Hypothalamus
Chapter 6
• Center that integrates autonomic, endocrine and
behavioral responses
• Regulates the internal environment (homeotasis)
• Makes survival and propagation more likely
• Combination of neural and endocrine inputs
and outputs
• Plays a major role in functions as diverse as
feeding, drinking, temperature regulation, sexual
responses and determining “How you feel.”
Hypothalamus and Homeostasis
• Close tolerances necessary for life
– Small percentage change in body
temperature, electrolytes, and blood pH can
cause death
• Homeostasis and the internal milieu
• Interface between external and internal
environment
– Endocrine system
– Autonomic nervous system
Hypothalamic Role in Emotion
Visceral
Afferents
Hypothalamic
Nuclei
Hormonal
Output
Nucleus
of the
Solitary Tract
Target
Organs
Autonomic
Output
Brain Stem
Nuclei
Autonomic
Preganglionic
Nuclei
Hypothalamus
Pituitary
Releasing Factors
Adenohypophysis
(Anterior Pituitary)
Autonomic
Nervous System
Neurohypophysis
(Posterior Pituitary)
Sympathetic
Parasympathetic
“I feel fear!”
stria
terminalis
mtt
Cortex,
septum
Amygdala
medial forebrain
bundle
Anterior Nucleus
dorsal long.
fasciculus
Brainstem
medial
forebrain
bundle
Brainstem
spinal cord
Hypothalamus
ventral
route
ant.
Amygdala
parvo
magno
(SO, PV)
Pituitary
post.
stria
terminalis
mtt
Cortex,
septum
Amygdala
medial forebrain
bundle
Anterior Nucleus
dorsal long.
fasciculus
Brainstem
medial
forebrain
bundle
Brainstem
spinal cord
Hypothalamus
ventral
route
ant.
Amygdala
parvo
magno
(SO, PV)
Pituitary
post.
The hypothalamus not only
influences how you feel, it
influences how you
interpret the consequences
of those feelings.
stria
terminalis
Physical
inputs
Cortex,
septum
Retina
humoral,
temperature
medial forebrain
bundle
fornix
Hippocampal
formation
dorsal long.
fasciculus
Brainstem
medial
forebrain
bundle
Brainstem
spinal cord
Hypothalamus
optic
tract
Amygdala
Amygdala
ventral
route
Thermo-regulation
(body temperature)
• Involves autonomic nervous, endocrine,
and skeletomotor systems
• Body temperature detectors
– Peripheral: skin, spinal cord, viscera
– Central: anterior hypothalamus
• Body temperature effectors
– Heat retention or generation:
posterior hypothalamus
– Heat dissipation: anterior hypothalamus
Thermo-regulation
(body temperature)
• Heat dissipating mechanisms
– Dilation of blood vessels in the skin
– Inhibition of shivering
• Heat conserving mechanisms
– Vasoconstriction of blood vessels in the
skin
– Shivering
– Increased secretion of thyroxin
Temperature control center. In the mammalian brain, a series of
neural pathways (red) control the body’s autonomic responses that
regulate heat conservation and production, respectively.
Cells in the paraventricular and dorsomedial hypothalamic nuclei,
and in the raphe (5HT), signal to sympathetic preganglionic neurons
in the spinal cord to control thermogenesis.
These pathways are in turn regulated by an inhibitory input (blue)
from the medial preoptic hypothalamus that is responsive to
preoptic temperature.
Thermogenesis is subserved by neural inputs
to brown adipose tissue, at least in small
mammals, where β3 adrenergic receptors
mediate production of uncoupling protein 1
(UCP-1). UCP-1 allows mitochondria in
brown adipose tissue to convert adenosine
5'-triphosphate (ATP) to heat, rather than to
energy for performing work. Thus, small
mammals that lack sufficient mass for heat
retention carry portable heaters in the form
of brown adipose tissue that allow them to
avoid hypothermia.
Low body temperature does prolong life span in
poikilothermic fish (in which body temperature
fluctuates with that of the external environment)
Homeotherms with a restricted caloric intake develop
a low body temperature and also have a prolonged
life span.
one might wonder whether 37°C is indeed the
optimal body temperature for humans, and why
evolution has not selected for a lower body
temperature and longer life span. However, there
would be little evolutionary pressure to extend the
number of years of life after reproduction is
finished
Response to Cold
Response to Heat
Methods of thermo-regulation by the body
Disorders of Thermo-regulation
• Lesions of heat conserving mechanisms
– Lesion of posterior hypothalamus
– Causes hypothermia
• Lesions of heat dissipating mechanisms
– Lesion of anterior hypothalamus
– Causes hyperthermia
• Disconnection syndrome
– Thermo-regulator mechanisms separated
from effectors
• Cannot control skin vasodilatation
• Cannot shiver
– Causes piokoliothermia
Hyperpyrexia
• Malignant Hyperthermia
– Response to general anesthesia
– Associated with neuroleptic medications
• Interferes with dopamine function in
the hypothalamus
– Interference with peripheral heat
dissipating mechanism
• Anti-cholinergic medications interfere
with sweating and heat dissipation
Hypothalamus
• Center that integrates autonomic, endocrine and
behavioral responses
• Regulates the internal environment (homeotasis)
• Makes survival and propagation more likely
• Combination of neural and endocrine inputs
and outputs
• Plays a major role in functions as diverse as
feeding, drinking, temperature regulation,
sexual responses
(CSF 1%)
Thirst
• Function of serum osmolality and blood volume
• Osmotic receptors in the hypothalamus
• Volume receptors in the right atrium of the heart
and great veins
– Vasopressin release from hypothalamus
• Increases water reabsorption from the kidney
• Inhibited by ethanol
• Neurogenic diabetes insipidus
OVLT
Two Kinds of Thirst
Drinking Behavior
• Shorter stay = more drinks/hr
• Drinking alone = more drinks/hr
• Rhythm that equals the heart
rate = more drinking
• Lyrics: sad songs = more
drinking
• More men than women = more
drinking
• Live band = more drinking
• Action photography =
more drinking
Circadian Rhythm
• Oscillations during the course of the day
– Corticosteriods
– Feeding and drinking behavior
– Growth hormone secretion
• Lesions of the suprachiasmatic nuclei of
the hypothalamus disrupts these
oscillations
Suprachiasmatic
Nucleus
Each nucleus contains about 20,000 neurons
Biological Clocks
May Exist in All
Cells of the Body
Control of Feeding
Feeding
• Complex interaction of many systems
• Regulation of energy metabolism by the
Ventromedial and Lateral nuclei of the
hypothalamus
– Physical Lesions produce hyperphagia and
obesity or reduced attention to food.
• Amygdala may also be involved indirectly
– Lesions produce hyperphagia-like symptoms
• Ventromedial hypothalamic lesions also cause
increased insulin secretion
Obesity.
The Yin and Yang
personalities of ghrelin
and obestatin.
Both hormones derive from
the same precursor protein
and are predominantly
secreted by the stomach and
released into the blood.
Each acts on a different
receptor (GPR39 and GHSR, as shown) and has an
opposite effect on food
intake, body weight, and
gastrointestinal motility.
K. SUTLIFF/SCIENCE, 2005
Orexin (hypocretin) neurons:
Peyron et al. J. Neurosci. 1998;18:9996-10015
- located only in hypothalamus
- widespread projections
- mutations produce narcolepsy symptoms
- prominent hypothesis: arousal
Functionally distinct orexin neuron groups
Projections to brainstem
arousal areas:
•LC
•TMN
•PPT/LDT
Projections to forebrain and
midbrain reward areas:
•VTA
•NAc
•Amy
LH
DMH/PFA
Reward-related inputs:
•Morphine
•Cocaine
•Food
Arousal-related inputs:
•Waking
•Stress
Basal Metabolic Rate
Relation between body size and
metabolism
Body Weight
Probability of dying from any cause
Data for 1,000,000 people
Effect of caloric
intake on:
(A)Body weight
(B)Percent survival
(C)Life-span
The potential synergy
between diet & exercise
could involve common
cellular pathways
important for neurogenesis,
cell survival, synaptic
plasticity and vascular
function.
Optimal maintenance of
brain health might depend
on exercise and intake of
natural products.
Van Praag, TINS, 2009
OXYGEN: A Pro-Aging
Molecule
• The risk is simply being alive, e.g.
breathing, eating, exercising…
• 2% of oxygen used in energy metabolism
forms oxygen free radicals that are toxic
and may damage DNA.
• The complement of anti-oxidant systems
your species possesses is directly related
to how long your species lives.
Effect of Caloric Restriction on Mice
Percent of Mice with Tumors
Fewer cancerous tumors among those on restricted diets
50
Normal Diet (control group)
Caloric Restrictions
45
40
30
20
10
15
11
9
2.1
0
Hepatoma
1
Lymphoma
All Tumors
Tumors, including hepatoma (cancer of the liver) and lymphoma (cancer of the lymph system)
were fewer in 2-year -old mice on the caloric restriction diet compared to mice on the regular diet.
Source: R.T. Bronson and R.D. Lipman, Growth, Development and Aging, 1991.
Degenerative Diseases
Control Rats vs. Restricted Rats
Percent of Rats with
Degenerative Disease
100
95
Normal Diet (control group)
Caloric Restrictions
80
80
75
55
60
35
40
25
19
20
0
Kidney
Muscle
18
Heart
Vascular
Diaease Type
The incidence of degenerative disease of the kidney, muscle, heart, and blood vessels,
in 2-year-old rats is higher on regular than on CR diets
Source: B.N. Berg, in Hypothalamus, Pituitary and Aging, 1976.
Dietary Restriction
Obesity: Why do we eat so much?
• Evolutionary: the fittest individuals
preferred a high calorie diet, ate to
capacity, stored excess calories as
fat and used those stores as
efficiently as possible.
• Cultural: 3 meals/day regardless of
whether you’re hungry.
• Social: high caloric food during
gatherings with friends.
Obesity: Why do we eat so much?
• We live in an environment in
which an endless variety of
foods of the highest positiveincentive value are readily and
continuously available.
Reactions to pain were suppressed during chocolate eating
Ingestion analgesia functions to defend eating from ending. Humans become hyperphagic
when palatable food is readily available suggesting that tasty food within easy reach is
destined for defended consumption in humans as well as other animals. Humans eat more
when more food is available even when the food is stale or even when they are made
cognizant of this tendency . The biological drive to consume palatable foods to completion
outweighs opposing cognitive and motivational factors and is likely a major factor in the
recent dramatic increase in obesity in modern human societies.
Copyright ©2009 Society for Neuroscience
Foo, H. et al. J. Neurosci. 2009;29:13053-13062
Obesity
• Average quality-of-life rating
assigned to U.S. children with
cancer: 69
•Average quality-of-life rating
assigned to obese children: 67
Obesity Treatment: Less eating or
more exercise?
• Simple exercise contributes little to
weight loss.
• Physical activity consumes only a
small portion of total energy.
• 80% of energy is used to maintain
resting physiological processes and
to digest food.
Obese people have elevated levels of
endogenous endocannabinoids
The Anti-Cannabinoid
Rimonabant
Liposuction?