Autonomic nervous system

The Autonomic Nervous System

The ANS coordinates cardiovascular, respiratory, digestive, excretory and reproductive systems

- Visceral afferents, interoceptive inputs, as well as projections from those parts of the CNS that control the viscera and other autonomic functions, by comparing current inputs with anticipated needs!

- Visceral efferents – autonomic motor neurons:– Innervates smooth muscle, cardiac muscle, secretory epithelia and glands– Regulates visceral functions

Heart rate, blood pressure, digestion, urination, etc

Rapidity and intensity in changing visceral functions:

within 3 -5 sec. it can increase 2x the HRwithin 10-15 sec. the arterial pressure can be doubled

(Langley, 1898)

Autonomic - from the Greek for "self-governing," functioning independently of the will

Enteric ANS is a system of afferent neurons, interneurons, and motor neurons that form networks of neurons called plexuses that surround GIT.

Function as a separate and independent nervous system, but it is normally controlled by the CNS through sympathetic and parasympathetic fibers.

The ANS has three divisions: sympathetic, parasympathetic, and enteric.

S & PS Divisions of the Autonomic Nervous System-work synergistically to control visceral activity and often exertantagonistic/opposite effects on the same target organs, but:

-most blood vessels are innervated only by S nerves. -PS activity dominates the heart and GI tract.

-exert cooperative effects on the external genitalia.

• Sympathetic effects

-wide spread, long-lasting mobilization of the “fight, flight, or fright” response

-activated during exercise, excitement, and emergencies

-exaggerated reaction - panic attacks…

• Parasympathetic effects

-“rest and digest”

-results in conserving energy

Sympathetic and parasympathetic ANS divisions -both have a two-synapse pathway

1st preganglionic neuron in the CNS (brainstem and spinal cord and synapse with

postganglionic neuron in peripheral ganglia that innervate the target cells

Comparison of Autonomic and Somatic Motor Systems

• Somatic motor system– One motor neuron extends from the CNS to skeletal muscle: voluntary,

direct synapse, always excitatory (Ach) – N1 nicotinic receptors– Axons are well myelinated, conduct impulses rapidly

• Autonomic nervous system – Chain of two motor neurons– Involuntary, two-synapsis pathway (Preganglionic & Postganglionic

neurons), either excitatory or inhibitory– Conduction is slower due to thinly or unmyelinated axons

Motor pathways of the somatic (a) & autonomic (b) nervous system

Anatomical differences in Sympathetic and Parasympathetic Divisions

S&PS originate from different CNS regions

– Sympathetic = thoracolumbar division

– Parasympathetic = craniosacral division

S&PS anatomical differences

-Length of postganglionic fibers

– S: long postganglionic fibers

– PS: short postganglionic fibers

-Branching of axons

– S: highly branched, influences many organs

– PS: few branches, localized effect

Anatomical differences in Sympathetic and Parasympathetic Divisions

Organization of the sympathetic and

parasympathetic divisions of the ANS.

The cell bodies of sympathetic

preganglionic neurons (red) are in the

lateral horn of the thoracic and lumbar

spinal cord (T1–L3). Their axons project to

paravertebral ganglia (the sympathetic

chain/trunk) and prevertebral ganglia.

Postganglionic neurons (blue) therefore

have long projections to their targets.

The cell bodies of PS preganglionic

neurons (orange) are either in the brain

(midbrain, pons, medulla) or in the sacral

spinal cord (S2–S4). Their axons project to

ganglia close to or inside the end organs.

Postganglionic neurons (green) have

short projections to their targets.

Sympathetic Preganglionic

Neurons are located in the

thoracic and upper lumbar spinal

cord between levels T1 and L3 in

the lateral horn, between the

dorsal and ventral horns.

Axons from preganglionic

sympathetic neurons exit the

spinal cord through the ventral

roots along with axons from

somatic motor neurons.

After entering the spinal nerves,

sympathetic efferents diverge

from somatic motor axons to enter

the white rami communicantes

(myelinated).

Anatomical aspects of the Sympathetic division of ANS

Paravertebral Ganglia – sympathetic ganglia that lie adjacent to the vertebral column and form the sympathetic trunk

Axons from preganglionic neurons emerge only from levels T1 to L3, and enter the nearest sympathetic paravertebral ganglion through a white ramus, however the chain of sympathetic ganglia extends all the way from the upper part of the neck to the coccyx (here left and right sympathetic chains merge in the midline to form the coccygeal ganglion).

In general, one ganglion is positioned at the level of each spinal root, but adjacent ganglia are fused in some cases:

The most rostral ganglion, the superior cervical ganglion, arises from fusion of C1 to C4 ganglia and supplies the head and neck.

The next two ganglia are the middle cervical ganglion, which arises from fusion of C5 and C6.

The inferior cervical ganglion (C7 and C8), which is usually fused with the first thoracic (T1) ganglion to form the stellate ganglion.

Anatomical aspects of the Sympathetic division of ANS

After entering a paravertebral ganglion, a preganglionic sympathetic axon has

one or more of three fates:

(1) synapse within that segmental paravertebral ganglion,

(2) travel up or down the sympathetic chain to synapse within a neighboring

paravertebral ganglion, or

(3) enter the greater or lesser splanchnic nerve to synapse within one of

the ganglia of the prevertebral plexus.

Anatomical aspects of the Sympathetic division of ANS

The major prevertebral ganglia are named

according to the arteries that they are adjacent to

and include the celiac, superior mesenteric,

aorticorenal, and inferior mesenteric ganglia.

Each preganglionic sympathetic fiber synapses on

many postganglionic sympathetic neurons that are

located within one or several nearby paravertebral

or prevertebral ganglia.

It has been estimated that each preganglionic

sympathetic neuron branches and synapses

on as many as 200 postganglionic neurons,

which enables the sympathetic output to have

more widespread effects.

Anatomical aspects of the Sympathetic division of ANS

Parasympathetic fibers :-leave CNS through cranial n. III (pupillary sphincter and ciliary muscle of the eye), VII (lacrimal, nasal, and submandibular glands), IX (parotid gland), X (heart, lungs, esophagus, stomach, entire small intestine, proximal half of the colon, liver, gallbladder, pancreas, kidneys, and upper portions of the ureters);

-additional PS fibers leave the lowermost part of the spinal cord S2-S3 spinal nerves (pelvic nerves) and occasionally S1, S4 nerves (descending colon, rectum, urinary bladder, and lower portions of the ureters).

-about 75 % of all PS nerve fibers are in the vagus nerves (cr. N. X), passing to the entire thoracic and abdominal regions of the body.

The visceral control system also has an important afferent pathway

All internal organs are densely innervated by visceral afferents.

-nociceptive (painful) inputs that travel in sympathetic nerves

-mechanical and chemical (physiological) stimuli, including stretch of the

heart, blood vessels, and hollow viscera, as well as PCO2, PO2, pH, blood glucose,

and temperature of the skin and internal organs. Most axons from physiological

receptors travel with parasympathetic fibers.

Cell bodies of visceral afferent fibers are located within the dorsal root ganglia or

cranial nerve ganglia (e.g., nodose and petrosal ganglia). 90% of these visceral

afferents are unmyelinated.

The largest concentration of visceral afferent axons can be found in the vagus

nerve, which carries non-nociceptive afferent input to the CNS from all viscera of

the thorax and abdomen. Most fibers in the vagus nerve are afferents, even

though all parasympathetic preganglionic output (i.e., efferents) to the abdominal

and thoracic viscera also travels in the vagus nerve.

Vagal afferents, whose cell bodies are located in the nodose ganglion, carry

information about the distention of hollow organs (e.g., blood vessels, cardiac

chambers, stomach, bronchioles), blood gases (e.g., PO2, PCO2, pH from

the aortic bodies), and body chemistry (e.g., glucose concentration) to the medulla.

Neurotransmitters of Autonomic Nervous System• Neurotransmitter released by preganglionic axons

– Acetylcholine for both S&PS branches (cholinergic)

• Neurotransmitter released by postganglionic axons

– Sympathetic – most release norepinephrine (adrenergic), also neuropeptide Y and ATP.

– Parasympathetic – release acetylcholine, also neuropeptides (VIP)

Autonomic postganglionic neurons can change their transmitters phenotype !

Some ANS neurons can change their transmitter phenotypes under appropriate environmental conditions, demonstrated both in vitro and in vivo – phenotypic switching/plasticity:

– During development (e.g. innervation of sweat glands by sympathetic postganglionic neurons that are cholinergic)

– Postganglionic cells grown in vitro in the presence of heart conditioned medium changed from an adrenergic to a cholinergic phenotype.

Secretion of Acetylcholine and Norepinephrine by Postganglionic Nerve Endings

• Many of the PS nerve fibers and almost all the S fibers connect with the effector cells or terminate in connective tissue located adjacent to the target cells

• Postganglionic fibers present bulbous enlargements =varicosities, where transmitter vesicles of Ach or NE are synthesized and stored.

• Also in the varicosities are large numbers of mitochondria that supply ATP, required to energize Ach or NE synthesis.

• AP depolarization calcium ions inflow into nerve transmitter substance is secreted.

• Synthesis of Ach

Ach acetate ion and choline, catalyzed by acetylcholinesterase(bound with collagen and glycosaminoglycans in the local connective tissue) fast end of Ach action

Synthesis of norepinephrine -begins in the axoplasm of the terminal adrenergic nerve endings, completed inside the secretory vesicles.

Transport of dopamine into the vesicles

In the adrenal medulla, this reaction goes still one stepfurther to transform about 80 % of the NE into E:

NE is removed from the secretory site by: (1) reuptake into the adrenergic nerve endings by an active transport process (50 -

80 % ); (2) diffusion away from the nerve endings into the surrounding body fluids and

then into the blood - accounting for removal of most of the remaining NE;(3) destruction of small amounts by tissue enzymes (monoamine oxidase in the

nerve endings, and catechol-O-methyl transferase, in all tissues).

Signal transmission in ANSA. Sympathetic

• Preganglion secretes Acetylcholine (Cholinergic)

• Receptor on the Postganglionic neuron = Nicotinic

• Postganglionic neuron secretes Norepinephrine (Adrenergic), NPY, ATP, etc

• Target (smooth muscle, cardiac muscle, glands)

Receptor = Adrenergic (α1, α2; β1, β2, β3)

! Sweat glands, some blood vessels, piloerector muscle:

• Preganglion secretes Acetylcholine• Postganglion – Nicotinic receptor

• Postganglionic neuron secretes Acetylcholine/NO (Cholinergic/nitroxidergic)

• Target:-sweat gland – muscarinic receptor -postganglionic fibers that innervate smooth m. in the small arteries in skeletal muscles and the brain release NO, that promotes vasodilation.

• Stimulation of S division has two distinctive results:

- release of NE at specific locations

- secretion of E and NE (4:1) into the general circulation.

- alpha receptors : activated by NE > E, isoproterenol; blocked by: phenoxybenzamine

- beta receptors: activated > by E; blocked by propranolol

Signal transmission in ANS

B. Parasympathetic

• Preganglionic neuron secretes Acetylcholine (Cholinergic)

• Receptors on postganglionic neurons = Nicotinic

• Postganglionic neuron secretes Acetylcholine, VIP

• Target receptor = muscarinic (smooth muscle, heart, glands)

Outflow via the Vagus Nerve (X)

• Fibers innervate visceral organs of the thorax and most of the abdomen (75%...)

• Stimulates - digestion, reduction in heart rate and blood pressure

• Preganglionic cell bodies

– Located in dorsal motor nucleus in the medulla

• Ganglionic neurons

– Confined within the walls of organs being innervated

Sacral Outflow

• Emerges from S2-S4

• Innervates organs of the pelvis and lower abdomen

• Preganglionic cell bodies

– Located in visceral motor region of spinal gray matter

Postganglionic sympathetic and parasympathetic neurons often have

muscarinic as well as nicotinic receptors

Some postganglionic neurons, both sympathetic and parasympathetic, have

muscarinic in addition to nicotinic receptors.

At all levels of the ANS, certain neurotransmitters and postsynaptic receptors

are neither cholinergic nor adrenergic.

If we stimulate the release of ACh from preganglionic neurons or apply ACh to an

autonomic ganglion, many postganglionic neurons exhibit both nicotinic and

muscarinic responses.

Because nicotinic receptors (N2) are ligand-gated ion channels, nicotinic

neurotransmission causes a fast, monophasic excitatory postsynaptic potential

(EPSP).

In contrast, because muscarinic receptors are GPCRs, neurotransmission by this

route leads to a slower electrical response that can be either inhibitory or excitatory.

Thus, depending on the ganglion, the result is a multiphasic postsynaptic response

that can be a combination of a fast EPSP through a nicotinic receptor plus either a

slow EPSP or a slow inhibitory postsynaptic potential (IPSP) through a muscarinic

receptor.

An example of dual nicotinic and muscarinic neurotransmission between

sympathetic preganglionic and postganglionic neurons. A, Stimulation of a frog

preganglionic sympathetic neuron releases ACh, which triggers a fast EPSP (due to

activation of nicotinic receptors on the postganglionic sympathetic neuron), followed by

a slow EPSP (due to activation of muscarinic receptors on the postganglionic neuron).

B, In a rat sympathetic postganglionic neuron, the M current (mediated by a K+

channel) is normally active, hyperpolarizing the neuron. Thus, injecting current elicits

only a single action potential. C, In the same experiment as in B, adding muscarine

stimulates a muscarinic receptor (i.e., GPCR) and triggers a signal-transduction

cascade that blocks the M current. One result is a steady-state depolarization of the

cell. Injecting current

now elicits a train of action potentials.

Nonclassic transmitters can be released at each level of the ANS

Central Control of the ANS

• Control by the brain stem and spinal cord– Reflex activity is mediated by spinal cord and brain stem

(medullary centers).

– Reticular formation exerts most direct influence• Medulla oblongata

• Periaqueductal gray matter

– Control by the hypothalamus and amygdala• Hypothalamus – the main integration center of the ANS that

interact with both higher and lower centers to orchestrate autonomic, somatic and endocrine responses.

• Amygdala – main limbic region for emotions

– Control by the cerebral cortex of the autonomic functioning via connections with the limbic system

Basic Structure of a Visceral Reflex

2nd processing center

Visceral reflex:

• Visceral sensory and autonomic neurons

• Participate in visceral reflex arcs

-PS reflexes include : gastric and intestinal reflexes, defecation, urination, direct light reflexes, swallowing reflex, coughing reflex, baroreceptor reflex and sexual arousal.

-S reflexes: cardioaccelaratory reflex, vasomotor reflex, pupillary reflex and ejaculation in males.

A variety of brainstem nuclei provide basic control of the ANS

One of the most important lower brainstem structures is the nucleus tractus solitarii

(NTS) in the medulla. The NTS contains second-order sensory neurons that receive all

input from peripheral chemoreceptors and baroreceptors input, as well as non-

nociceptive afferent input from every organ of the thorax and abdomen.

Visceral afferents from the vagus nerve make their first synapse within the NTS, where

they combine with other visceral (largely unconscious) afferent impulses derived from

the glossopharyngeal (CN IX), facial (CN VII), and trigeminal (CN V) nerves. These

visceral afferents form a large bundle of nerve fibers—the tractus solitarius—that the

NTS surrounds. Afferent input is distributed to the NTS in a viscerotopic manner, with

major subnuclei devoted to respiratory, cardiovascular, gustatory, and GI input. The

NTS also receives input and sends output to many other CNS regions including the

brainstem nuclei described above as well as the hypothalamus and the forebrain.

Hypothalamus (HT)

- part of diencephalon (1% of brain volume), located within the walls & floor of 3rd

ventricle, constitutes an integrative center essential for survival & reproduction,

that regulates and controls the complex interactions between physiology and

behavior (temperature regulation, heart rate, blood pressure, blood osmolarity,

food and water intake, emotion and sex drives).

- structure – cytoarchitecture – neurochemistry functional

specializations (e.g., appetite, weight control, water balance, autonomic

control, reproductive function, emotional behavior)

- reciprocal connections with

-almost every major subdivision of the CNS (bidirectional)

-peripheral organ systems by converting synaptic information to

hormonal signals (neuroendocrine regulation)

- “Here in this well concealed spot, almost to be covered with a thumb

nail, lies the very mainspring of primitive existence – vegetative,

emotional, reproductive- on which, with more or less success, man has

come to superimpose a cortex of inhibitions.” (Cushing, 1929).

HT Cytoarchitecture

• HT is organized into 3 longitudinal columns on either side of the 3rd ventricle, that

extend through the entire rostrocaudal extent of the HT

– periventricular (suprachiasmatic and arcuate nuclei),

– medial (contains distinct nuclei),

– lateral (neurons diffusely distributed)

Functional organization - Integrative processing in the HT

• HT: Brain-periphery interconnections: nervous, hormonal…

• HT receive:– Monosynaptic projections, such as first-order information from the

periphery (vision)

– Multisynaptic cerebral pathways (limbic projections)

• HT integrate information

• HT regulatory outputs on physiology and behavior: hormonal and synaptic

HT & Visceral sensation

-Sensory information (visceral, CV, respiratory, taste): topographically organized input through cranial nerves X & IX nucleus of solitary tract (NST) of the caudal brain stem ascending direct projections to paraventricular HT nucleus (PVH) & lateral HT area (LHA)

Nucleus tractus solitarii (NST) coordinates reflex regulation of peripheral organ

function

-send processed sensory information to forebrain nuclei, to be integrated in the control of more complex physiological processes and behaviors.

-together with the parabrachial nucleus relay splanchnic visceral and nociceptive sensory information from the spinal cord

- indirect projections to HT through ventrolateral medulla and parabrachial nucleus in the pons

- many of these projections are bidirectional

- connections with amygdala, stria terminalis, insular cortex

interoceptive sensory feedback that influences autonomic and endocrine outputs of HT homeostasis, mood

! Stress induces activation of the autonomic and endocrine axes

Functional organization - Integrative processing in the HT

HT & Central integration of autonomic function

• descending projection from the HT to autonomic cell groups in the brainstem and spinal cord exerts a strong influence upon the S (thoracic) and PS (cranial-lumbosacral) divisions of the ANS

• there are also indirect influences from HT cell groups on preganglionic neurons of the spinal cord

Coordination of autonomic functions and behavioral responses to environmental challenges

coordinates the “the wisdom of the body” (Cannon, 1937): tissue-, organ-, and system-level integration of the body’s physiology to achieve homeostasis and support behavior; continuous and automatically.

HT & immune function & thermoregulation

• HT influences immune system through neuroendocrine and autonomic outputs:

- activity of immune cells of the spleen is influenced directly by synaptic-like contacts of NA neurons of the sympathetic ANS

- immune system activation fever

- HT neurons stimulate or inhibit heat production:

heat sensitive neurons in the medial preoptic area act to reduce core body temperature by inhibiting other neurons

in the HT and caudal brainstem to induce thermogenesis

- nonshivering thermogenesis in small animals is achieved through the activation of sympathetic activation of brown adipose tissue (BAT)- its mitochondria converts energy from fatty acids metabolism into heat

• There is a considerable overlap of cell groups that regulate energy balance, stress and fever !