Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_123_библиотеки_им_акад_М_И_Перельмана
.pdf
CHAPTER 6 Communicating throughChemicals 111
Finding receptors everywhere
ATP and adenosine bind to specic purinergic receptors expressed in neurons and
glial cells. The ionotropic receptors are the P2X receptors. P2X receptors are non-
selective cation channels that conduct sodium, potassium, and calcium. They bind
ATP better than adenosine. The metabotropic ATP receptors are the P2Y receptors
that activate PLC or regulate adenylyl cyclase. P2X and P2Y receptors are expressed
throughout the CNS and PNS and are localized to both presynaptic and postsyn-
aptic regions. They modulate synaptic transmission and plasticity by eects on
ion channels, receptors, and gene expression.
In postganglionic and somatic motor neurons, ATP is co-released with ACh or
norepinephrine. Sensory axons co-release ATP in the spinal cord. In the taste
system, ATP is released by taste receptor cells in response to tastants where it
activates purinergic receptors in taste relay neurons. ATP receptors are expressed
throughout the cerebral cortex, hippocampus, and brainstem.
Snoozing with adenosine
The adenosine P1 receptors include the A1, A2A, A2B, and A3 receptors. The A1Rs
and A3Rs inhibit adenylyl cyclase and calcium channels and activate potassium
channels. A2A and A2B receptors stimulate adenylyl cyclase. A2Rs and A3Rs may
also activate PLC.A1Rs are highly expressed by neurons in the neocortex, hippo-
campus, cerebellum, and brainstem. Presynaptic A1 and A2A receptors modulate
neurotransmitter release. The A2B and A3 receptors are expressed at lower levels
in many CNS regions.
Through its eects on ion channels and second messengers, adenosine is neuro-
modulatory. The neuromodulatory eects of adenosine are mediated though the
activation of P1 receptors that act on ion channels and second messengers.
Adenosine inhibits neuronal excitability.
One widely accepted function for adenosine is in sleep. During waking periods, as
ATP is used as an energy source and dephosphorylated, the levels of adenosine
increase in synapses, most notably in the basal forebrain. Adenosine levels peak in
the evening before sleep and then decrease during sleep as ATP is regenerated.
Adenosine receptors function to decrease neuronal activity and facilitate sleep.
Adenosine is involved in slow wave sleep and modulates the release of neurotrans-
mitters in brain regions known to be involved in sleep.
Adenosine and its receptors have also been implicated in the CNS in learning and
memory. In the periphery, adenosine is involved in non-neural cells in modula-
tion of vascular function and immune responses.
https://t.me/med1917
112 PART 1 Getting Started with Neurobiology
Modulating with Monoamines
The three categories of monoamine neurotransmitters are
»
Catecholamines, including dopamine, norepinephrine, and epinephrine
»
Indolamines like serotonin
»
Histamine
Monoamine neurons represent only a small percentage of total brain neurons, but
they have essential neuromodulatory functions. The majority of monoamine
neuronal cell bodies are located in distinct nuclei in the brainstem, while their
axons extend out to innervate many brain regions.
Monoamines, which we examine in greater detail in the following sections, are
synthesized in the presynaptic region from amino acids and transported into syn-
aptic vesicles by vesicular monoamine transporters.
Each monoamine activates its specic metabotropic receptors that function
in neuromodulation. Only serotonin also has ionotropic receptor subtypes.
Monoamines are removed from the synapse by plasma membrane transporters
that are specic for each monoamine.
Feeling motivated with dopamine
Neurons that synthesize and release dopamine are dopaminergic neurons. Their
cell bodies are located in the substantia nigra and ventral tegmental area in the
midbrain. Dopamine is synthesized from the amino acid tyrosine. Dopaminergic
neurons project to nearly every region of the brain. Dopamine is involved in motor
control, pleasure and euphoria, motivation and reward, reward-driven learning,
and cognitive functions. Degeneration of dopaminergic neurons in the substantia
nigra occurs in Parkinson’s disease.
Five subtypes of dopamine receptors are expressed. D1-like receptors are mainly
postsynaptic, activate the cAMP pathway, and can be excitatory or inhibitory.
D2-like receptors are located in both the presynaptic and postsynaptic area,
inhibit the cAMP pathway, and usually produce inhibition. Many antipsychotic
drugs used in the treatment of schizophrenia and bipolar disorder are antagonists
of D2-like receptors.
https://t.me/med1917
CHAPTER 6 Communicating throughChemicals 113
Becoming alert with norepinephrine
Neurons that synthesize and release norepinephrine are noradrenergic neurons.
Their cell bodies are located in the locus coeruleus in the pons. Norepinephrine is
synthesized from dopamine. The general function of norepinephrine is to mobi-
lize the brain and body for action. In the CNS norepinephrine regulates attention,
arousal, and alertness, sleep and wake cycles, pleasure and anxiety, sensory pro-
cessing, and learning and memory.
In the PNS, norepinephrine is the main neurotransmitter released by sympathetic
postganglionic neurons to their target organs and tissues and mediates the
ght-or-ight response.
Epinephrine is synthesized from norepinephrine in adrenergic neurons located in
the lateral tegmental system and medulla. The functions of epinephrine in the
CNS aren’t well characterized. In the PNS, sympathetic stimulation of the adrenal
gland releases both epinephrine and norepinephrine into the blood.
Norepinephrine and epinephrine work through adrenergic receptors. Alpha and
beta adrenergic receptors are expressed throughout the CNS and PNS. In the
brain adrenergic receptors are present in the cerebral cortex, hippocampus,
brainstem, thalamus, and cerebellum. As metabotropic receptors working
through G proteins, they can activate the PLC pathway or regulate the cAMP
pathway. Phenylephrine is an agonist of the alpha 1 receptor while clonidine is
an antagonist of the alpha -2 receptor. Isoproterenol is a beta receptor agonist
while propranolol, a beta blocker, is a beta receptor antagonist.
Aecting mood with serotonin
Neurons that synthesize and release serotonin are serotonergic neurons.
Serotonin is synthesized from the amino acid tryptophan. Chemically it’s
5-hydroxytryptamine (5HT). Serotonergic cell bodies are located in the dorsal
Raphe nuclei in the midbrain and pons. Serotonergic neurons project throughout
the brain, including the cerebral cortex. Serotonin is involved in mood, arousal,
memory processing, circadian rhythms, appetite and eating, cognition, and
motor behaviors. The dysfunction of serotonin pathways has been implicated in
depression and obsessive-compulsive disorder.
Five types of ionotropic 5HT receptors and ten 5HT metabotropic receptor iso-
forms have been identied. Ionotropic receptors are nonselective cation channels
that produce EPSPs. The metabotropic receptors work through G proteins that
activate PLC or regulate cAMP pathways. Serotonin (5HT) receptors are expressed
throughout the CNS and are located in both postsynaptic and presynaptic regions.
5HT1A receptor agonists such as buspirone have shown ecacy in relieving
depression and anxiety. 5HT2A receptor antagonists have antipsychotic properties.
https://t.me/med1917
114 PART 1 Getting Started with Neurobiology
Rewiring with serotonin
Serotonin receptor subtypes 5-HT1A and 5-HT2A are involved in regulating syn-
aptic plasticity. Serotonin stimulates dendritic branching and formation of new
neurons, which can lead to new synapse formation. Serotonin has also been impli-
cated in adaptation to environmental and adaptive plasticity.
The eects of serotonin are consistent with neuroplasticity actions of psycho-
plastogens like psilocybin, dimethyltryptamine (from ayahuasca) and lysergic acid
diethylamide (LSD). These are serotonin receptor agonists.
Resting with histamine
Histaminergic neuron cell bodies are located in the hypothalamus. They project
throughout the forebrain and function in wakefulness and sleep, modulation of
the circadian rhythm and have a role in nausea.
One side eect of centrally acting antihistamines is drowsiness, supporting the
role for histamine in wakefulness.
Targeting transporters
Monoamines are transported into the presynaptic neuron by plasma membrane
transporters. Specic transporters for dopamine, norepinephrine, and serotonin
have been identied. The majority of approved antidepressants act through
monoaminergic mechanisms, including these transporters.
Antidepressants include the selective serotonin reuptake inhibitor (SSRIs such as
Prozac, and Zoloft), serotonin-norepinephrine reuptake inhibitors used to treat
depression and bromyalgia, and tricyclic antidepressants (nonselective mono-
amine uptake inhibitors).
The monoamine hypothesis of depression was well accepted in the last century.
However today it’s clear that disruption of neuroplasticity occurs in depression
and that antidepressants may work by restoring neuroplasticity in areas involved
in mood and cognition.
Ketamine and the psychoplastogens are being investigated as fast-acting antide-
pressants that may rapidly rewire the brain to restore disrupted neuroplasticity
and restore circuits.
https://t.me/med1917
CHAPTER 6 Communicating throughChemicals 115
Getting your attention
The therapeutic drugs Ritalin (methylphenidate) and Adderall, which are used to
treat attention decit hyperactivity disorder (ADHD), function by acting on dopa-
mine transporters and increasing synaptic dopamine levels, though by dierent
mechanisms:
»
Ritalin blocks the plasma membrane dopamine transporter and reduces
dopamine reuptake.
»
Adderall blocks the vesicular monoamine transporter and reduces uptake of
dopamine into synaptic vesicles. It also reverses the direction of the plasma
membrane dopamine transporter.
The recreational drugs of misuse amphetamine and methamphetamine work like
Adderall does, while cocaine behaves in a similar manner to Ritalin.
Recreational drugs that aect monoamines are more potent than their therapeutic
counterparts, leading to psychoactive eects, rewiring of circuits that lead to tol-
erance, and increasing the potential for addiction and misuse.
Behaving with Neuropeptides
Neuropeptides are short polypeptides that function as modulatory neurotrans-
mitters when released at synapses in the brain. A few neuropeptides (oxytocin and
vasopressin) also function as hormones when released into the blood. And hypo-
thalamic neurons release neuropeptides onto pituitary cells, stimulating the
release of pituitary hormones into the blood.
More than a hundred known neuropeptides have been identied in mammals,
with more than a thousand genes predicted to encode signaling peptides. Many
neurons synthesize and release one small molecule and one neuropeptide
neurotransmitter.
The following sections examine neuropeptide characteristics and functions.
Making and releasing peptides
Neuropeptides are synthesized in the cell soma by the rough endoplasmic reticu-
lum, packaged in the Golgi into secretory vesicles (or dense core vesicles), and
transported along the axon to the presynaptic region. Some neuropeptides are
cleaved by proteases during transport.
https://t.me/med1917
116 PART 1 Getting Started with Neurobiology
Neuropeptide-containing vesicles are located farther away from the active zone,
so they require a higher frequency of action potentials for release and can be
released into the synaptic cleft or extracellular uid. Neuropeptides function as
neuromodulators by activating metabotropic receptors located in synaptic, pre-
synaptic, perisynaptic, and extra-synaptic regions.
Controlling behaviors
Some neuropeptides are used by small populations of neurons while others are
used in neurons located throughout the brain. Many neuropeptides were initially
discovered for their roles in the hypothalamus. And many neuropeptides function
in regulating homeostatic and survival behaviors.
In the CNS, oxytocin has been implicated in mate-pair and parent-child bonding,
pro-social behaviors, and empathy. In the CNS, neuropeptide Y (NPY) has been
implicated in food intake, fat storage, and metabolism. In the PNS, NPY is released
by sympathetic neurons with norepinephrine, and together they work as
vasoconstrictors.
Current studies have examined neuropeptide function in the neocortex and
hippocampus where NPY has been implicated in learning and memory.
Relieving pain and feeling happy
The endogenous opioid neuropeptides (enkephalins, endorphins, and dynorphins)
bind to opioid receptors, the same receptors that bind morphine, heroin, and
oxycodone. Endogenous opioids are involved in analgesia and euphoria. Neuro-
peptides may also play a role in migraine, with calcitonin gene related peptide
(CGRP) antagonists are used in migraine treatment.
Neuropeptides aren’t actively removed from synapses but diuse away. The neu-
ropeptide receptors are metabotropic receptors that produce dierent modulatory
eects depending on the G protein involved.
Many neuropeptides are released together with small molecule neurotransmit-
ters, so their eects will be combined with that of their co-transmitter. Neuro-
peptides can produce eects on the membrane potential within seconds to
minutes. They can also regulate metabolism and gene expression over the course
of hours to days.
https://t.me/med1917
2
Controlling
Muscles,
Movement,
andSurvival
https://t.me/med1917
IN THIS PART...
Find out how motor neurons command your muscles
to accomplish movements.
Appreciate how dierent parts of the brain work
together to control movements.
See how the spinal cord and brainstem are organized,
generate reexes, and ensure survival functions.
Recognize how the older parts of your brain
coordinate to maintain survival, homeostasis,
and emotion.
Discover how the neocortex— the newest part of the
brain — processes information and functions with
older parts of the brain.
Find out more about disorders of motor systems and
current therapies to treat them.
https://t.me/med1917
CHAPTER 7 Moving Muscles with Motor Neurons 119
Chapter7
Moving Muscles with
Motor Neurons
E
ven when you’re sitting quietly— perhaps as you are right now, reading this
book — your body is always moving. You consciously control some
movements your body makes, whereas other types of movement happen
without you even being aware.
The human body has distinct muscle types that produce involuntary and
voluntary movements, all of which this chapter explores. Here we discuss how
muscle cells contract to produce movements. The human body has dierent
neural circuits that control these contractions. Speaking of circuits, this chapter
tells you about sensory feedback circuits, which allow reexes to occur quickly
and automatically and take care of details of movement so you don’t have to
concentrate on every step you take.
The nal sections of this chapter discuss what exercise does to your muscles,
gaining and losing muscle mass as you age, the dierence in muscle composition
between men and women, and how muscles could communicate with neurons. So,
don’t move a muscle, and read on!
IN THIS CHAPTER
»
Dealing with distinct muscle types
and functions
»
Checking out how muscle cells
contract
»
Manipulating muscle contraction
»
Locating your limbs
»
Reacting to reexes
»
Considering factors of exercise, aging,
and sex
https://t.me/med1917
120 PART 2 Controlling Muscles, Movement, and Survival
Making a Move: Muscle Types
and What They Do
The body produces very dierent kinds of movement— from intestinal contrac-
tions to heartbeats to bending (exion) and stretching (extension) of limbs. Dif-
ferent kinds of neural circuits control these movement types. There are circuits
that mediate reexes and involuntary movements, rhythmic motor patterns, and
voluntary movement sequences that we consciously control. The following sec-
tions discuss the two major types of muscle in the body: smooth and striated.
Processing with smooth muscle
Smooth muscle controls many involuntary internal movements that you’re gener-
ally not aware of, such as stomach and intestinal contractions. Some smooth
muscle contracts spontaneously, such as in the intestines, whereas for other
types, contraction or relaxation is controlled by the autonomic nervous system.
The body’s smooth muscles are located in a variety of places such as the walls of
organs and blood vessels, the iris of the eye, the bladder, and the uterus.
Smooth muscles include single-unit and multiunit types:
»
In single-unit smooth muscle, an action potential in one cell spreads to other
muscle cells through gap junctions (refer to Chapter5). The result is that the
entire muscle— made of many cells— contracts as a unit.
»
In multiunit smooth muscles, dierent motor neuron terminals innervate
individual muscle cells. This allows for variations in the strength of
contractions and ner neural control.
Smooth muscle diers signicantly in structure and function from striated mus-
cles, which are the cardiac and skeletal muscles. Though they also use actin and
myosin for contraction, smooth muscle lacks sarcomeres and has no striations. It
typically has greater elasticity that’s important in organs like the intestines and
bladder.
Striated muscle for hearts and limbs
Striated muscles enable both involuntary and voluntary movements. It gets its
name because of the striped appearance of repeating sarcomeres. The two major
types of striated muscle are:
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана