Q3: Neurology: The Hypothalamus

Front 1

The HYPOTHALAMUS is the key center involved in what three things?

Back 1

1) Homeostasis
2) Integrative center for a) endocrine b) autonomic c) somatomotor systems and also plays role in
3) modulating affective behavior

Front 2

What are a fewt things that the hypothalamus does regulate?

Back 2

1) temperature
2) heart rate
3) blood pressure
4) blood osmolarity
5) calcium homeostasis
6) water and food intake
7) electrolyte balance
8) sexual,
9) reproductive,
10)nurturing behaviors
11)sleep
12)circadian rhythym

Front 3

What's important to note?

Back 3

Consistent with its role of integrating and odering behavioral priorities, specific nuclei within the hypothalamus typically subserve more than one physiological function, and neurons within a given cytoarchitecturally- defined region are heterogeneous with regard to cellular phenotype.

Front 4

What are the 5 functions of the hypothalamus?

Back 4

1) receives sensory information from almost entire body

2) gets visceral inputs, olfactory and retinal inputs

3) has internal "sensor" neurons that respond to changes in physiological state incoming sensory info is compared with "bio set point"

4) It is a primary target of steroid and peptide hormones

5) plays an active role regulating physiological and cognitive aspects of emotion (via amygdala)

Front 5

I. OVERVIEW OF HYPOTHALAMIC ANATOMY

Where is the hypothalamus located?

Back 5

1) ventral half of diencephalon
2) bilateral symmetry and surrounds 3rd ventricle
3) lies just above the pituitary gland (hypophysis)
4) connected to the pituitary
5) Extends anteriorly from the regoin of the optic chiasm to the posterior edge of the mammilary body
6) Merges with the basal ol factory anteriorly
7) Merges without demarcation into the midbrain centrak grey and the tegmentum
8) The thalamus is immediately dorasal to the hypothalamus
9) Subthalamic region is lateral and caudal to it

Front 6

What are the 3 regions of the HYPOTHALAMUS?

Back 6

1) ANTERIOR/ PREOPTIC AREA

2) TUBERAL (above the tuber cinereum: "the greay swelling" on the ventral surface of the brain, giving rise to the infundibulum)


3) POSTERIOR above and including the MAMMILARY BODIES

Front 7

What is the MEDIAN EMINANCE?

Back 7

It is the raised area on the infundibulum hypothalami at the floor of the third ventricle of the brain

Below the infundibular stem or stalk of the pituitary gland, and it contains the primary capillary network of the hypophysial portal system

It's included as part of the tuber cinereum

Front 8

NOTE: The hypothalamic functions are highly interrelated.

Back 8

*

Front 9

What are the 3 regions of the brain and the different functions should know? (I)

Back 9

I. PREOPTIC/ ANTERIOR REGION

A) Thermosensitive neurons (temperature regulation) (MEDIAL PREOPTIC AREA)

B) Reproductive, sexual and maternal behaviors: gonadotroptin secretion (MEDIAL PREOPTIC AREA)

C) Circadian rhythyms (SUPRACHIASMIATIC NUCLEUS)

Front 10

(II)

Back 10

II. TUBERAL REGION:
A) Reproductive and sexual behavior (VENTROMEDIAL NUCLEUS)

B) Regulation of food intake (LATERAL HYPOTHALAMIC AREA: feeding center)

C) General arousal and sensitization associated with motivated behaviors (LATERAL HYPOTHALAMIC AREA)

Front 11

(III)

Back 11

III. POSTERIOR REGION

Front 12

II. MAJOR TRACTS OF THE NUCLEUS

What are the major afferents to the hypothalamus? (SHAORB)

Back 12

1) Septal nuclei and neighboring forebrain

2) Hippocampus

3) Amygdala

4) Orbital/ frontal cortex

5) Retina

6) Brainstem and spinal cord

Front 13

What are the MAJOR AFFERENTS (MANY BIDIRECTIONAL)? (3)

*see notes for pathway!!

Back 13

1) LIMBIC

A) MEDIAN FOREBRAIN BUNDLE (mfb)- - lateral hypothalamus

B) PAPEZ CIRCUIT (AFFERENT WING): FORNIX - - mammillary body

C) STRIA TERMINALIS - - amygdala

2)FROM BRAINSTEM/ SPINAL CORD (carry sensory information)

3) FROM RETINA

a) RETINOHYPOTHALAMIC TRACT

Front 14

What are the MAJOR EFFERENTS? (3)

*see notes for pathway

Back 14

1) LIMBIC
A) PAPEZ CIRCUIT (EFFERENT WING): mammillothalamic tract

2) RETICULAR SYSTEM
A) Mammillotegmental tract

3) AUTONOMIC
A) MFB
B) DLF (dorsal longitudinal fasciculus)

4) ENDOCRINE
A) PITUITARY: supraopticohypophyseal tract
B) TUBERINFUNDIBULAR TRACT

Front 15

What is a PARVOCELLULAR NEURON?

Back 15

PARVOCELLULAR neurons in the paraventricular region of the hypothalamus (arcuate, preoptic area, ventromedial nucleus) influence hormonal release from the anterior pituitary via the hypophyseal portal system. Releasing/inhibiting hormones (e.g., gonadotropin releasing hormone: GnRH), in turn, regulate hormonal release from the anterior pituitary via this vascular connection. The collection of axons that are from neurons that secrete releasing/inhibitory factors is called the tuberoinfundibular tract.

Front 16

III. REPRODUCTIVE BEHAVIORS AND SEXUAL DIFFERENTIATION OF THE HYPOTHALAMUS

What are the 4 major aspects of sexual differentiation?

Back 16

1) genetic sex

2) gonadal sex

3) phenotypic or body sex

4) brain or behavioral sex
gender identity: whether one thinks of oneself as male/female

Front 17

IV. SEXUALLY DIMORPHIC REGIONS OF THE HYPOTHALAMUS

What does the MEDIOBASAL HYPOTHALAMUS include and what does it do?

Back 17

It includes the VMN and mPOA

1) Regulates gonadotropin secretion (GnRH neurons)

2) Regulates for expression of sexual and reproductive behaviors

3) Express highest levels of androgen, estrogen and progestin receptors in the brain

4) Both regions needed to manifest sex-appropriate sexual behaviors

Front 18

What are organizational effects of gonadal steroids on the brain?

Back 18

Gonadal steroids act during a limited critical period in perinatal development to impart permanent, sex-specific differences in brain organization and function. These organizational differences are believed to underlie, and are required for, the manifestation of sex-specific sexual behaviors.


If changes in steroid environment are made AFTER the critical period, the reversal of the brain anatomy and of the sex-specific behavior does not occur.

Front 19

What are the Activational Effects of Gonadal Steroids on the Brain?

Back 19

Transient increases in gonadal steroids act to alter the brain and resultant behavior. The effects are transitory, reverting when steroid levels drop.

Example: Steroid-dependent increases in dendritic spines in the hippocampus: may contribute to the positive effects of estrogen on memory

Front 20

Sexual dimorphism in the human nervous system:

At what age is sexual dimorphism evident?

Back 20

Sex differences in relative brain size are evident in humans as early as two years of age
>75% of cases of anorexia nervosa and bulimia occur in women
>75% of cases of dyslexia, sleep apnea and Tourette's syndrome occur in men

Front 21

V. What is OBESITY and what diseases is it associated with?

Back 21

OBESITY: a condition that is relevant to 33% of the US population and is associated with development of type 2 diabetes mellitus, coronary heart disease, an increased incidence of some cancers, of obstructive sleep apnea, and of osteoarthritis.

Hint 21

associated with 5 diseases

Front 22

What are the MOST IMPORTANT regions that contain pathways that signal neuropeptides that stimulate or inhibit eating?

Back 22

1) VMN, ARCUATE - decrease food intake, SATIETY
2) LHA - increase food intake, HUNGER

Front 23

What did the early lesion/ stimulation studies ential?

Back 23

*

Front 24

What molecules STIMULATE feeding?

OREXIGENIC

Back 24

NPY (neuropeptide Y)

****orexin (hypocretin)

cannabinoids (exogenous and endogenous)

agouti-related protein (AGRP)

MCH (melatonin-concentrating hormone)

galanin

ghrelin

Front 25

What molecules SUPPRESS feeding?

ANOREXIGENIC

Back 25

****Leptin

CRH (corticotropin releasing hormone)

POMC (proopiomelanocortin)

α-MSH (α-melanocyte stimulating hormone)

CART (cocaine- and amphetamine-regulated transcript)

insulin

neurotensin

interleukin 1β

TRH (thyrotropin –releasing hormone)

Peptide YY

Front 26

What is LEPTIN?

Back 26

molecular signal from body to brain:
reflects the state of nutrition/energy reserves
Small peptide hormone
Product of the ob gene.
Produced mainly by white adipose cells
Has direct access to hypothalamic nuclei because the blood brain barrier is compromised at the hypothalamus (there is a "window" where the median eminence protrudes).
Leptin receptors expressed in the Arcuate nucleus
Mice engineered to be leptin-deficient (ob/ob) or leptin receptor-deficient (db/db) are obese

Front 27

What is NPY?

Back 27

the most orexigenic peptide known
Arcuate neurons (have leptin receptors) secrete NPY
Abnormally high NPY produces hyperphagia and obesity
Leptin decreases NPY expression
Starvation or fasting decreases leptin: increase in NPY expression

Front 28

I. Wakefulness and Food Intake

What is the most important region for integration and what does it do?

Back 28

LHA

Regulates weight and food intake (internal set point)

Stimulation promotes smooth transitions between sleep to wakeful states

Lesions induce somnolence and loss of attention

Antagonism of orexin inhibits male copulatory behavior

Front 29

What is orexin?

What is it produced by?

What are levels of orexin dependent on?

Back 29

orexigenic peptide

Produced by a small group of neurons in the LHA.
Orexin neurons have profuse arborizations and innervate widespread areas of the brain

Levels of orexin and the response of orexin-sensitive neurons dependent on circadian time

Front 30

What is NARCOLEPSY?
(neurodegenerative disease with loss of orexin neurons)

Back 30

In humans, 90% loss (neurodegeneration) of orexin neurons

1 in 2000 people: 3rd most prevalent neurodegenerative disease

Daytime sleep disorder (excessive sleepiness)

Abnormal REM sleep

Cataplexy

Front 31

II. Energy balance and reproduction

What is the REPRODUCTIVE STATE DEPENDENT upon?

Back 31

Reproductive state is dependent upon feeding and body weight.

Fertility is compromised in both severely undernourished and obese females

Orexin neurons are activated in male sexual behavior

Hypothalamus provides a molecular/cellular substrate for integrating information about energy utilization and reproductive fitness and subsequently regulating reproduction in a manner consistent with the available energy stores.

Front 32

What is the significance of OREXIN?

Back 32

Orexin plays a central role in behavioral states that require arousal (wakefulness, eating, drug-seeking, sexual behavior)

Front 33

VI. Circadian Rhythm

What is it?

What is it generated by?

Back 33

Circadian rhythms are generated by "circadian clocks" encoded in neural substrates of the CNS

1) oscillations with a cycle length (period) of ~24 hrs even in constant environmental conditions
2) ability of environmental stimuli (light) to reset or entrain the clock
3) resistance of the period to temperature change within physiological limits
4) molecular control of biological clocks involves interactions of a number of transcription factors

Front 34

What is involved in the primary feedback loop?

Back 34

the positive transcription factors CLOCK and BMAL1 form heterodimers that turn on transcription of two subsets of genes, the period genes Per) and the cryptochrome genes (Cry)

PER and CRY form heterodimers that shut down transcription of the clock/bmal genes

CLOCK:BMAL1 dimers also turn on Rev-erbα/Rorα transcription and the transcription factors made by these genes bind to promoters in Bmal1 to both positively AND negatively regulate its expression

The proteins made from these genes are not very stable and their stability is regulated by casein kinases

• Mutations in the casein kinases cause decreased stability and shorter circadian cycles. Mutations in casein kinase and in Per genes are implicated in familial advanced sleep phase syndrome (FASPS)

Front 35

What MUST YOU REMEMBER?

Back 35

DO remember the concept of:

Circadian control is via interactions of short-lived transcription factors (negative and positive feedback loops) and that a genetic defect in these feedback loops is implicated in FASPS.

Front 36

What is Suprachiasmatic nucleus (SCN)

Back 36

The master clock: The SCN is both necessary and sufficient to generate circadian rhythmicity
Receives a direct input from the retina
Major efferent projections to:

periventricular zone of the hypothalamus
VMN
LHA

Front 37

Rozerem (ramelteon)

Back 37

melatonin receptor (MT1 and MT2) agonist FDA-approved for treatment of insomnia (not a controlled substance)

Melatonin receptors are expressed in the SCN and regulate both the onset of sleep (MT1) and normal circadian rhythm (MT2)

Ramelteon has a greater affinity for MT1 than does melatonin itself

Phase II and II trials for treatment of jet-lag and shift-work sleep disorder