HypothalamusHypothalamusChapter 6Chapter 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 HomeostasisHypothalamus 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

VisceralAfferents

Nucleusof the

Solitary Tract

Brain StemNuclei

AutonomicPreganglionic

Nuclei

HormonalOutput

AutonomicOutput

TargetOrgans

HypothalamicNuclei

Hypothalamic Role in Emotion

Hypothalamus

PituitaryReleasing Factors

AutonomicNervous System

Adenohypophysis(Anterior Pituitary)

Neurohypophysis(Posterior Pituitary)

Sympathetic

Parasympathetic

“I feel fear!”

Hypothalamus

AmygdalaAmygdala

Cortex, Cortex, septumseptum

medial forebrain

bundle

Amygdala Amygdala ventral

routeBrainstemBrainstemspinal cordspinal cord

medial

forebrain

bundle

stria

terminalis

Anterior NucleusAnterior Nucleusmtt

BrainstemBrainstemdorsal long.

fasciculus

post.post.magno

(SO, PV)ant.ant.parvo

PituitaryPituitary

Hypothalamus

AmygdalaAmygdala

Cortex, Cortex, septumseptum

medial forebrain

bundle

Amygdala Amygdala ventral

routeBrainstemBrainstemspinal cordspinal cord

medial

forebrain

bundle

stria

terminalis

Anterior NucleusAnterior Nucleusmtt

BrainstemBrainstemdorsal long.

fasciculus

post.post.magno

(SO, PV)ant.ant.parvo

PituitaryPituitary

The hypothalamus not only The hypothalamus not only influences how you feel, it influences how you feel, it

influences how you influences how you interpret the consequences interpret the consequences

of those feelings.of those feelings.

Hypothalamus

PhysicalPhysicalinputsinputs

humoral,

temperature

AmygdalaAmygdala

Cortex, Cortex, septumseptum

medial forebrain

bundle

RetinaRetina optic

tract

Amygdala Amygdala ventral

route

BrainstemBrainstemspinal cordspinal cord

medial

forebrain

bundle

stria

terminalis

HippocampalHippocampalformationformation

fornix

BrainstemBrainstemdorsal long.

fasciculus

Thermo-regulation Thermo-regulation (body temperature)(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 Thermo-regulation (body temperature)(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

Methods of thermo-regulation by the body

Response to Cold Response to Heat

Disorders of Thermo-regulationDisorders 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

HyperpyrexiaHyperpyrexia• 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

HypothalamusHypothalamus

• 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%)

ThirstThirst

• 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 RhythmCircadian 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

Biological Clocks May Exist in All Cells of the Body

Effects on Effects on Cardiovascular FunctionCardiovascular Function

• Main centers for controlling heart rate and contractility are in the medulla

• Lesions of the hypothalamus can cause abnormalities in cardiac conduction

– Subarachnoid hemorrhage can produce EKG abnormalities due to direct irritation of the hypothalamus

Control of Feeding

FeedingFeeding• 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.

Feedback Mechanisms Feedback Mechanisms Controlling FeedingControlling Feeding

• Notion of "Set Point"

• Feedback from gut hormones

– e.g. Cholecystokinin

• Released from small intestine in response to feeding

• Inhibits or suppresses feeding

• Slow onset

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 GHS-R, as shown) and has an opposite effect on food intake, body weight, and gastrointestinal motility.K. SUTLIFF/SCIENCE, 2005

Dietary polyunsaturated fatty acids are incorporated into membrane phospholipids, which can subsequently be metabolized into the two major endocannabinoids, 2-AG and anandamide, by membrane-associated enzymes.

Degradative enzymes for endocannabinoids are localized to internal membranes. Leptin signaling can influence 2-AG biosynthesis in the hypothalamus and anandamide hydrolysis

Copyright ©2009 Society for Neuroscience Foo, H. et al. J. Neurosci. 2009;29:13053-13062

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.

Body Weight

Bas

al M

etab

olic

Rat

e

Relation between body size and metabolism

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

Van Praag, TINS, 2009

The potential synergy between diet & exercise could involve common cellular pathwaysimportant for neurogenesis, cell survival, synaptic plasticity and vascular function.

Optimal maintenance of brain health might depend on exercise and intake of natural products.

OXYGEN: A Pro-Aging OXYGEN: A Pro-Aging MoleculeMolecule

• 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 MiceEffect of Caloric Restriction on MiceFewer cancerous tumors among those on restricted dietsFewer cancerous tumors among those on restricted diets

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.

Hepatoma Lymphoma All Tumors0

10

20

30

40

50

Pe

rcen

t of M

ice with T

um

ors

Normal Diet (control group)Caloric Restrictions

9

2.1

15

1

45

11

Degenerative DiseasesDegenerative DiseasesControl Rats vs. Restricted RatsControl Rats vs. Restricted Rats

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.

Kidney Muscle Heart Vascular0

20

40

60

80

100

Pe

rcent of R

ats with

D

ege

nera

tive Dise

ase

Normal Diet (control group)Caloric Restrictions

55

35

75

18

80

19

95

25

Diaease Type

• 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?Obesity: Why do we eat so much?

• We live in an environment in which an endless variety of foods of the highest positive-incentive value are readily and continuously available.

Obesity: Why do we eat so much?Obesity: Why do we eat so much?

• Average quality-of-life rating assigned to U.S. children with cancer:

ObesityObesity

•Average quality-of-life rating assigned to obese children:

69

67

• 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.

Obesity Treatment: Less eating or Obesity Treatment: Less eating or more exercise?more exercise?

Liposuction?