spinal cord. Sympathetic preganglionic nerves arise from the spinal cord and synapse at one of the chain ganglia. Then, the postganglionic fiber extends to an effector, a visceral organ. The preganglionic fibers are short, and the postganglionic fibers are long.

Question 24

sources and projections of the parasympathetic system

Answer 24

• Transverse section of the medulla oblongata illustrating the vagal motor system.
• Parasympathetic Preganglionic nerves arise from both the brainstem and sacral divisions of the spinal cord. Most parasympathetic preganglionic axons are longer than most sympathetic preganglionic axons because most parasympathetic ganglia are in the walls of visceral organs they serve. Thus, the parasympathetic has much shorter postganglionic axons.

Question 25

homeostasis and control theory

Answer 25

Physiologists have applied engineering control theory to the analysis of complex homeostatic systems in order to understand them better and to identify and quantify key variables
A system is a collection of components arranged and interconnected in a specific wy so that there is an identified output for a known input
One approach to understanding the function of control mechanisms is to examine the effects of varying strength of a challenge on the response of a system
Physiologists have applied engineering control theory to the analysis of complex homeostatic systems in order to understand them better and to identify and quantify key variables.
One approach to understanding the nature of control mechanisms is to examine the progressive complexity of control that can be exerted on a system.
A system is a collection of components arranged and interconnected in a specific way so that there is an identified output for a known input.

Question 26

similarities between sympathetic and parasympathetic systems

Answer 26

All preganglionic fibers are myelinated
All postganglionic fibers are unmyelinated
The number of postganglionic fibers is higher than the number of preganglionic fibers
Ganglia of both systems are equally susceptible to drugs
Neurotransmitter at ganglia of both systems is acetylcholine
Both systems elicit denervation supersensitivity of target tissue (effector organ) upon removal of ganglia. Supersensitivity becomes apparent within 24-48 hours of denervation
Denervation supersensitivity is the sharp increase of sensitivity of postsynaptic membranes to a chemical transmitter after denervation. It is a compensatory change

Question 27

unique to the sympathetic nervous system

Answer 27

1) Neurons exit from the thoracolumbar region of the CNS
2) Most ganglia located paravertebrally
3) Preganglionic fibers are short
4)Postganglionic fibers are long
5) Pre-to postganglionic fiber ratio is 1:20 to 1:50
6) Prepares for emergency action (fight or flight)
7) Stimulation produces a more generalized response
8) Neurotransmitter at almost all postganglionic nerve is norepinephrine

Question 28

unique to the parasympathetic system

Answer 28

1) Neurons exit from the craniosacral region of the CNS
2)Ganglia located either within the organs innervated or adjacent to the organs
3)Preganglionic fibers are long
4)Postganglionic fibers are short
5)Pre- to postganglionic fiber ratio is 1:2
6)Concerned with conservative vegetative functional states (rest and repair)
7) Stimulation produces effects that are sharply localized
8) Neurotransmitter at postganglionic nerve endings is acetylcholine

Question 29

chemical synapses in the autonomic ganglia

Answer 29

The parasympathetic division uses acetylcholine as the neurotransmitter in both preganglionic and postganglionic fibers. The sympathetic division uses acetylcholine in the preganglionic fibers but uses norepinephrine (noradrenalin) in the postganglionic fibers. (i.e., both divisions use acetylcholine as the preganglionic neurotransmitter but acetylcholine (parasymp) or norepinephrine (symp) postganglionic. Note also the different receptors and receptor subtypes involved: the ganglionic receptors are nicotinic cholinergic for both divisions, while the target tissue receptors are muscarinic cholinergic for the parasympathetic and, of course, adrenergic for the sympathetic.

Question 30

muscarinic receptors

Answer 30

more sensitive to muscarine
- but also sensitive to acetylcholine
- belong to the receptor class metabotropic receptors

Question 31

nicotinic receptors

Answer 31

more sensitive to nicotine
- but also sensitive to acetylcholine
- belong to the receptor class ionotropic receptors

Question 32

nicotine is an antagonist to

Answer 32

hexamethonium
(nicotine receptor antagonist ganglion)

Question 33

atropine

Answer 33

muscarinic receptor antagonist at postganglionic site

Question 34

ganglionic blockade

Answer 34

• Can be used to find the intrinsic level of activity of an organ in the absence of the autonomic nervous system
• The direction of change from the resting level before ganglionic blockade to after blockade can be used to determine the contribution of a limb of the ANS to the basal level of activity

Question 35

ganglion blockers are antagonists at

Answer 35

nicotinic receptors in autonomic ganglia. The net effect of a ganglionic blocker is to reduce the predominant tone in a given organ. Effects are predictable and depend on the relative dominance in terms of parasympathetic or sympathetic.

For example, in a healthy person or animal administered hexamethonium, blood pressure will fall. This means that the normal level of blood pressure was supported predominantly by effects of the sympathetic nervous system. Both divisions are working simultaneously, but the sympathetic is producing more effect under normal conditions.

Hexamethonium is a ganglionic blocker, a nicotinic ACH receptor antagonist. It does not have any effect on the muscarinic acetylcholine receptors located on target organs of the parasympathetic nervous system but acts as antagonist at the nicotinic acetylcholine receptors located in sympathetic and parasympathetic ganglia.

Question 36

arterioles

Answer 36

sympathetic (adrenergic predominant tone)
- vasodilation, increased peripheral blood flow, hypotension

Question 37

veins

Answer 37

sympathetic (adrenergic predominant tone)
- dilation, pooling of blood, decreased venous return, decreased cardiac output

Question 38

parasympathetic predominant tone

Answer 38

heart, iris, ciliary muscle, GI tract, urinary bladder, Salivary glands

Question 39

sympathetic (adrenergic) predominant tone

Answer 39

arterioles, veins, sweat glands

Question 40

adrenergic receptors

Answer 40

a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications which are used to treat high blood pressure and asthma for example.

Question 41

subdivisions of adrenoreceptors

Answer 41

There are two main groups of adrenoreceptors, α and β, with 9 subtypes in total:
α are divided to α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor)
α1 has 3 subtypes: α1A, α1B and α1D
α2 has 3 subtypes: α2A, α2B and α2C
β are divided to β1, β2 and β3. All 3 are coupled to Gs proteins, but β2 and β3 also couple to Gi

Question 42

adrenergic agonists and antagonists bind either…

Answer 42

alpha- or beta- adrenergic receptors

Question 43

synthesis of dopamine, norepinephrine, and epinephrine

Answer 43

tyrosine => dopa => dopamine => norepinephrine
(slide 28)

Question 44

degradation of catecholamines

Answer 44

The enzymes that degrade DA and NE are Monoamine oxidase (MAO) and Catechol–O-methyltransferase (COMT).

Question 45

entry of visceral and somatic afferents into the spinal cord via dorsal roots

Answer 45

Visceral and somatic afferents follow parallel, but distinct paths in the central nervous system. Visceral and somatic afferents consist of different populations of dorsal root ganglion neurons which project to laminae I and V of the dorsal horn of the spinal cord. These relay sites provide local spinal reflexes and also project to higher autonomic and somatic sites, respectively in the brain (A). Although visceral and somatic afferents follow similar trajectories, more detailed tracer studies indicate the two types of afferents end in distinctly different distributions and densities within the spinal cord (B). IML, intermediolateral cell column

Question 46

ascending pathways carrying visceral information in the brain

Answer 46

Visceral afferent information (solid line) enters the brain through the nucleus of the solitary tract (NTS. The afferent information is then distributed to preganglionic neurons, to an area in the ventrolateral medulla that coordinates autonomic and respiratory reflexes, and via ascending pathways to the forebrain. Less direct inputs (dotted line) relay input from the parabrachial nucleus projecting visceral sensory information to the hypothalamus, the amygdala, the septum (not shown), the cortex, and the periaqueductal gray.

Question 47

descending autonomic pathways

Answer 47

Direct outputs to autonomic preganglionic neurons (solid line) arise from the paraventricular and lateral hypothalamus, the parabrachial nucleus, the nucleus of the solitary tract, certain monoamine groups such as the A5 noradrenergic neurons (not shown), serotonergic raphe neurons (not shown), and adrenergic neurons in the ventrolateral medulla. Less direct output from the cerebral cortex, amygdala, and periaqueductal gray matter (dotted line) are relayed into the cell groups with direct input to the preganglionic inputs. Nearly all of the cell groups illustrated in these drawings are also connected with one another, forming a central autonomic network.

Question 48

classes of agents

Answer 48

neurotransmitters, hormones, cytokines, growth factors

Question 49

chemical mediators that play multiple roles

Answer 49

polyfunctional peptides and polyfunctional catecholamines

Question 50

extracellular chemical communication systems

Answer 50

(a) In synaptic transmitter (neurocrine) communication, a chemical signal is released from the presynaptic terminal of the neuron and binds to receptor molecules on a postsynaptic target cell.
(b) Autocrine mechanisms are the feedback effects of a chemical signal on the very cell from which it was released. Some synaptic transmitters are also autocrine signals in that they affect receptors on the presynaptic terminal (autoreceptors).
(c) In paracrine communication, chemical signals diffuse through extracellular space to nearby target cells. The strongest effects are produced in the nearest cells.
(d) Endocrine glands produce chemical signals and release them into the bloodstream. Effects are produced in the body wherever receptors for the hormone are found.
(e) Pheromones carry a message from one individual of the species to other individuals. Often pheromones indicate whether the individual emitting them is ready to mate.
(f) Allomones are produced by individuals of one species to communicate with (and affect the behavior of) individuals of other species. Some plants even communicate with animals via allomones.

Question 51

endocrine

Answer 51

secreting into circulation inside of the body

Question 52

exocrine

Answer 52

secreting into fluids that are outside of the body such as breast milk or saliva

Question 53

amine hormone

Answer 53

amino acids with modified groups

Question 54

peptide hormone

Answer 54

short chains of linked amino acids

Question 55

protein hormone

Answer 55

long chains of linked amino acids

Question 56

steroid hormones

Answer 56

derived from the lipid cholesterol

Question 57

peptide and steroid receptorrs

Answer 57

Two mechanisms of action have been delineated by which hormones alter cell function. Certain amino acid and polypeptide hormones interact with cell surface receptors, stimulating intracellular production of cyclic AMP (cAMP), which binds to an intracellular receptor and stimulates phosphorylation of intracellular proteins. Steroid hormones, in contrast, enter the target cell and bind to a specific cytoplasmic receptor. The hormone-receptor complex is then transported into the nucleus, where it binds to specific sites on the genome (DNA) and activates transcription of new RNA, which mediates the response characteristic of the cell by directing protein synthesis.

Question 58

pituitary gland

Answer 58

gland has long been regarded as one of the most important endocrine glands in the body. Rathke’s pouch is an evagination at the roof of the developing mouth in front of the buccopharyngeal membrane. It gives rise to the anterior pituitary (adenohypophysis), a part of the endocrine system. Note that the tissue it connects to at the base of the brain is the hypothalamus

Question 59

anterior pituitary

Answer 59

adenohypophysis
(slide 42)

Question 60

posterior pituitary

Answer 60

neurohypophysis
- receives direct neural connections from the brain

Question 61

neurosecretion

Answer 61

the synthesis, storage, and release of hormones from neurons. These neurohormones, produced by neurosecretory cells, are normally secreted from nerve cells in the brain that then circulate into the blood. Neurosecretory cells synthesize and package their product in vesicles and release them (via exocytosis) at axon endings just as normal neurons do, but into blood rather than into a synapse.

Question 62

anterior pituitary releasing

Answer 62

releasing hormones are made in the brain proper, released into the base of the brain (i.e., hypothalamus) and transported by blood (via a portal system) to the anterior pituitary. For our purposes, we will only concern ourselves in this course with the control of the adrenocorticotrophic hormone (ACTH) released by corticotropin-releasing hormone (CRH or CRF). Therefore, it is not necessary to learn all of the releasing hormones anterior pituitary hormones., or their functions.

Note that dopamine is very likely to be an inhibitory factor inhibiting the release of prolactin. This fact be a relevant when we discuss pharmacotherapy for schizophrenia.

Question 63

adrenal cortex

Answer 63

Glucocorticoids
Cortisol
Corticosterone
Mineralocorticoid
AldosteroneHuman adrenal glands. Adrenocortical tissue is stippled; adrenal medullary tissue is black. Note the location of the adrenals at the superior pole of each kidney. Also shown are extra-adrenal sites at which cortical and medullary tissue is sometimes found.

Question 64

adrenal medulla

Answer 64

Norepinephrine-secreting adrenal medullary cell. The granules are released by exocytosis, and the granule contents under the bloodstream (arrow).

Question 65

physiological effects of glucocorticoids

Answer 65

Action on intermediary metabolism of carbohydrate, protein and fat
- increased protein breakdown
- increased hepatic glycogenesis and gluconeogenesis
- glucose 6-phosphatase activity is increased
- plasma glucose rises
- “directs” glucose to brain and heart (via an anti-insulin action)
Permissive action for glucagon and catecholamines to exert their caloric effects
Permissive action for catecholamines to exert their lipolytic effects
Permissive action for catecholamines to produce their pressor responses and bronchodilation
Inhibit ACTH secretion
Increase number of red blood cells, platelets and neutrophils
Decrease number of eosinophils and basophils
Decrease circulating lymphocytes and size of lymph nodes and thymus

Question 66

immune system

Answer 66

-host defense system comprising many biological structures and processes within an organism that protects against disease and insult to the body.. To function properly, an immune system must detect a wide variety of agents, known as pathogens and indicators of tissue damage.
- can be classified as innate vs adaptive or humoral versus cell mediated

Question 67

under healthy conditions the blood-brain barrier normally

Answer 67

normally separates the peripheral immune system from the neuro-immune system, but activation of the peripheral immune system can have profound effects on the central system..

Question 68

innate immune system

Answer 68

The strength of the innate immune system is to be able to take action very quickly. It works to repel pathogens, and if they enter the body detects and starts to destroy them within a few hours.

As the innate immune response is not specialized or specific for a given pathogen, it does not need a long start-up time. Because of this broad effect, it is only capable to a certain degree of stopping germs from entering and spreading in the body. The innate defense consists of several elements:

Question 69

the adaptive or specific immune system consists of

Answer 69

highly specialized cells called T lymphocyte cells and B lymphocyte cells with the capacity to generate immunological memory, so that it allows recognizing the pathogens which have encountered before.

Question 70

proteins and defense cells

Answer 70

When pathogens make it past the skin or mucous membranes and enter the body, the innate system’s second line of defense is activated.
Inflammatory cells move to the site of infection, or defensive cells that are already there are activated.
Soluble protein substances of the complement system are also activated body.
Infection leads to an inflammatory reaction where blood circulation is increased, and the affected area becomes swollen and hot. Sometimes there is also a fever.
Bacteria or viruses entering the body are attacked by immune system phagocytes which enclose the pathogens and digest them in their interior. The most effective ones are:
- Macrophages, which are found in the tissue
- Neutrophil granulocytes, which are in the blood and tissue.
Phagocytes act best if the pathogen has already been marked by antibodies or by complement proteins making the pathogen more “palatable”.
Antibodies of the adaptive immune system support the innate defense and vice versa, the scavenger cells can help the adaptive immune system by taking up and digesting the marked pathogens very quickly.

Question 71

signals activating the innate immune system

Answer 71

damage-associated molecular pattern molecules (DAMPs) and pathogen-associated molecular patterns (PAMPs)

Question 72

damage-associated molecular pattern molecules

Answer 72

host molecules that can initiate and perpetuate a noninfectious inflammatory response
- patterns, danger signals, and alarmin, are host biomolecules that can initiate and perpetuate a noninfectious inflammatory response. In contrast, pathogen-associated molecular patterns (PAMPs) initiate and perpetuate the infectious pathogen-induced inflammatory response

Question 73

pathogen-associated molecular patterns (PAMPs)

Answer 73

molecules associated with groups of pathogens, that are recognized by cells of the innate immune system

Question 74

the acute phase response

Answer 74

IL-6 = Interleukin 6 IL-6 is secreted by T cells and macrophages to stimulate immune response which includes the production of many so-called acute-phase proteins and “complements”.

The complement system enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism.

Question 75

cytokines

Answer 75

• are a broad and loose category of small proteins (~5–20 kDa) that are important in extra-cellular signaling.
• They are released by cells and affect the function of other cells and in some cases can also act as autocrine signals.

Question 76

cytokines are produced by

Answer 76

a broad range of cells, including immune cells like macrophages, B cells, T cells and mast cells as well as endothelial cells fibroblasts and various stromal.

Question 77

some cytokines promote

Answer 77

inflammation whereas others are anti-inflammatory

Question 78

cytokines affect

Answer 78

the function of other cells and in some cases can also act as autocrine signals

Question 79

adaptive immune system

Answer 79

If the innate immune system is unsuccessful in destroying the pathogens, the specific adaptive immune response is activated.
The adaptive defense takes longer, but it targets pathogens more accurately. Importantly, it can remember the aggressor and acts specifically against certain antigens.
The capacity for memory makes the defense responses of the adaptive immune system more efficient and faster than those of the innate defense, if the antigen is already known.
The adaptive immune system produces memory cells.
The adaptive immune system has several parts that react in different ways, depending on the place in the body where the pathogen is.
These parts of the adaptive defense include:
- T lymphocytes
- B lymphocytes
- Antibodies as soluble proteins in the blood
- Cytokines in the blood and tissue as hormone-like messenger substances

Question 80

connecting the systemic immune system with the brain

Answer 80

: Mechanisms of brain actions of cytokines. Proinflammatory cytokines are released by activated innate immune cells in the periphery in response to PAMP. PAMP and circulating cytokines act on TLRs on macrophages in the circumventricular organs (CVOs), choroid plexus, and adjacent to blood vessels (perivascular macrophages) leading to the production of brain cytokines and prostaglandin E2 (PGE2) that diffuse by into the brain parenchyma. The action of peripheral proinflammatory cytokines also can be relayed to the brain by afferent nerves, resulting in the production of brain proinflammatory cytokines by microglial cells. In both cases, the action of brain proinflammatory cytokines can be mediated by prostaglandins that diffuse to brain targets or by activation of neural pathways within the brain, which enables the immune message to be transported far away from its site of origin. Prostaglandins can be synthesized only by endothelial cells of brain venules in response to circulating cytokines. Red arrows represents neural transmission of the immune message from the periphery to the brain.

Question 81

pathways that transduce immune signals from the periphery to the brain

Answer 81

communicate through different pathways. a | In the neural pathway, peripherally produced pathogen-associated molecular patterns (PAMPs) and cytokines activate primary afferent nerves, such as the vagal nerves during abdominal and visceral infections8,9 and the trigeminal nerves during oro-lingual infections10. Vagal afferents project to the nucleus tractus solitarius (NTS), and from there to the parabrachial nucleus (PB), the ventrolateral medulla (VLM), the hypothalamic paraventricular and supraoptic nuclei (PVN, SON), the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST). These last two structures form part of the extended amygdala, which projects to the periaqueductal grey (PAG). b | The humoral pathway involves circulating PAMPs that reach the brain at the level of the choroid plexus (CP) and the circumventricular organs11, including the median eminence (ME), organum vasculosum of the laminae terminalis (OVLT), area postrema (AP) and subfornical organ (SFO). In the circumventricular organs, PAMPs induce the production and release of pro-inflammatory cytokines by macrophage-like cells expressing Toll-like receptors (TLRs). As the circumventricular organs lie outside the blood–brain barrier (BBB), these cytokines still need to reach the brain. They do so by mechanisms that are still not well understood, but involve volume diffusion of cytokines or other humoral factors such as prostaglandin PGE2.

Question 82

brain microglia constitute the brain’s immune mechanism

Answer 82

Under “resting “ conditions microglia are ramified and testing their environment.
When activated microglia can secrete destructive molecules and become phagocytes.
Microglia can also play a reparative role,
- Illustration of the stages of microglial activation from a resting (ramified) state, to a primed state and finally to a fully activated phenotype. The exact phenotype and physiology of each stage of activation is determined by a number of extraneuronal molecules and environmental conditions

Question 83

activated microglia attacking a damaged neurons

Answer 83

Illustration of fully activated microglia in a neuro destructive phenotype, with the release of proinflammatory cytokines, chemokines and excitatory amino acids, all acting in concert to damage the surrounding neurons

Question 84

microglia in a reparative mode

Answer 84

Illustration of a microglia in a primary reparative phenotype, which can be in either the resting mode or an activated-reparative mode, both of which release neurotrophic factors and antiinflammatory cytokines. This repairs the damage done during neuro destructive microglial activation

Question 85

efferent controls of the peripheral immune system from the CNS

Answer 85

Schematic illustration of connections between the nervous and immune systems. Signaling between the immune system and the central nervous system (CNS) through systemic routes, the vagus nerve, the hypothalamic–pituitary–adrenal (HPA) axis, the sympathetic nervous system (SNS) and the peripheral nervous system (PNS) are shown.