Download NSCI 525 RWood 1-22-15

Ruth Wood, 1/21/16
NEUROENDOCRINE SYSTEMS & THE HYPOTHALAMUS
"People tend to stay away from the hypothalamus. Most brain scientists (including myself until recently)
prefer the sunny expanses of the cerebral cortex to the dark, claustrophobic regions at the base of the
brain. They think of the hypothalamus- though they would never admit this to you- as haunted by animal
spirits and the ghosts of primal urges. They suspect that it houses, not the usual shiny hardware of
cognition, but some witches' brew of slimy, pulsating neurons adrift in a broth of mind-altering chemicals.
Let us descend to this underworld."
Simon LeVay, The Sexual Brain, 1993
Reading: Kandel: Chapter 47 (hypothalamus), Chapter 58 (sex differences)
Beery AK, Zucker I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav
Rev. 2011 Jan;35(3):565-72.
1. Organization and neural connections of the hypothalamus.
• Hypothalamus: The hypothalamus is
part of the diencephalon, the caudal
portion of the forebrain. As the name
implies, it sits below the thalamus,
flanking the third ventricle, and directly
above the pituitary gland. Proximity to
the pituitary reflects the role of the
hypothalamus as an essential link
between the nervous and endocrine
systems. Through activity of
hypothalamic neuroendocrine neurons,
the brain communicates with the
endocrine system. In turn, the
hypothalamus has receptors for many
hormones, thereby permitting the
endocrine system to communicate with the brain.
• Pituitary: The pituitary is composed of two lobes consisting of glandular and neural tissue,
derived from the oral ectoderm and neuroectoderm, respectively. The anterior pituitary arises
from Rathke’s pouch, an evagination of the oral ectoderm. The posterior pituitary is neural
ectoderm, a downward
extension of the diencephalon.
The posterior pituitary remains
connected to the
hypothalamus via a thin stalk
of neural tissue, while the
larger anterior pituitary wraps
around the rostral face of the posterior pituitary. The pituitary is encased within a bony socket,
the sella turcica. Dorsally, the pituitary is bounded by the optic chiasm and the median
eminence, a thin strip of hypothalamic tissue at the base of the third ventricle. Because the
pituitary is surrounded by bone except at the dorsal surface, pituitary tumors may cause vision
disturbances and hypothalamic damage as they press against the overlying brain.
• Neuroendocrine neurons: Neuroendocrine neurons resemble other neurons of the central
nervous system. They are often multipolar cells with branching dendrites. Stimulation is by
synaptic input from afferent
neurons. Like other neurons,
neuroendocrine neurons
release chemical signals from
vesicles in boutons at the end
of a long axon. However,
unlike typical neurons, the
axon terminals of
neuroendocrine neurons are in
close proximity to capillaries.
Transmitters released at the
axon terminals enter the capillary lumen.
Most neuroendocrine neurons release their products near capillaries at the base of the
hypothalamus, the median eminence. The median eminence is one of the circumventricular
organs, sites along the ventricles where the blood-brain barrier is weak, allowing for
communication between the blood and the brain. Neuroendocrine neurons release releasing
hormones from synaptic vesicles stored in axon terminals. Releasing hormones diffuse into
blood vessels which travel down the pituitary stalk to the anterior pituitary, where they trigger
release of pituitary hormones. Hormones from the anterior pituitary are trophic: they stimulate
activity at their target glands. Neuroendocrine secretions from the hypothalamus are releasing
hormones because they stimulate release of trophic hormones from the pituitary. Rather than
being the "master gland" , the pituitary is an amplifier for signals from the hypothalamus.
• Hypothalamo-hypophyseal portal vasculature: A portal system has two capillary beds
arranged in series. For the hypothalamo-hypophyseal portal system, the median eminence is
supplied by the superior hypophyseal artery, which branches to form the 1˚ capillaries of the
median eminence. These converge to form the portal veins, which travel down the rostral
surface of the pituitary stalk.
When they reach the anterior
pituitary, the portal veins fan
out to form 2˚ capillaries.
Why is the anterior pituitary
supplied by a portal system?
Releasing hormones are
produced in very small
quantities, and often have a
short half-life in blood. The
portal system provides an
efficient means to deliver
releasing hormones to the
anterior pituitary in sufficient
quantity. Because hormones
from the anterior pituitary
have a much longer half-life,
and are released in larger
amounts, the anterior pituitary functions as an amplifier for the hypothalamus.
2. Neuroendocrine systems regulated by the hypothalamus, and their key functions
• Parvicellular neurons and the anterior pituitary: The anterior pituitary releases 6 hormones
from 5 different cell types. Release of anterior pituitary hormones is controlled by releasing
hormones from parvicellular neuroendocrine neurons in the hypothalamus. Cell bodies of
neuroendocrine neurons are scattered in various hypothalamic nuclei. These neurons extend
their axons to the median eminence.
TARGET
Thyroid
Adrenal
Growth
Gonad
Gonad
Breast
PITUITARY HORMONE
Thyroid-stimulating hormone (TSH)
Adrenocorticotropic hormone (ACTH)
Growth hormone (GH)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Prolactin
HYPOTHALAMIC SECRETION
Thyrotropin-releasing hormone (TRH)
Corticotropin-releasing hormone (CRH)
Growth hormone-releasing hormone (GHRH)
Gonadotropin-releasing hormone (GnRH)
Gonadotropin-releasing hormone (GnRH)
Dopamine (inhibitory)
• Magnocellular neurons & the Posterior Pituitary: The posterior pituitary releases two
hormones: oxytocin and vasopressin (anti-diuretic hormone, ADH). Both oxytocin and
vasopressin are nonapeptides. The neurons that make oxytocin and vasopressin are large
magnocellular neurons, with cell bodies in the paraventricular (PVN) and supraoptic (SON)
nuclei of the hypothalamus.
Oxytocin is made primarily in the
paraventricular nucleus, while
the supraoptic nucleus
synthesizes mostly vasopressin.
These magnocellular neurons
project caudally to the posterior
pituitary. Their axons form the
pituitary stalk, with the axon
terminals in the neurohypophysis.
Although the posterior pituitary is
neural tissue, it does not contain
neuronal cell bodies. Cells
within the posterior pituitary are
pituicytes. These are glial cells
similar to astrocytes. The
posterior pituitary is supplied by
small arteries, which branch into
fenestrated capillaries. The
blood-brain barrier is absent.
Vasopressin promotes water retention. It is released in response to increases in plasma
osmolarity (also stress and hypovolemia). Alcohol inhibits vasopressin, thereby functioning as a
diuretic. Vasopressin acts on the kidney to facilitate reabsorption of water from the urinary
filtrate. Diabetes insipidus is caused by lack of vasopressin.
Oxytocin is important during parturition and lactation. At parturition, oxytocin causes contraction
of the myometrium to expel the fetus and placenta. During lactation, oxytocin is essential for
milk release (but not milk synthesis) to move milk towards the nipple in response to suckling.
Oxytocin also acts centrally as a neurotransmitter to promote pair-bonding and social interaction.
3. Behaviors and homeostatic regulatory mechanisms under hypothalamic control
• Hypothalamic anatomy: Unlike the organized laminar structure of cortex or cerebellum, the
hypothalamus consists of paired clusters of neurons, termed "nuclei", on either side of the third
ventricle. Hypothalamic nuclei are heavily interconnected, and are interspersed with diffuse
fiber bundles. From rostral to caudal, the
hypothalamus can be divided into 4 regions:
preoptic, anterior, tuberal, and mammillary.
The preoptic region sits just rostral to the optic
chiasm. Developmentally, it is part of the
telencephalon, but is structurally and
functionally similar to the hypothalamus. The
anterior region extends from the level of the
optic chiasm to the beginning of the median
eminence. The tuberal region is particularly
important for ingestive behavior. In a
mediolateral plane, the hypothalamus can be
divided into 3 zones: periventricular, medial
and lateral. The periventricular zone is a thin
strip of tissue adjacent to the 3rd ventricle.
Most of the principal hypothalamic nuclei are
in the medial zone. The lateral zone (lateral to
the fornix) has sparse and indistinct nuclei,
with fibers en passant.
• Function: It has been said that the hypothalamus controls the 4 Fs: fighting, fleeing, feeding
and... reproduction. This statement is memorable, but not entirely accurate. A more
comprehensive summary of the major functions of the hypothalamus is:
Social behavior
Aggression
Sexual behavior
Maternal behavior
Ingestive behavior
Feeding
Drinking
Homeostatic mechanisms
Circadian rhythms
Thermoregulation
Stress
Medial preoptic area (MPOA): MPOA coordinates sexual and parental behavior with
reproductive function. GnRH neurons at the base of the preoptic region stimulate gonadal
function in males and females. In turn, the MPOA has receptors for gonadal hormones
(testosterone in males, estrogen and progesterone in females). By themselves, hormones don't
cause behavior. Instead, hormones enhance the salience of sensory information. In MPOA,
gonadal hormones promote response to social cues from conspecifics related to sexual and
parental behavior.
MPOA receives sensory input from the olfactory, visual and somatosensory systems. All these
sensory inputs facilitate social behavior. MPOA also receives projections from the amygdala
which contributes to the emotional components of social behavior. In addition to humoral output
via neuroendocrine GnRH neurons, MPOA projects to other hypothalamic nuclei, and to
midbrain circuits for motivation and reward. This accounts for the rewarding aspects of both
sexual and parental behavior.
Periventricular nucleus (PeVN): PeVN is a thin strip of tissue immediately rostral to the 3rd
ventricle. It contributes to the sensation of thirst. Increases in blood osmolarity and decreases
in blood volume are sensed in the hindbrain, and this information is relayed to the PeVN.
Lesions of this brain area reduce the desire to drink.
Anterior hypothalamic area (AHA): AHA is important for aggressive behavior in much the same
way that MPOA regulates sexual behavior. AHA and MPOA have similar neural (amygdala,
sensory systems) and humoral inputs (testosterone receptors).
Neurons in AHA and MPOA are also involved in body temperature regulation as a 'heat-loss
center'. When the temperature of the blood increases, temperature-sensitive neurons in AHA
and MPOA initiate heat-loss mechanisms: sweating, peripheral vasodilation. Body temperature
is responsive to hormones from the thyroid and gonad, and from infectious agents to initiate
fever. Lesions in AHA/MPOA cause hyperthermia.
Paraventricular and supraoptic nuclei (PVN, SON):
Their names describe their locations: adjacent to the
3rd ventricle (PVN), and above the optic tract (SON).
PVN and SON have magnocellular neuroendocrine
neurons that project to the posterior pituitary (see
above). PVN also has parvicellular neuroendocrine
neurons that regulate anterior pituitary secretion. PVN
plays an important role in the response to chronic
stress via CRH neurons which control secretion of
cortisol from the adrenal cortex. TRH neurons in PVN
stimulate the thyroid.
Suprachiasmatic nucleus (SCN): SCN sits directly over
the optic chiasm. It is the brain's master oscillator,
where it regulates rhythms, particularly circadian
rhythms. SCN receives retinal input to entrain
endogenous rhythms of activity with the external
environment. In turn, SCN controls rhythmicity throughout the body through secretion of
melatonin from the pineal gland. Melatonin is released only in the dark.
Ventromedial nucleus (VMH): VMH is considered to
be a 'satiety center' in the brain. Lesions of VMH
dramatically increase food intake. By contrast, the
lateral hypothalamus stimulates food intake. VMH
receives input about metabolic state from the
arcuate nucleus.
In addition, VMH is important for female sexual
behavior in many animals, while MPOA is central for
male sexual behavior. VMH has many estrogen
receptors, and receives somatosensory information
from the pudendal area.
Arcuate nucleus (ARC): ARC lies immediately
adjacent to the median eminence. It is particularly
responsive to humoral signals about hunger, satiety
and metabolism, including leptin, insulin, glucose
and fat. ARC has neuroendocrine neurons that
regulate prolactin and growth hormone secretion
from the anterior pituitary. Dopamine neurons in
ARC inhibit prolactin secretion. GHRH neurons
stimulate growth hormone.
Posterior nucleus (PN): PN is part of the mammillary
region, and is involved in body temperature
regulation, but opposite to the 'heat-loss' center in
AHA/MPOA. PN is a heat-gain center activated by lower-than-normal blood temperature.
Activation of PN induces shivering, piloerection, and peripheral vasoconstriction. Lesions to PN
cause hypothermia. Outputs of PN project to spinal sympathetic neurons.
4. Sex differences in brain and behavior
• Genetic sex: Genetic sex is determined at fertilization. In mammals, genetic females are
homogametic (XX), while genetic males are heterogametic (XY). Under normal circumstances,
genetic sex (XX or XY) determines phenotypic sex (male or female). When this process does
not proceed normally, this gives rise to Disorders of Sexual Development (DSDs).
• Phenotypic sex: Phenotypic sex encompasses the sexually-dimorphic characteristics that we
express as male or female. If all sexually-dimorphic traits were specified individually in the
genetic code, this would be unwieldy. Instead, the Y chromosome in males induces the early
gonad to develop into a testis, which produces the male hormone testosterone that signals
development of a masculine phenotype throughout the body. If no Y chromosome is present, the
early gonad becomes an ovary. Although the developing ovary is relatively quiescent,
development of a female phenotype does not require a similar stimulatory signal because the
female is the default phenotype. Again, DSDs may arise when these processes go awry.
Sex is a biologic definition that distinguishes male and female; gender is the sense of one's own
self as a man or woman. As such, gender represents a combination of biologic and cultural
factors. And ultimately, each of us defines our own gender. Accordingly, the distinction of male
or female sex applies to all animals, but only humans can be said to have gender.
• Gonadal steroid hormones: Gonadal steroid
hormones are relatively long-lasting lipophilic
signals derived from cholesterol that are produced in
the gonads. Thus, in addition to producing gametes
(oocytes and sperm), the ovaries and testes are also
endocrine glands.
Whether a particular cell responds to gonadal steroid
hormones depends upon whether the cell has
receptors for that hormone. Steroid hormone
receptors are intracellular proteins that are widely distributed throughout the body, and in
specific regions of the brain.
• Males: Androgens are produced by the testes, and confer masculine characteristics.
Testosterone is the
principal androgen.
Testosterone secretion
during the 2nd trimester of
fetal development is
responsible for initial
differentiation towards a
male phenotype. In
childhood, the testes are
essentially inactive.
However, testosterone
production resumes at
puberty. After reaching
peak levels in the 20s,
testosterone production
declines slowly.
• Females: The ovaries
produce estrogens and
progestagens, of which
estradiol and progesterone
are the most abundant. The
ovaries remain quiescent
throughout prenatal
development and childhood.
At puberty, the ovaries begin
to produce estradiol and
progesterone in a regular
monthly pattern. At
menopause, the ovary is
depleted of hormoneproducing cells, and the
blood levels of estradiol and
progesterone fall to
undetectable levels.
Thus, males and females differ in the types of steroid hormones (androgens vs estrogens &
progestagens), the pattern of hormone secretion (continuous in males vs cyclic in females) and
the persistence of hormone production with aging (present in males vs absent in females). The
changing pattern of estradiol and progesterone throughout the monthly menstrual cycle presents
a particular challenge for research, since it is difficult to control for the different hormone levels
among female research subjects. Historically, this concern has slowed the progress of research
using women as study subjects.
5. Organizational vs activational effects of steroids
Steroid hormone production has different effects depending on the stage of development.
These can be divided into organizational vs activational effects.
• Organization: Exposure to steroid
hormones during early development
produces permanent changes that
persist even when the hormones are no
longer present. These are known as
organizational effects. These can
include the acquisition of masculine
characteristics (masculinization), as
well as the suppression of feminine
characteristics (defeminization). For
example, the male genitalia
differentiate prenatally under the
influence of testosterone. Although
testosterone is no longer present at
birth or in childhood, the penis and
scrotum persist.
• Activation: Activational effects of steroid hormones are relatively transient actions during
adulthood. In adult men, testosterone increases libido. However, as testosterone levels decline
in older men, libido may also be diminished.
Often, the organizational effects of steroids during development determine and interact with the
activational effects in adulthood. For example, monthly menses in women represents the
combination of organizational effects (development of a uterus) and activational effects (cyclic
secretion of estradiol and progesterone). Because he lacks a uterus, reproducing the same
pattern of hormones in a man would not induce menstruation.
• Anatomical sex differences in the brain: Most of our information regarding differentiation of the
hypothalamus and
regulation of
sexually dimorphic
behavior comes
from animal
studies. However,
analogous
structures have
been found in the
human. In humans
and animals, there
are sexually
dimorphic nuclei in the hypothalamus. These nuclei are ~ 2x as large in males as in females.
Animal studies suggest that there is a critical period during early development when steroid
exposure increases the size of the sexually dimorphic nuclei. If there is no steroid hormone in
the brain during this early period, the nuclei remain permanently smaller (female). Interestingly,
in most cases, estrogen is responsible for masculinization of the brain, via local aromatization
from testosterone. Although there are numerous examples of sexual differentiation in behavior
and brain function, as well as sexually dimorphic nuclei, it has
been difficult to link particular sexually dimorphic brain regions
to specific behaviors. The photos at top show the sexuallydimorphic nucleus of the preoptic area (SDN-POA) in rats. Left:
normal male. Center: normal female. Right: female treated with
testosterone at birth
• Sex differences in behavior: How different are we? As applied
to sex differences in behavior, the debate on Nature vs Nurture
continues. However, there is increasing recognition in the
scientific community that aspects of sexual and non-sexual
behavior appear to be determined before birth, presumably due
to prenatal steroids (that is, Nature not Nurture). A 2008 study
compared toy preferences (plushies vs trucks) in male and
female rhesus monkeys (at right). Sex differences in monkey
toy preferences were remarkably similar to those of human
children.
On the other hand, a 2007 study (below) used eye-tracking to
evaluate sex differences and effects of oral contraceptives on
how men and women view sexual stimuli (pornographic
photos). Men spent more time looking at female faces.
Naturally-cycling women (NC females) spent more time looking
at genitals, while women on oral contraceptives (OC females)
spent a higher proportion of time looking at contexual elements
of the pictures. However, the overall patterns of viewing were
similar.
6. Sex-related and hormone-sensitive disorders in research and medicine
Sex differences in disease can include differences between males and females in the incidence
of a particular disease, the presenting symptoms, the clinical course, and the response to
therapy.
• Childhood: When a sex-related disease presents in childhood, it is reasonable to expect an
organizational effect of hormones. This is not to say that testosterone (or its absence) causes
the disorder per se, but that the hormonal environment during development conveys
susceptibility to this disorder. Examples include autism and ADHD, which both show increased
incidence in boys.
• Puberty: Other sex-related diseases may present around the time of puberty (schizophrenia,
substance abuse disorders in males; depression, anxiety and eating disorders in females).
These diseases may represent activational effects of hormones, with or without an underlying
organizational effect. Cultural and peer influences also play a significant role in this age group.
• Adulthood: Some sex-related diseases in women are exacerbated by the fluctuating levels of
estradiol and progesterone across the menstrual cycle. In particular, the decline in steroid
hormones at menses can precipitate premenstrual syndrome, migraines, and seizures
(catamenial epilepsy) in susceptible women.
• Aging: As men and women age, additional sex-related diseases emerge. While steroid
hormone production decreases in both sexes, women have a marked drop in estradiol and
progesterone at menopause. The loss of potentially protective effects of estrogen can increase
disease incidence in post-menopausal women. Examples of sex-related neurologic diseases in
older adults include Alzheimer’s disease in women, and Parkinson’s Disease in men. In some
cases, sex-differences in risk factors such as diet and exercise contribute to disease.
7. Implications for research
When considering research and evidence-based medicine ask:
• Is there gender bias inherent in the hypothesis of a study?
• Is the inclusion or exclusion of women as participants in a study appropriate?
• Does data analysis properly identify results by sex?
• Can findings from studies that exclude particular groups such as women, children, or particular
races, be generalized and applied to those groups?
In recent years, clinical research studies have increased the numbers of women as human
subjects. This has not happened in basic science research using cells and animals. In May of
2014, the NIH announced a new policy that basic science research must incorporate plans to
balance male and female research subjects.