What is a hormone

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(No Transcript)
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Outline of todays lecture

• Part I
• Why YOU should care about hormones?
• Definition--What is a hormone?
• Introduction to behavioral endocrinology (4
  levels of analysis)
• Common techniques in behavioral endocrinology
  (50 of today)
• Part II
• The endocrine system (other 50)
• major hormones hypothalamic, pituitary, thyroid,
  GI, pancreatic, steroid, monoamines
• Regulation
• Revisiting question 1 and comparison with fMRI

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Why should social-personality psychologists study
hormones?

• Conservative estimate--the human brain is riddled
  with billions and billions of endocrine
  receptors?
• Prima facie evidence of hormonal influence on
  behavior, thought, mood, emotion, personality?
• Ignorance of the hormone-behavior link could have
  dire consequences
• Corticotropin-releasing hormone (CRH) is a key
  neuroendocrine factor implementing endocrine,
  immune and behavioral responses to stress. The
  expression of CRH receptors was analyzed for the
  first time in pituitaries of suicide victims by
  in situ hybridization (2001--Molec. Psych). There
  was a shift in the ratio of the two major CRH
  receptors (R1 and R2) in the pituitaries of
  suicide victims, relative to those who died of
  natural causes. Causality unclear.
• Todays lecture does NOT focus on the
  hormone-behavior link. That stuff you can pick
  up from journal articles, with new and exciting
  research coming out each week! Today we need to
  cover the bedrock, the core, the basics, the
  stuff that you need to function effectively and
  intelligently in this world.
• And just to keep you from drifting off during the
  biological onslaught that is about to hit, lets
  take a peek at the final slide next.

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What is a hormone?
Testosterone plays a crucial role in neuronal
function, but elevated concentrations may have
deleterious effects. Here it is shown that
supraphysiological levels of testosterone
(micromolar range) initiate the apoptotic
cascade. Short periods of elevated testosterone
levels (six to 12 hours), such as those resulting
from the use of muscle-building steroids,may lead
to "cell death" and may have long term effects on
brain function.

• Hormones coordinate the physiology and behavior
  of an animal by regulating, integrating, and
  controlling its bodily functions.
• Example The same hormone (e.g., Luteinzing
  Hormone--LH) that causes egg or sperm maturation
  also stimulates mating behavior in many species.
  
• This dual function ensures that mating occurs
  ONLY when animals have mature gametes (eggs or
  sperm) available for fertilization.
• Hormones are similar to neurotransmitters, but
  can operate over a greater distance and over a
  much greater temporal range than
  neurotransmitters.
• Differences between hormones and
  neurotransmitters
• Neural messages can only travel along existing
  nerve tracts hormonal messages can travel in the
  circulatory system thus any cell receiving blood
  is potentially able to receive a message.
• Neural messages are digital, all-or-none events
  that have rapid onset and offset neural signals
  can take place in milliseconds plus, electrical
  signal can travel along myelinated axons at
  speeds up to 100 meters per sec! Hormonal
  messages are analog, graded events that can take
  seconds, minutes or hours to occur (more detail
  to follow).
• How does a hormone exert its influence?
• Only cells with receptors for that hormone can be
  influenced
• Called target cells
• Interaction of a hormone with its receptor leads
  to a genomic response whereby the hormone
  activates genes that regulate protein synthesis
  (e.g., up-regulation synthesis of a receptor for
  that hormone).
• Some hormone effects are nongenomic.The
  monoamines.
• Nongenomic (transcription-independent) effects
  are principally characterized by their
  insensitivity to inhibitors of transcription and
  protein synthesis. The most obvious experimental
  evidence suggesting their existence is rapid
  onset of action (within seconds to minutes).
  These rapid effects are likely not be mediated
  through intracellular receptors.

The dual effect of LH LH stimulates gonads to
produce gametes, and stimulates gonads to produce
testosterone
Action potentials propagate faster in axons of
larger diameter, other things being equal. They
typically travel from 10-100 m/s.
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Hormonal Effects
Androgen receptor (computer image, left electron
micrograph, right)

• Sufficient number of receptors must be available
  for hormonal effects to occur.
• Popular belief that individual differences in
  behavior reflects differences in hormone
  concentrations. For example, it is assumed that
  roosters that crow frequently have more
  testosterone than roosters that seldom crow (or
  that aggressive men have higher T).
• Not necessarily true!
• Individual differences in behavior can reflect
  hormone concentrations,pattern of hormone
  release, numbers and location of hormone
  receptors, and the efficiency of those receptors
  in affecting gene transcription.
• Hormones rarely change the function of a cell
  rather, they alter the rate of normal cellular
  function.
• Thus, hormones affect cell morphology and size
  (including development of muscle and neuronal
  cells), and affect cell death (apoptosis)
  throughout the nervous system.
• Although hormones obviously affect behavior, it
  is also true that behavior can influence hormonal
  levels and hormonal effects.

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How might behavior affect hormones (most research
does not look at this)
little Dutch football fan

• Behavior can and often does affect hormone levels
  which in turn can influence subsequent behavior.
• World Cup Soccer Fans were assayed for
  testosterone before and after the Brazil-Italy
  final. Brazil won on penalty kicks. 11/12
  Brazil fans showed an increase in testosterone,
  whereas 9 of 9 Italian fans showed a decrease.
• Testosterone concentrations were measured in four
  heterosexual couples over a total of 22 evenings.
  On 11 evenings, saliva samples were obtained
  before and after sex on the remaining 11
  evening, two samples were obtained, but there was
  no sex. Having sex caused an increase in
  testosterone in both men and women. No changes
  were seen in the no-sex nights. The early
  evening samples revealed no difference in
  testosterone concentrations between sex and
  no-sex evenings, suggesting that sex increases
  testosterone more than testosterone
  (concentrations) cause sex. Alternatively,
  physical exercise may have caused the increase
  (it increases CORT, which can correlate
  positively with T).

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How does one go about answering a research
question in the field of behavioral
endocrinology? Example What causes the Zebra
Finch to sing?

• (What causes Zebra Finches to Sing?)
• Four correct answers, based on Levels of Analysis
• Immediate causation mechanisms mediated by the
  nervous and endocrine systems
• Example Singing in male zebra finches (In
  contrast to mammals in which structural
  differences in neural tissues have not been
  directly linked to behavior, structural
  differences in avian brains have been directly
  linked to a sexually dimorphic behavior bird
  song).
• Female zebra finches never sing, even after
  testosterone treatment in adulthood.
• Other species (wrens, canaries) show no or a
  diminished sex difference
• The size of nuclei in two major brain circuits
  (HVc, RA, Area X) implicated in learning and
  production of bird song parallel sex differences
  in singing behavior (e.g., large dimorphisms in
  zebra finches,undetectable dimorphisms in wrens
  in which no singing difference is observed).
• But why the sex difference in the zebra finch?
• If female finches are treated with androgen soon
  after hatching, and then treated with androgen
  when adults, they dont sing, but they showed a
  small increase in the number of neurons in the
  song production region.
• If female finches are treated with estrogen soon
  after hatching, then as adults, they show a
  marked increase in the number and size of neurons
  in this region, but still no singing.
• However, if treating with estrogen soon after
  hatching and then treated with androgen as
  adults, they show the same size and number of
  neurons as their male conspecifics, and they
  SING. Conclusion Estrogens are necessary to
  organize the neural machinery underlying the song
  system, and androgens activate it. Bird testes
  produce circulating androgens which enter neurons
  containing aromatse, an enzyme which converts
  androgens to estrogen. These neurons are
  generally found in the hypothalamus, as well as
  in the structures constituting the neural circuit
  controlling bird song.
• Development
• Behavioral responses change through the lifespan
  as a result of gene X environment interaction.

The mating dance of columba chippendalia is
virtually unique in the animal kingdom
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Levels of Analysis (Zebra Finch song)

• Hormonal events affecting the fetal and neonate
  can have profound consequences later in life.
• Most research has focused on how early events
  influence adult behavior however, the decay of
  behavioral patterns during aging is also a new
  and expanding area to those pursuing
  developmental questions.
• Possibly, zebra finches sing because they have
  undergone puberty or because they learned songs
  from their fathers.
• Evolution
• This approach involves many generations of
  animals and addresses the ways that specific
  behaviors change during the course of natural
  selection.
• Biologists study the evolutionary bases of
  behavior in order to learn why behavior varies
  between closely related species as well as to
  understand the specific behavioral changes that
  occur during the evolution of a new species.
• Behaviors rarely leave interpretable traces in
  the fossil record, so this approach relies upon
  comparing existing species that vary in
  relatedness (e.g., old v. new world monkeys).
• Someone at this level might say that zebra
  finches sing because they are finches, and that
  all finches sing because they have evolved from a
  common ancestral species that sang.
• Adaptive Function
• Synonymous with adaptive significance role that
  behavior plays in the adaptation of animals to
  their environment and with the selective forces
  that currently maintain behavior.
• Could be argued that male zebra finches sing
  because it will increase the likelihood of
  reproduction by attracting females to their
  territories and dissuading competing males from
  entering.
• So, if we want to study HOW, then focus on
  questions of immediate causation and development.
• If WHY, then questions of evolution and function.

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How might hormones affect behavior

• The study of the hormone-behavior relationship is
  organized around the idea that animals are
  composed of three interacting components
• Input systems (sensory)
• Integrators (CNS)
• Output systems (e.g., muscles)
• Example Removing the testes of the male zebra
  finch stops it from singing. Reinplant the
  testes, or provide the primary testicular
  hormone, testosterone, and singing resumes.
  Obviously, testosterone is involved in singing,
  but how?
• Input Examine the sensory system. Does
  testosterone alter the birds sensory
  capabilities, making the environmental cues that
  elicit singing more salient? If this were the
  case, females or intruders might be seen or heard
  more easily.
• CNS Testosterone could change the Neural
  Architecture or speed of neural processing.
  Higher processes (e.g., motivation, attention)
  might be influenced.
• Effectors Testosterone concentrations might
  affect the muscles of the syrinx (the avian vocal
  organ).
• This 3-part framework can aid in the design of
  hypothesis and experiments to help understand how
  hormones affect behavior.

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Classes of evidence for determining
hormone-behavior interactions

• 1st A hormonally-dependent behavior should
  disappear when the hormonal source is removed or
  actions of the hormone are blocked. Example--ADT.
• 2nd After the behavior stops, restoration of the
  missing source or its hormone should reinstate
  the absent behavior. Again, ADT.
• 3rd Hormone concentrations and the behavior
  should covary in practice, the behavior should
  be observed when concentrations are relatively
  high and never or rarely observed when
  concentrations are low.
• This 3rd class of evidence is difficult to obtain
  because many hormones have a long latency of
  action (why? up-regulation.) and/or a long offset
  latency (why? down-regulation) and are released
  in a pulsatile manner. For example, a pulse may
  be released into the blood and then no more
  released for an hour or more, so a single sample
  will not provide an accurate picture of the
  endocrine status of the animal.
• Another problem is that biologically effective
  amounts of hormones are TINY and thus difficult
  to measure accurately. Effective concentrations
  are measured in micrograms, nanograms, or
  picograms (10 to the negative 6th, 9th, or 12th,
  respectively).
• Unfortunately, the 1st two classes of evidence
  are thus considered more reliable, but research
  on humans is typically limited to the 3rd (with
  exceptions--ADT, for example).

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Common techniques in behavioral endocrinology

• Ablation replacement
• Bioassays
• Immunoassays
• Immunocytochemistry (ICC)
• Autoradiography
• Blot tests
• In situ hybridization
• Pharmacological Techniques
• Genetic Techniques (transgenics and knockouts)

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Common techniques in behavioral endocrinology

• Ablation and replacement
• 1. A gland that is suspected to the the source of
  the hormone affecting behavior is surgically
  removed
• 2. Effects on behavior are observed
• 3. Hormone is replaced, by reinplantation,
  injection of an extract from the gland or
  injecting a purified hormone
• 4. Determination is made whether the observed
  consequences of ablation are reversed by
  replacement therapy.
• 5. Is the surgically removed gland the hormonal
  source?

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Common techniques in behavioral endocrinology

• Bioassays
• Once the existence of a hormone has been
  established, the next step is to identify the
  chemical processes involved in its actions.
• Typically, this involved a test of its effects on
  a living animal (which can serve as a reliable,
  quantifiable response system on which to test
  hormonal extracts and chemical fractions).
• A bioassay need not be conducted on the same
  species from which the hormone was obtained.
• Example THE RABBIT TEST (or Friedman test).
• Developed by Maurice Friedman in 1929 (used until
  the late 1950s). Used to test for the presence
  of human chorionic gonadotropic (hCG--a hormone
  released from the implantation site of a
  blastocyst. hCG prevents menstruation). hCG
  found in womens urine.
• BTW, hCG produced by the rudimentary placenta
  that forms immediately after blastocyst formation
  (hCG maintains corpus luteal function during
  pregnancy--thus, progesterone secretion--and
  inhibits ovulation).
• Urine injected into a rabbit, and if hCG present,
  rabbits ovaries would form corpora lutea, or
  yellow bodies (temporary ovarian endocrine
  structures formed following ovulation within 48
  hours and produce progestins--horomones that
  support pregnancy).
• It is a common misconception that the injected
  rabbit would die only if the woman was pregnant.
  This led to the phrase "the rabbit died" being
  used as a euphemism for a positive pregnancy
  test. In fact, all rabbits used for the test
  died, because they had to be surgically opened in
  order to examine the ovaries. While it was
  possible to do this without killing the rabbit,
  it was generally deemed not worth the trouble and
  expense.
• The rabbit test was better than the earlier mouse
  test (developed in 1928) which required 6 or more
  mice and 96 hours to complete.
• However, if the rabbit was stressed, spontaneous
  corpora lutea formation occurs (in the absence of
  hCG), so there was a significant false positive
  rate.
• In the frog test for pregnancy, a womans urine
  is injected into a male frog or toad. In 2-4
  hours, the animal would begin to produce sperm if
  the womans urine contained hCG. However, there
  were seasonal variations in frogs--in the summer,
  they had a greater tendency to produce false
  negatives.

corpus luteum
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Common techniques in behavioral endocrinology

• Immunoassays
• Bioassays require a great deal of time, labor,
  and the sacrifice of many animals for every
  assay.
• The development of the radioimmunoassay (RIA)
  reduced these problems and increase the precision
  with which hormone concentrations could be
  measured.
• Based on competitive binding of an antibody to
  its antigen. An antibody produced in response to
  any antigen (defn any molecule that stimulates
  an immune response) has a binding site THAT IS
  SPECIFIC FOR THAT ANTIGEN.
• Antigen molecules can be labeled with
  radioactivity, and an antibody cannot
  discriminate between an antigen that has been
  radiolabeled (or hot) and one that is normal
  (or cold). A given amount of antibody
  possesses a given number of binding sites for its
  antigen.
• STEPS INVOLVED IN RIA
• 1. First, inject the hormone of interest (e.g.,
  T) into an animal to raise antibody (anti-T)
• 2. Then, collect antibody from blood, and purify.
• 3. Develop a standard curve
• Set up 5 or 6 reaction tubes, each containing the
  same amount of antibody, the same amount of
  radiolabeled hormone, and different amounts of
  cold purified hormone of known concentrations
  (from low to high concentration) .
• (The radiolabeled and cold hormone compete for
  binding sites on the antibody, so the more cold
  hormone present, the less hot hormone will bind
  to the antibody)
• 4. The quantity of hot hormone that was bound can
  be determined by precipitating the antibody and
  measuring its radioactivity.
• 5. The concentration of hormone in an UNKNOWN
  sample can then be determined by subjecting it to
  the same procedure (substituting unknown sample
  for cold hormone in STEP 3) and comparing the
  results with the standard curve
• The enzymoimmunoassay (EIA) works on the
  principle of competitive binding of an antibody
  to its antigen. The major difference is that
  EIAs do not require radioactive tags. Rather,
  the antibody is tagged with a compound that
  changes optical density (color) in response to
  binding with the antigen.
• Example The home pregnancy test.
• However, most EIAs provided quantitative
  information, and thus a standard curve is
  generated, so that different amounts of the
  hormone in question provide a color gradient that
  is read on a spectromoter. A similar technique
  is called enzyme-linked immunosorbent assay
  (ELISA).

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Anatomy of an ELISA test

• Animation of an HIV ELISA test (both positive and
  negative test--notice that you can test for
  presence of antigen (e.g., a hormone assay) or
  its complement antibody (viral assay).

• http//www.biology.arizona.edu/IMMUNOLOGY/activiti
  es/elisa/technique.html

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Common techniques in behavioral endocrinology

• Immunocytochemistry (ICC)
• ICC techniques use antibodies to determine the
  location of a hormone in the body.
• Antibody molecules linked to marker molecules
  (usually a fluorescent dye) are introduced into
  dissected tissue from an animal, where they bind
  with the hormone or neurotransmitter of interest.
• Tissue is examined under a fluorescent
  microscope, and concentrated spots of
  fluorescence will appear, indicating where the
  protein hormone is located.
• Commonly used marker is the enzyme horseradish
  peroxidase.

human sputum cells
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Common techniques in behavioral endocrinology

• Autoradiography
• Typically used to determine hormonal uptake and
  indicate receptor location.
• An animal can be injected with a radiolabeled
  hormone, or the study can be conducted in vitro.
• Top picture Human NMDA receptor (NDMA is a
  receptor for the amino acid glutamate, which is
  the most abundant neurotransmitter in the
  mammalian nervous system).
• Bottom indicates transport in a young tomato
  plant The distribution of elements (e.g.
  micronutrients, pollutants) are visualized by
  autoradiographic techniques.

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Other techniques in behavioral endocrinology

• Blot tests (uses a technique called gel
  electrophoresis to separate proteins based on
  their length and weight (in kDa)
• Used to determine presence of a particular
  protein or nucleic acid in a specific tissue.
• Southern blot used to assay DNA
• Northern blot used to assay RNA
• Western blot used to assay proteins
• In Situ Hybridization
• Previous techniques can determine only whether or
  not a particular substance is present in a
  specific tissue, but in situ hybridization can be
  used to determine if the substance is produced in
  a specific tissue.
• Used at the cellular level to examine gene
  expression.
• More specifically, used to identify cells that
  are producing mRNA for a specific protein (e.g.,
  a hormone or neurotransmitter).
• Called hybridization because a radiolabeled cDNA
  probe (cDNA, or complementary DNA is synthesized
  from mature mRNA by the enzyme reverse
  transriptase) is introduced into the tissue. If
  the mRNA of interest is present, the cDNA will
  form a tight association (i.e., hybridize) with
  it.

These are chromosomes from the canola seed
showing the location of various retrotransposons,
which are genetic elements that can amplify
themselves within a genome.
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Other techniques in behavioral endocrinology

• Pharmacological Techniques
• Use of synthetic agonists (mimics) and
  antagonists (blockers) to determine endocrine
  functioning.
• Some agents act to stimulate or inhibit endocrine
  functioning by affecting the release of hormones
  they are called general agonists/antagonists.
• Others act directly on receptors, enhancing or
  negating the effects of the focal hormone these
  are receptor agonists/antagonists.
• Example CPA is a powerful anti-androgen used
  clinically to treat male sex offenders (about 20
  of patient dont show the expected behavioral
  response). CPA binds to androgen receptors but
  doesnt activate them, thereby blocking effects
  of androgen.

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Other techniques in behavioral endocrinology

• Common genetic manipulations in behavioral
  endocrinology are the insertion (transgenic) or
  removal (knockout) of the genetic instructions
  encoding a hormone or hormone receptor.
• Briefly The genetic instructions for each
  individual are contained in the DNA, located in
  the nucleus of nearly every cell.
• Each gene (composed of a specific order of four
  nucleotides adenine, thymine, cytosine, and
  guanine) is determined by the sequence of
  nucleotides along the rails of the double
  helix.
• To inactivate (knockout) a gene, you scramble the
  order of the nucleotides that make up the gene.
  The identification of the genome has been most
  successful in the mouse thus mice are most
  commonly used in knockout studies.
• Knocking out a gene is more difficult than it
  sounds
• gene of interest must be identified, targeted,
  and marked precisely.
• A mutated form of the gene is then created (e.g.,
  mutating the marker gene via genetic
  engineering).
• Embryonic stem cells are harvested and cultured,
  and the mutated gene is introduced into the
  cultured cells by microinjection.
• A small number of the altered genes are
  incorporated into the DNA of the stem cells via
  recombination.
• The mutated embryonic stem cells are inserted
  into normal embryos (blastocycts), which are then
  implanted into surrogate mothers.
• Thats it!!!!
• All of the cells from the mutated stem cells will
  have the altered gene the descendents of the
  normal embryonic cells will have normal genes.
• Thus, the offspring will have a mixture of
  cells--some containing the mutated gene and some
  containing the normal (wild-type) gene.
• This animal is called a chimera
• The chimeras are then bred (interbred or bred
  with wild-type animals) to produce wild-type
  (/), heterozygous (/-), and homozygous (-/-)
  animals with respect to that gene. Behavioral
  performance can then be compared.
• n.b In Greek mythology, a Chimera is a monster,
  depicted as an animal with the head of a lion,
  the body of a she-goat, and the tail of a dragon

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Chimeras

• Chimeric animals
• Pictured on the right is a baby geep, made by
  combining a goat and sheep embryo. Notice the
  chimerism evident in the skin - big patches of
  skin on front and rear legs are covered with
  wool, representing the sheep contribution of the
  animal, while a majority of the remainder of the
  body is covered with hair, being derived from
  goat cells.
• There is also some potential that this technique
  can be applied to problems such as rescue of
  endangered species. It is possible, for example
  to construct a goat-sheep chimera such that a
  goat fetus is "encased" in a sheep placenta. This
  enables a sheep to carry a goat to term, which
  will not occur if you simply transfer goat
  embryos into sheep (the sheep will
  immunologically reject the goat placenta and
  fetus). It may be possible to extend this
  procedure to allow embryos from severely
  endangered species to be carried by recipient
  mothers from another species.

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Fat mice--Using all of the techniques discussed
previously to understand obesity

• Effects of Leptin
• Recently leptin (derived from Greek leptos,
  meaning thin) discovered as a hormone released
  from fat cells.
• It is known that a specific mutation in mice on
  the ob gene can cause extreme obesity (in mice
  homozygous for defective ob).
• Thus, these naturally-occuring mutants can be
  considered natural knockouts for the ob gene.
• ob/ob mice have a pair of defective ob genes,
  overeat, are obese, and are sterile.
• The ob gene normally codes for leptin, which is
  released into the bloodstream and travels to
  specific receptors in the CNS and elsewhere to
  regulate feeding and energy balance.
• Although it has been known for a long time that
  the ob/ob mutation affects body weight in mice,
  only recently has the ob gene been cloned,
  inserted into a bacterial system, and thus
  purified leptin made available to researchers.
• Replacement studies could now be done in which
  leptin was provided to ob/ob mice to determine if
  leptin replacement would ameliorate obesity.
• It did (see mouse on the right (25g--average
  mouse is 15g one on the left is w/out
  replacement at 35g).

• Availability of purified leptin allowed for the
  development of antibodies used to develop assays
  to determine blood concentrations.
• RIA determined that there was no connection
  between plasma leptin concentrations and
  obesity/diatetes IN HUMANS.
• A leptin ELISA was developed for rats, which
  determined that fasting or exposure to low
  temperatures caused leptin to fall.
• Immunocytochemistry determined that leptin was
  present in both white (energy utilization) and
  brown (generation of body heat) adipose tissue.
• Autoradiography determined that tagged leptin was
  found in a brain area located in the front of the
  third ventricle.
• This tissue was then used to clone a leptin
  receptor
• In situ hybridization found that the mRNA for the
  leptin receptor was expressed in the
  hypothalamus.
• Efforts to cure obesity involved
  transgenics--treating ob/ob mice with a
  recombinant virus expressing mouse leptin cDNA,
  resulting in leptin production. A dramatic
  reduction in food intake and body mass resulted.
• This treatment also reverses the sterility found
  in ob/ob mice.
• However, only two (out of thousands) of obese
  humans displayed a ob mutation. Sadly, the
  effects of leptin on humans have been
  disappointing, dashing the Nobel dreams of more
  than a handful of psychologists.

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The Endocrine System

• Where do hormones come from?
• They are produced by glands, and are secreted
  into the bloodstream.
• Where do hormones go?
• They travel to target tissues containing
  hormone-specific receptors.
• What do hormones do?
• By interacting with their receptors, they
  initiate biochemical events that activate genes
  to induce certain biological responses (e.g.,
  protein synthesis). In some cases,
  hormone-receptor interactions result in
  nongenomic effects on cellular function (these
  are fast, and are just now being studied in their
  role in mediating behavior).

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Types of chemical communication

• Intracrine mediation
• regulation of intracellular events
• Autocrine mediation
• autocrine substances feedback to influence the
  same cells that secreted them.
• Paracrine mediation
• paracrine cells secrete substances that affect
  adjacent cells (e.g., nerve cells).
• Endocrine mediation
• endocrine cells secrete chemicals into the
  bloodstream where they may travel to distant
  target cells.
• Ectocrine mediation
• Ectocrine substances, such as pheromones, are
  released into the environment to communicate with
  others.

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General Features of the Endocrine System

• Endocrine glands are ductless
• Endocrine glands have a rich blood supply.
• Product of endocrine glands (hormones) are
  secreted into the blood stream
• Hormones can travel to virtually any cell in the
  body (cells in the lenses of the eye are an
  exception--no blood supply)
• Hormone receptors are specific binding sites,
  embedded in the cell membrane (in the case of
  peptide hormones) or in the cytoplasm (in the
  case of steroid hormones) that interact with a
  hormone or class of hormones
• Exocrine glands have ducts or tubes (e.g.,
  salivary, sweat, mammary). Some glands have both
  endo- and exo- structures (e.g., pancreas)

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The Endocrine Glands
In touch with his feminine side
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Four classes of hormones

• Protein peptide hormones
• Steroid hormones
• Monoamines
• Lipid-based hormones (prostaglandins)

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Cellular and molecular mechanisms of hormone
action--Protein Hormones (the majority of
hormones)

• Protein hormones require a second messenger
  (i.e., a molecular middleman--typically, an
  enzyme or another protein) to transduce
  (conversion of one type of signal into another)
  the hormonal signal
• In really simple terms, the hormone binds to the
  receptor which is coupled to a protein called G.
  When this mess is formed, a messenger called cAMP
  is created. cAMP combines with an enzyme that
  activates another enzyme which acts on the target
  substance (e.g., in the case of glucagon, this
  final enzyme converts glycogen into glucose).
• Receptors are coupled to special proteins (G)
  that mediate intracellular events (all G proteins
  have 3 different subunits). The G protein
  receptor family includes glucagon, oxytocin, and
  vasopressin receptors.
• When the hormone-receptor complex binds to G, G
  in turn activates adenylate cyclase, which in
  turn stimulates that formation of cyclic
  adenosine monophosphate, or cAMP.
• When formed in response to a hormone-receptor
  bind, cAMP is referred to as the 2nd messenger
  (the hormone is the 1st messenger)
• Once formed, cAMP can combine with an enzyme
  called protein kinase A (PKA), an enzyme that in
  turn activates (phosphorylates) another enzyme
  called phosphorylase kinase in a variety of
  cells.
• For example, phosphorylase kinase A breaks down
  glycogen into glucose to provide intracellular
  energy.

glycogen
29
Cellular and molecular mechanisms of hormone
action--Steroid Hormones

• Steroid hormones are fat soluble and move easily
  through cell membranes (as a result, these
  hormones are never stored but leave the cells in
  which they are produced almost immediately--nomadi
  c).
• The precursor to all vertebrate steroid hormones
  is cholesterol (made from acetate in the liver).
• In the blood, steroid hormones must bind to
  water-soluble carrier proteins to increase their
  solubility and the ability of the blood to carry
  them to their target tissues.
• Upon arrival, they dissociate from their carrier
  proteins and diffuse through the cell membrane
  into the cytoplasm of the target cell, where they
  bind to cytoplasmic receptors.
• The steroid-receptor complex is transported into
  the cell nucleus, where it binds to DNA sequences
  called hormone response elements and then either
  stimulates or inhibits the transcription of
  specific mRNA.
• The precise mechanism through which binding to
  the hormone response elements occurs is unknown.
• The transcribed mRNA migrates to the cytoplasmic
  rough endoplasmic reticulum, where it is
  translated into specific proteins or enzymes that
  produce the physiological response (much more on
  this later).
• Note changes in the types of proteins a cell
  makes (aka, the gene products) can be observed
  within 30 minutes of hormone stimulation.

cholesterol
30
The major vertebrate hormones

• Protein peptide hormones
• Make up the majority of hormones
• Protein hormones that are only a few amino acids
  in length are called peptide hormones (larger
  ones called protein or polypeptide hormones)
• Include insulin, the glucagons, the
  neurohormones of the hypothalamus (monoamines),
  the hormones of the anterior pituitary, inhibin,
  calcitonin, parathyroid hormone, the GI hormones,
  leptin, and the posterior pituitary hormones
• These hormones are blood-soluble (they dont need
  a carrier protein to travel to their target
  cells, as do steroid hormones). However, they
  may bind with other blood plasma proteins
• The metabolism of a hormone is reported in terms
  of its half-life, which is the amount of time
  required to remove half of the (radioactively
  tagged) hormone from the blood
• Generally, larger protein hormones have longer
  half-lives (e.g., growth hormone with 200 amino
  acids has a half life of 20-30 mins, whereas
  thyroid releasing hormone has 3 amino acids and a
  half life of fewer than 5 minutes).

Insulin (not Europe)
Human growth hormone
Too much human growth hormone (tumor on the
anterior pituitary)
31
Hypothalamic hormones

• The peptide hormones secreted by the hypothalamus
  are best thought of as a special class of
  neurotransmitters that act on a variety of cells
  in the anterior pituitary.
• Five releasing hormones and one inhibiting
  hormone have been isolated.
• TRH--thyrotropin-releasing hormone
• GHRH--growth hormone-releasing hormone
• GnRH--gonadotropin-releasing hormone
• MSH--melanotropin-releasing hormone
• CRH--corticotropin-releasing hormone
• Somatostatin--growth hormone-inhibiting hormone
• Peptide and protein hormones vary in amino acid
  sequence (and vary by species--e.g., GnRH
  possesses a different sequence in frogs than in
  horses horse GnRH will not affect a frogs
  reproductive function (although salmon calcitonin
  is used in humans to promote bone
  mineralization). Hormones differ in species
  specificity.

Notice inter-species discrepancies in the 2nd
position (glycine), 8th position
(methionine),10th, 11th, and many others moving
forward. Calcitonin is a thyroid hormone. It
lowers blood levels of calcium by inhibiting
calcium release from bone. Interestingly, it is
regulated by blood calcium levels, not by
pituitary hormones.
32
Anterior Pituitary hormones

• All protein hormones, all, ranging in length from
  39 to 220 amino acids.
• Anterior pituitary is composed of three types of
  cells
• Acidophils (these cells stain readily with acidic
  stains)
• Basophils (stain readily with basic stains)
• Chromatophils (do not take up either acidic or
  basic stains)
• Basophil-secreted
• Lutenizing hormone (LH), follicule-stimulating
  hormone (FSH), and thyroid-stimulating hormone
  (TSH) are secreted by basophils.
• LH and FSH and controlled by hypothalamic GnRH.
  TSH is controlled by hypothalamic TRH.
• All consist of 200-220 amino acids and have
  molecular weights of 25-35K daltons.
• Note LH and FSH are known as gonadotropins
  because in response to GnRH, they stimulate the
  production of steroids in the gonads.
• Acidophil-secreted
• Growth hormone (GH) and prolactin (PRL)
• TRH stimulates PRL secretion hypothalamic
  dopamine inhibits. GHRH and Somatostatin control
  GH.
• 190-220 amino acids in length.
• GH shows fair amount of species specificity.
• GH stimulates body growth INDIRECTLY (does not
  induce skeletal growth).
• Stimulates production of growth-regulating
  substances--somatostedins--by the liver and
  kidneys. Somatostedins cause bone to take up
  sulfates leading to growth.
• GH also stimulates protein synthesis, fat
  mobilization,and hyperglycemia (because of its
  anti-insulin properties).
• Prolactin (PRL) best known for promoting
  lactation in female mammals, but in fact PRL has
  hundreds of physiological functions. Was
  originally called luteotropic hormone because its
  1st known function was to promote corpus luteum
  function in rat ovary.

Salt marsh killfish
actual crop milk
crop sac
33
Anterior Pituitary hormones (cont.)

• chromatophil secreted
• ACTH (Adrenocorticotropic hormone) secreted by
  the chromatophils.
• 39 amino acids 4500 daltons in weight
• ACTH released in response to CRH from the
  hypothalamus stimulates the adrenal cortex to
  secrete mineralocorticoids and glucocorticoids
  (including cortisol, the primary glucocorticoid,
  which may feed back to control ACTH release.
  This conclusion is based on an increase in ACTH
  secretion after adrenalectomy.)

Relationship between CRH, ACTH, and adrenals
34
Posterior Pituitary hormones

• Two peptides, oxytocin and vasopressin, are
  released from the posterior lobe of the pituitary
  in mammals.
• Oxytocin regulated by electrical activity of the
  oxytocin cells in the hypothalamus. Vasopressin
  secreted in response to increased osmotic
  pressure in the heart, veins, and carotid
  arteries.
• Oxytocin (Greek quick birth) influences
  reproductive function
• Important in birth
• Causes uterine contractions (synthetic
  oxytoxin--Pitocin--used to induce labor)
• Causes the letdown reflex (in response to sensory
  stimulation of the nipples, oxytocin is released,
  travels to the mammary glands, which contract
  upon exposure, causing milk letdown--and because
  of prior associations--cry of a hungry baby, or
  the sound of a milking machine (in cows) produces
  the same mechanism.
• Behaviorally
• oxytocin injected into the cerebrospinal fluid
  causes spontaneous erections in rats
• In the Prairie Vole, oxytocin released into the
  brain of the female during sexual activity is
  important for forming a monogamous pair bond with
  her sexual partner
• Sheep and rat females given oxytocin antagonists
  after giving birth do not exhibit typical
  maternal behavior. By contrast, virgin female
  sheep show maternal behavior towards foreign
  lambs upon cerebrospinal fluid infusion of
  oxytocin
• Crossing the placenta, maternal oxytocin reaches
  the fetal brain and induces a switch in the
  action of neurotransmitter GABA from excitatory
  to inhibitory on fetal cortical neurons. This
  silences the fetal brain for the period of
  delivery and reduces its vulnerability to hypoxic
  damage
• Vasopressin (aka antidiuretic hormone--ADH--or
  arginine vasopressin--AVP--acts to retain water
  in four-footed vertebrates.
• Rate of filtration in the kidneys slows in
  response to ADH, resulting in water retention.
• ADH has hypertensive effects during serious blood
  loss--blood vessels constrict in response to
  severe hemorhage, slowing blood flow.
• Behaviorally, vasopressin seems to induce the
  male to become aggressive towards other males.

35
Review

• Hypothalamic hormones
• GHRH
• GnRH
• MSH
• TRH
• CRH
• Somatostatin

• Pituitary Hormones
• Anterior
• GH (GHRH)
• FSH, LH (GnRH)
• TSH, PRL (TRH)
• ACTH (CRH)
• Posterior
• Oxytocin (hypothalamic oxytocin cells)
• Vasopressin (aka, ADH, AVP--increases in osmotic
  pressure).

36
Some other protein hormones
37
The Thyroid hormones

• Thyroid gland releases its hormones in response
  to TSH stimulation from the anterior pituitary
• There are two biologically active thyroid
  hormones, both derived from a molecule called
  thyroglobulin
• T3, also known as tri-iodothyronine and T4,
  thyroxine have three general effects
• Increases metabolism--generally, thyroid activity
  is greater in the winter.
• Growth and differentiation--closely related to
  actions of GH in fact, effects probably
  represent permissive actions on GH target cells
• permissive effects occur when one hormone induces
  receptor production for a second hormone. These
  effects are common.
• Behavioral effects--insufficient production can
  affect CNS development, causing cretinism
  insufficient production can also delay sexual
  maturation

Endemic cretinism in the Democratic Republic of
Congo. Four inhabitants aged 15-20 years a
normal male and three females with severe
longstanding hypothyroidism with dwarfism,
retarded sexual development, puffy features, dry
skin and hair and severe mental retardation
38
The GI hormones

• Three major gastrointestinal hormones
• Secretin
• Released by the duodenum (1st segment of small
  intestine). Stimulates pancreas to produce water
  and bicarbonate, which aid in digestion. Also
  stimulates liver to produce bile.
• Gastrin
• Released by the stomach. Stimulates insulin
  release, smooth muscle contractions of gut,
  gallbladder, and uterus.
• Cholecystokinin (CCK)
• Released by duodenum. Causes pancreas to secrete
  digestive enzymes causes gallbladder to contract
  and release bile

39
The Pancreatic hormones

• Insulin
• Only known hormone in the animal kingdom that can
  lower blood sugar (many hormones act to raise
  blood glucose levels). All cells (except for CNS
  cells) have insulin receptors. When an insulin
  receptor is activated, glucose is taken up into
  the cell, used, or stored as glycogen in muscle
  or fat cells.
• Glucagon
• Travels to the liver, where it breaks down stored
  glycogen (glycogenolysis), serving to increase
  blood levels of glucose. It acts in opposition
  to insulin.

40
Other peptide hormones

• Enkephalins
• Possibly involved in the stress response
  released by the adrenal medulla
• Inhibin
• Blocks secretion of FSH and aromatase (an enzyme
  that converts estrogens from androgens) released
  by the gonads (testes and ovaries). See figure
  at right.
• Activin
• Directly stimulates aromatase activity in the
  gonads (opposite of inhibin?) released by the
  gonads
• Relaxin
• Softens pelvic ligaments during pregnancy to
  allow the large head of the fetus clear passage
  through the vaginal canal during birth released
  by the ovaries

Female mouse on top left is a transgenic mouse
used to explore the potential effects of excess
inhibin on the reproductive axis. The inhibin
subunit protein was overexpressed in transgenic
mice. The transgene is expressed in numerous
tissues and levels of inhibin are highly elevated
compared to control mice, leading to a decrease
in serum FSH, and an increase in testosterone and
serum LH. Activin levels are also somewhat
depressed. The female mice are subfertile and
have very small litters. This is a consequence of
decreased ovulation, probably secondary to
alterations in FSH and LH. Most interestingly,
female mice that carry this transgene develop
several unique ovarian pathologies, including
distension of the bursal sac, the presence of
large fluid-filled cysts, and the presence of
atypical follicles that contain multiple oocytes
(Figure 3).
41
The Steroid hormones

• All steroids have a common chemical
  structure--three six-carbon rings plus one
  conjugated five carbon ring
• The precursor to all steroid hormones is
  cholesterol (produce from acetate in the liver)
• Recall that steroid hormones are fat-soluble and
  move easily through cell membranes (slide 25)
• Further recall that in circulation, they must
  bind to water-soluble carrier proteins (slide 25)
• Three major classes of steroid hormones
• Progestins/Corticoids
• Androgens
• Estrogens

cholesterol
42
The C21 steroids Progestin Corticoids

• Two types of C21 hormones--progestins and
  corticoids
• In response to anterior pituitary signals,
  cholesterol is converted into various steroid
  hormones in the adrenals
• P450-linked side chain cleaving enzyme, or
  desmolase cuts cholesterol down into
  pregnenolone, which is a progestin and is the
  precursor to all other steroid hormones
• Pregnenolone is a prohormone.
• A prohormone is a substance that can act as a
  hormone and can be converted into another hormone
  with different endocrine properties
• Progestins are named for their pregnancy-maintaini
  ng effects. Progesterone is important in
  maintaining pregnancy and in the initiation and
  cessation of mating behaviors (also, perhaps
  attachment)
• Two types of corticoids glucocorticoids and
  mineralocorticoids
• The glucocorticoids are involved in carbohydrate
  metabolism and are released under stress the two
  primary are corticosterone and cortisol. All
  reptiles and birds, as well as rats and mice
  secrete corticosterone the primary
  glucocorticoid in primates is cortisol
• Aldosterone is the most important
  mineralocorticoid. Primarily responsible for
  retaining sodium and excreting potassium

43
The C19 steroids The Androgens

• Progestins are precursors to all androgens.
• Enyzmes found in the gonads convert pregnenolone
  to several different androgens (from Greek andros
  for man).
• Most biologically important are testosterone,
  androstendione, and dihydrotestosterone (DHT)
• Produced in the Leydig cells of the testes
  Sertoli cells are source of the androgen-binding
  proteins that carry androgens through the blood
• Another androgen, DHEA (and DHEA-S) are produced
  in the adrenal cortex.
• Relatively weak
• Physio functions unknown
• DHEA replacement may ameliorate certain aging
  effects (increased muscle mass, decreased fat
  mass)
• Physiological functions of androgens
• Spermatogenosis
• Maintenance of the genital tract
• Maintenance of the accessory sex organs (prostate
  et al.)
• Secondary sex characteristics (body hair in
  humans, comb size in roosters, antler growth in
  deer)
• Behavioral functions
• Courtship
• Copulation
• Aggression
• Dominance
• Many other social behaviors (just beginning to be
  discovered)

44
The C18 steroids The Estrogens

• Androgens are the precursors of all estrogens
  just as progestins are the precursors of all
  androgens
• Estrogen means producing (coined 1927)
• Enzymes in the ovaries convert testosterone and
  androstendione to estrogen by a process called
  aromatization (because removal of the 19th carbon
  results in an aromatic compound).
• Biologically significant estrogens are estradiol,
  estrone, and estriol.
• Note that the ovaries produce androgens, which
  are then aromatized into estrogens.
• Sometimes excess androgens are produced or
  insufficient enzymes are present and the female
  is masculinized.
• Conversely, if high levels of enzymes that
  convert androgens to estrogens are present in the
  testes, then estrogens will be secreted into the
  blood and the male will be feminized. DHT cannot
  be aromatized (why is this important?)
• Physiolgical functions
• Initiate corpora lutea formation
• Uterine mass density (estrogen levels positively
  correlated with . . .)
• Development of secondary sex characteristics
• Metabolic functions
• Water retention
• Calcium metabolism (bone mass increases in the
  presence of estrogen)
• Behavioral functions
• Very important in maternal aggression and sexual
  behavior (e.g., in combination with progesterone,
  prolactin, oxytocin, estradiol induces rats to
  behave maternally in the presence of pups).
• Progesterone is primary in maternal aggression,
  but estrogens may play a role. Maternal
  aggression in women has not been studied. Many
  other social behaviors (just beginning to be
  discovered)

45
Androgens Estrogens are not sex-linked

• All males produce estrogens and progestins
• All females produce androgens
• The sex difference in circulating hormone levels
  is due to levels of gonadal enzymes.
• Testes have more enzymes for making androgens and
  less aromatase than do ovaries
• Ovaries produce high concentrations of androgens
  but these are easily aromatized into estrogens in
  the ovaries. These can be converted back into
  androgens, but this is an energetically expensive
  reaction
• Recall that the adrenals produce sex hormones
• Gene mutation(s) can lead to enzyme deficiencies
  which in turn can lead to an ovary or adrenal
  gland producing large quantities of androgens.
  See example at right

Congenital andrenal hyperplasia (lacking the
enzyme to metabolize cortisol and aldosterone,
and as a result, produce too much androgen. This
is a female with an extremely virilized clitoris.
46
Review
FYI, no such medically recognized condition as
adrenal fatigue.
47
The monoamines

• Derived from a single amino acid
• Two classes
• Catecholamines
• Indole amines
• Adrenal medulla monoamines
• epinephrine
• norepinephrine
• dopamine
• All derived from Tryosine
• Released in response to sympathetic neural
  signals (evoked by stress, exercise, low temp,
  anxiety, emotionality, and hemorrhage). In
  humans, norepi and epi are released at a ratio of
  14
• Actions
• Increase heart rate
• Vasoconstriction of deep arteries and veins
• Dilation of skeletal and liver blood vessels
• Increased glycolysis
• Increased blood glucagon concentrations and
  decreased insulin secretion
• Pineal gland indole amines
• Serotonin (5-HT)
• Melatonin

The brains of baby rhesus monkeys who endured
high rates of maternal rejection and mild abuse
in their first month of life produced less
serotonin. Low levels of serotonin are linked to
anxiety and depression and impulsive aggression
in both humans and monkeys.
48
Regulation

• Negative feedback
• Example
• GnRH is released from hypothalamus
• Gonadotropins are released from anterior
  pituitary
• Steroid and gamete production in gonads is
  stimulated
• Resulting steroid hormones turn off GnRH
  production in the hypothalamus, which shuts down
  gonadotropin release
• Up-regulation
• Increase in PRL stimulates production of more PRL
  receptors
• Back to point raised on Slide 11 (many hormones
  have a long latency of action ). Up-regulation is
  the result of protein synthesis, and can take
  weeks for the necessary quantity of receptors to
  accommodate to the higher hormone levels (case in
  point--action of certain anti-depressives require
  a substantial increase in of receptors to show
  effects must wait on receptor synthesis).
• This point also explains the failure of
  short-term hormone experiments (insufficient
  receptors to accommodate the sudden supra-physio
  hormone load).
• Down-regulation
• High insulin concentrations reduce the number of
  insulin receptors

49
So, WHY should social-personality psychologists
study hormones?

• Tiny handful of folks doing this stuff
• Upside potential is unlimited
• Grant is untapped
• Prostate cancer example
• Opportunities for collaboration