Central Regulation of Visceral Function

INTRODUCTION
» The levels of autonomic integration within the CNS are arranged, like their somatic
counterparts, in a hierarchy.
» Simple reflexes such as contraction of the full bladder are integrated in the spinal cord.
» Those that regulate respiration and blood pressure are integrated in the medulla oblongata.
» Those that control pupillary responses to light and accommodation are integrated in the
midbrain.
» The complex autonomic mechanisms that maintain the chemical constancy and temperature
of the internal environment are integrated in the hypothalamus.

MEDULLA OBLONGATA
Control of Respiration, Heart Rate, & Blood Pressure
 The medullary areas for the autonomic reflex control of the circulation, heart, and lungs
are called the vital centers because damage to them is usually fatal.
 The specialized receptors include not only those of the carotid and aortic sinuses and
bodies but also receptor cells that are located in the medulla itself.
 The motor responses are graded and delicately adjusted and include somatic as well as
visceral components.

Other Medullary Autonomic Reflexes

 Swallowing, coughing, sneezing, gagging, and vomiting are also reflex responses integrated
in the medulla oblongata.
 Swallowing is controlled by a central program generator in the medulla. It is initiated by the
voluntary act of propelling what is in the mouth toward the back of the pharynx and involves
carefully timed responses of the respiratory as well as the gastrointestinal system.
 Coughing is initiated by irritation of the lining of the trachea and extrapulmonary bronchi. The
glottis closes, and strong contraction of the respiratory muscles builds up intrapulmonary
pressure, whereupon the glottis suddenly opens, causing an explosive discharge of air.
 Sneezing is a somewhat similar response to irritation of the nasal epithelium. It is initiated by
stimulation of pain fibers in the trigeminal nerves.

Vomiting
 Vomiting starts with salivation and the sensation of nausea.
 Reverse peristalsis empties material from the upper part of the small intestine into the
stomach.
 The glottis closes, preventing aspiration of vomitus into the trachea. The breath is held in mid
inspiration.
 The muscles of the abdominal wall contract, and because the chest is held in a fixed position,
the contraction increases intra-abdominal pressure. The lower esophageal sphincter and the
esophagus relax, and the gastric contents are ejected.
 The "vomiting center" in the reticular formation of the medulla really consists of various
scattered groups of neurons in this region that control the different components of the
vomiting act.

Afferents
 Irritation of the mucosa of the upper gastrointestinal tract causes vomiting.
 Impulses are relayed from the mucosa to the medulla over visceral afferent pathways in the
sympathetic nerves and vagi.
 Afferents from the vestibular nuclei mediate the nausea and vomiting of motion sickness.
 Other afferents presumably reach the vomiting control areas from the diencephalon and
limbic system, because emetic responses to emotionally charged stimuli also occur. Thus,
we speak of "nauseating smells" and "sickening sights."
 Chemoreceptor cells in the medulla initiate vomiting when they are stimulated by certain
circulating chemical agents.
 The chemoreceptor trigger zone in which these cells are located is in the area postrema, a
V-shaped band of tissue on the lateral walls of the fourth ventricle near the obex.
 This structure is one of the circumventricular organs and is more permeable to many
substances than the underlying medulla.
 There are 5-HT3 receptors in the small intestine, and serotonin (5-HT) released from
enterochromaffin cells appears to initiate impulses in afferents that trigger vomiting.
 In addition, there are dopamine D2 receptors and 5-HT3 receptors in the area postrema
and adjacent nucleus of the solitary tract.
 5-HT3 antagonists such as ondansetron and D2 antagonists such as chlorpromazine and
haloperidol are effective antiemetic agents.
 Corticosteroids, cannabinoids, and benzodiazepines, alone or in combination with 5-HT3 and
D2 antagonists, are also useful in treatment of the vomiting produced by chemotherapy.
 The benzodiazepines probably reduce the anxiety associated with chemotherapy.

HYPOTHALAMUS
ANATOMIC CONSIDERATIONS
Introduction
The hypothalamus is the portion of the anterior end of the diencephalon that lies below the
hypothalamic sulcus and in front of the interpeduncular nuclei.

Relation to the Pituitary Gland

 There are neural connections between the hypothalamus and the posterior lobe of the
pituitary gland and vascular connections between the hypothalamus and the anterior lobe.
 Embryologically, the posterior pituitary arises as an evagination of the floor of the third
ventricle.
 It is made up in large part of the endings of axons that arise from cell bodies in the supraoptic
and paraventricular nuclei and pass to the posterior pituitary via the
hypothalamohypophysial tract.
 Most of the supraoptic fibers end in the posterior lobe itself, whereas some of the
paraventricular fibers end in the median eminence.
 The anterior and intermediate lobes of the pituitary arise in the embryo from Rathke's pouch,
an evagination from the roof of the pharynx.
 Sympathetic nerve fibers reach the anterior lobe from its capsule, and parasympathetic fibers
reach it from the petrosal nerves, but few if any nerve fibers pass to it from the
hypothalamus.
 However, the portal hypophysial vessels form a direct vascular link between the
hypothalamus and the anterior pituitary. Arterial twigs from the carotid arteries and circle of
Willis form a network of fenestrated capillaries called the primary plexus on the ventral
surface of the hypothalamus
 The median eminence is generally defined as the portion of the ventral hypothalamus from
which the portal vessels arise. This region is "outside the blood-brain barrier"

Afferent & Efferent Connections of the Hypothalamus

» The principal afferent and efferent neural pathways to and from the hypothalamus are mostly
unmyelinated. Many connect the hypothalamus to the limbic system.
» There are also important connections between the hypothalamus and nuclei in the midbrain
tegmentum, pons, and hindbrain.
» Norepinephrine-secreting neurons with their cell bodies in the hindbrain end in many different
parts of the hypothalamus
» Paraventricular neurons that probably secrete oxytocin and vasopressin project in turn to
the hindbrain and the spinal cord.
» Neurons that secrete epinephrine have their cell bodies in the hindbrain and end in the
ventral hypothalamus.
» There is an intrahypothalamic system of dopamine-secreting neurons which have their cell
bodies in the arcuate nucleus and end on or near the capillaries that form the portal vessels
in the median eminence.
» Serotonin-secreting neurons project to the hypothalamus from the raphe nuclei.

HYPOTHALAMIC FUNCTION
Relation to autonomic function
Effects of Stimulation
 Stimulation of the superior anterior hypothalamus occasionally causes contraction of the
urinary bladder, a parasympathetic response. However, hypothalamic stimulation causes
very few other parasympathetic responses.
 Stimulation of some parts of the hypothalamus can cause cardiac arrhythmias; these are due
to simultaneous activation of vagal and sympathetic nerves to the heart.
 Stimulation of various parts of the hypothalamus, especially the lateral areas, produces
diffuse sympathetic discharge and increased adrenal medullary secretion like the mass
sympathetic discharge seen in animals exposed to stress (the flight or fight reaction)

Relation to sleep: The basal forebrain sleep zone includes parts of the hypothalamus.

Relation to cyclic phenomena

 Most if not all living organisms have rhythmic fluctuations in bodily function that are about 24
hours in length, i.e., they are circadian (L circa "about"  dia "day").
 Normally they become entrained, i.e., synchronized to the day-night light cycle in the
environment.
 In mammals, including humans, the rhythms that are controlled include the rhythms in ACTH
secretion and melatonin secretion sleep-wake cycles, the body temperature cycle, and
activity patterns in laboratory animals.
 Most of these rhythms are controlled by the suprachiasmatic nuclei (SCN), one nucleus on
each side above the optic chiasm
 In mammals, the SCN cells contain a clock that is made up of at least six proteins.
 PER proteins are produced and then phosphorylated by kinases, and the phosphorylated
PERs inhibit the production of PERs in a regular circadian pattern.
 The afferent signal that entrains the circadian rhythms to the day-night cycle comes from the
eyes, since removal of the eyes abolishes entrainment and there are retinohypothalamic
fibers that pass directly from the optic chiasm to the SCN.
 It is interesting that exposure to bright light can either advance, delay, or have no effect on
the sleep-wake cycle in humans depending on the time of day when it is experienced.
 During the usual daytime it has no effect, but just after dark it delays the onset of the sleep
period, and just before dawn it accelerates the onset of the next sleep period. Injections of
melatonin have similar effects.

HUNGER
Feeding & Satiety
 Body weight is determined by the balance between caloric intake and energy
expenditure. Both are regulated on a day-to-day and longer-term basis. Food intake is
regulated not only on a meal-to-meal basis but also in a way that generally maintains
weight at a given set point.
 Dieters can lose weight when caloric intake is reduced but when they discontinue their
diets, 95% of them regain the weight they lost.
 Similarly, during recovery from illness, food intake is increased in a catch-up fashion until
lost weight is regained.
 Energy output is also regulated. Energy output is increased after meals by the specific
dynamic action (SDA) of the food and an increase in sympathetic discharge.
 The SDA is not regulated, but the increase in sympathetic discharge is.
 Fasting decreases the metabolic rate over a period of days, conserving energy
Role of the Hypothalamus
 Hypothalamic regulation of the appetite for food depends primarily upon the interaction of
two areas: a lateral "feeding center" in the bed nucleus of the medial forebrain bundle at its
junction with the pallidohypothalamic fibers, and a medial "satiety center" in the
ventromedial nucleus.
 Stimulation of the feeding center evokes eating behavior in conscious animals, and its
destruction causes severe, fatal anorexia in otherwise healthy animals.
 Stimulation of the ventromedial nucleus causes cessation of eating, whereas lesions in
this region cause hyperphagia and, if the food supply is abundant, the syndrome of
hypothalamic obesity
 Satiety center functions by inhibiting the feeding center.
 The feeding center is chronically active and that its activity is transiently inhibited by activity
in the satiety center after the ingestion of food.
 However, it is not certain that the feeding center and the satiety center simply control the
desire for food.
 Neuropeptide Y when injected into the hypothalamus, this 36-amino-acid polypeptide
increases food intake, and inhibitors of neuropeptide Y synthesis decrease food intake.
 Neuropeptide Y-containing neurons have their cell bodies in the arcuate nuclei and project
to the paraventricular nuclei.
 Neuropeptide Y mRNA in the hypothalamus increases during feeding and decreases during
satiety.
 Neuropeptide Y exerts its effect through three known receptors-Y1, Y2, and Y5-all coupled
to G proteins. Activation of the Y5 receptor increases food intake, but the situation is
complex because activation of the Y2 receptor has an apparent inhibitory effect.
 Other polypeptides that increase food intake include orexin-A and orexin-B, derived from
the same gene by alternate splicing. They act on two receptors.
 Orexins are synthesized in neurons located in the lateral hypothalamus. They are also of
interest because a mutation in one of the orexin receptor genes causes narcolepsy in dogs.
 Another polypeptide that increases food intake in mammals is melanin-concentrating
hormone, a 19-amino-acid polypeptide which is secreted by the pituitary in fish and is
involved in the control of their skin color. In mammals, its mRNA is found only in the lateral
hypothalamus and the zona incerta.
 On the other hand, pro-opiomelanocortin (POMC) derivatives decrease food intake.
 There are four established receptors for these derivatives: MC1-R, which is involved in skin
pigmentation; MC2-R, which is involved in adrenal glucocorticoid production; MC3-R, which
is associated with the control of sebaceous gland secretion; and MC4-R, which mediates the
effects on appetite.
 Another neuropeptide found in the hypothalamus that inhibits food intake is CART (cocaine-
and amphetamine-regulated transcript). CRH, the brain hormone that stimulates ACTH
secretion, also inhibits food intake.
 Catecholamines are also involved in the regulation of body weight.

Afferent Mechanisms
Four main hypotheses about afferent mechanisms that are involved in the control of food intake
have been advanced, and they are not mutually exclusive.
1. The lipostatic hypothesis holds that adipose tissue produces a humoral signal that is
proportionate to the amount of fat and acts on the hypothalamus to decrease food intake
and increase energy output.
2. The gut peptide hypothesis postulates that food in the gastrointestinal tract causes the
release of one or more polypeptides which act on the hypothalamus to inhibit food intake.
3. The glucostatic hypothesis holds that increased glucose utilization in the
hypothalamus produces a sensation of satiety.
4. The thermostatic hypothesis holds that a fall in body temperature below a given set
point stimulates appetite and a rise above the set point inhibits appetite.

Other Factors Affecting Food Intake

 Food intake is increased in cold weather and decreased in warm weather.
 Distention of the gastrointestinal tract inhibits appetite, and contractions of an empty stomach
(hunger contractions) stimulate appetite, but denervation of the stomach and intestines
does not affect the amount of food eaten. Especially in humans, cultural factors, environment,
and past experiences related to the sight, smell, and taste of food also affect food intake.
 Brown fat, a special form of body fat that has an extensive sympathetic innervation, may
also contribute to the regulation of body weight.

Long-Term Regulation of Appetite

The net effect of all the appetite-regulating mechanisms in normal adult animals and humans is
an adjustment of food intake to the point where caloric intake balances energy expenditures, with
the result that body weight is maintained.

TEMPERATURE REGULATION
Introduction
 In the body, heat is produced by muscular exercise, assimilation of food, and all the vital
processes that contribute to the basal metabolic rate
 It is lost from the body by radiation, conduction, and vaporization of water in the respiratory
passages and on the skin.
 Small amounts of heat are also removed in the urine and feces.
 The balance between heat production and heat loss determines the body temperature.
 Because the speed of chemical reactions varies with the temperature and because the
enzyme systems of the body have narrow temperature ranges in which their function is
optimal, normal body function depends upon a relatively constant body temperature.
 In birds and mammals, the "warm-blooded" (homeothermic) animals, a group of reflex
responses that are primarily integrated in the hypothalamus operate to maintain body
temperature within a narrow range in spite of wide fluctuations in environmental temperature.

Normal Body Temperature

» In humans, the traditional normal value for the oral temperature is 37 °C (98.6 °F), but in one
large series of normal young adults, the morning oral temperature averaged 36.7 °C, with a
standard deviation of 0.2 °C.
» Therefore, 95% of all young adults would be expected to have a morning oral temperature of
36.3-37.1 °C (97.3-98.8 °F; mean ± 1.96 standard deviations).
» Various parts of the body are at different temperatures, and the magnitude of the temperature
difference between the parts varies with the environmental temperature
» The extremities are generally cooler than the rest of the body. The temperature of the
scrotum is carefully regulated at 32 °C. The rectal temperature is representative of the
temperature at the core of the body and varies least with changes in environmental
temperature.
» The oral temperature is normally 0.5 °C lower than the rectal temperature, but it is affected by
many factors, including ingestion of hot or cold fluids, gum-chewing, smoking, and mouth
breathing.
» The normal human core temperature undergoes a regular circadian fluctuation of 0.5-0.7 C.
» In individuals who sleep at night and are awake during the day (even when hospitalized at
bed rest), it is lowest at about 6 AM and highest in the evenings
» It is lowest during sleep, is slightly higher in the awake but relaxed state, and rises with
activity.
» In women, there is an additional monthly cycle of temperature variation characterized by a
rise in basal temperature at the time of ovulation
» Temperature regulation is less precise in young children, and they may normally have a
temperature that is 0.5 C or so above the established norm for adults.
» During exercise, the heat produced by muscular contraction accumulates in the body, and the
rectal temperature normally rises as high as 40 °C (104 °F).
» This rise is due in part to the inability of the heat- dissipating mechanisms to handle the
greatly increased amount of heat produced, but there is evidence that in addition there is an
elevation of the body temperature at which the heat-dissipating mechanisms are activated
during exercise
» Body temperature also rises slightly during emotional excitement, probably owing to
unconscious tensing of the muscles.
» It is chronically elevated by as much as 0.5 °C when the metabolic rate is high, as in
hyperthyroidism, and lowered when the metabolic rate is low, as in hypothyroidism.
» Some apparently normal adults chronically have a temperature above the normal range
(constitutional hyperthermia).

Heat Production
 A variety of basic chemical reactions contribute to body heat production at all times.
 Ingestion of food increases heat production because of the specific dynamic action of the
food but the major source of heat is the contraction of skeletal muscle
 Heat production can be varied by endocrine mechanisms in the absence of food intake or
muscular exertion.
 Epinephrine and norepinephrine produce a rapid but short-lived increase in heat production;
thyroid hormones produce a slowly developing but prolonged increase.
 Furthermore, sympathetic discharge is decreased during fasting and increased by feeding,
 A source of considerable heat, particularly in infants, is brown fat. This fat has a high rate of
metabolism, and its thermogenic function has been likened to that of an electric blanket.

Heat Loss
 The amount of heat reaching the skin from the deep tissues can be varied by changing the
blood flow to the skin.
 When the cutaneous vessels are dilated, warm blood wells into the skin, whereas in the
maximally vasoconstricted state, heat is held centrally in the body.
 The rate at which heat is transferred from the deep tissues to the skin is called the tissue
conductance.
 When the thickness of the trapped layer is increased by erection of the hairs (horripilation),
heat transfer across the layer is reduced and heat losses (or, in a hot environment, heat
gains) are decreased.
 "Goose pimples" are the result of horripilation in humans; they are the visible manifestation of
cold-induced contraction of the piloerector muscles attached to the rather meager hair
supply.
 The other major process transferring heat from the body in humans and other animals that
sweat is vaporization of water on the skin and mucous membranes of the mouth and
respiratory passages. Vaporization of 1 g of water removes about 0.6 kcal of heat.
 A certain amount of water is vaporized at all times. This insensible water loss amounts to
50 mL/h in humans.