The hypothalamus as a major integrating center

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The hypothalamus as a major integrating center
In 1859 the french physiologist Claude Bernard
made explicited the importance of the stability
of the milieu interior, the internal medium. He
wrote "La fixité du milieu intérieur est la
condition d'une vie libre et indépendante" ("The
constancy of the internal environment is the
condition for a free and independent life").
This is still the underlying principle of
homeostasis today for any warm-blooded animal .
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The hypothalamus has evolved for controlling the
connection between Body and External Environment
through Behavior
External environment
body
hypothalamus

• This control is achieved by receiving information
  about the state and condition of the body, and
  consequently altering
• body conditions directly through changes in the
  autonomic system and bodily function, and
• 2) by modifying or inducing behavior

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• Hypothalamus relation between anatomical
  location and function
• The anatomical location of the hypothalamus, well
  placed in the middle of limbic structures, at the
  end of the brainstem, and close to the pituitary
  gland makes is suitable for
• receiving information on the body state
• directly from the body organs,
• indirectly through the emotional/motivational
  part of the brain, and
• modifying the interface between individual and
  environment by affecting bodily functions
• directly (autonomic and enteric systems)
• indirectly, through behavior

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What is known what is not know

• The hypothalamus controls very diverse functions,
  some of them relatively well (yet not completely)
  understood like
• metabolic energy production
• Food consumption
• water intake
• electrolyte balance
• Reproduction
• growth and development
• Immune response
• Sleep cycles
• thermoregulation

Some other functions of the hypothalamus,
particularly its relation with behavior, are a
lot less understood
(hypothalamus brains black hole) We will
start with what is known and will venture on the
unknown territory later on in the course
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• Feedback mechanisms
• There are two main mechanisms of action used by
  the hypothalamus
• -feedback (positive or more often- negative)
• -reflexive (somehow similar to a muscular reflex)
• Example of negative feed back control of
  temperature
• Elements
• A set point (more or less fixed and determined
  biologically)
• A transducer monitoring an external or internal
  variable (producing an error signal)
• One or more means of changing the variable
  (autonomic control or behavior)

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Feedback mechanisms
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• in the case of temperature control, the set point
  is a biological requirement for optimizing
  biochemical enzymatic protein control, whose
  temperature dependence is brutal (T(normal body)
  99 1 F). It is unknown how this set point is
  biochemically established
• Negative error induce
• Shivering (peripheral, autonomic system)
• Vasoconstriction (peripheral, autonomic system)
• Increase in metabolic energy production (thyroid
  up-regulation)
• But also more complex activities like
• Increasing the house thermostate temperature
• Getting another blanket or closer to your partner
• Or even deciding to go to Florida or Texas or
  California for living
• Vice versa, a positive error induces
• Sweating (cools the body absorbing water
  evaporation heat)

Feedback mechanisms (contd)
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Feedback mechanisms (contd)
Example of positive feedback parturition (baby
delivery) Intrauterine pressure induces the
release of oxytocin from posterior pituitary
(reflex) Oxytocin increase leads to increase in
uterine contractions The cycle repeats itself
closing the loop and lasting until the pressure
is finally release with the delivery of the fetus
(autocatalytic process) Similar and related
is the release of preovulatory gonadotropin
during the menstrual cycle -Ova ready to be
released produce estrogen -Estrogen induces the
release of GnRH (gonadotropin releasing hormone)
by the hypothal. -GnRH activates the pituitary
which produces more gonadotropins which stimulate
further release of estrogen by the female
reproductive organs -the cycle repeats until the
ovum is removed from its site Positive feedback
once a system variable departs from its
homeostatic level it gets even further until a
desirable system change is obtained (snowballing
effect)
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• Hypothalamus pituitary end organ axes
• Basic extremely important concept in
  neuroendocrine regulation
• The skeleton of neuroendocrine regulation is
  based on the sequential connection between
• Hypothalamus
• Hypophysis (pituitary gland)
• End organ
• the hypothalamus releases a substance that
  activates the pituitary
• The pituitary releases a substance that activates
  an end organ
• The end organ releases a substance that produces
  the desirable effect

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• Hypothalamus loops normal, short, ultra-short
• To complete the actual functioning, there are the
• normal loop negative feedback from the end
  organ to terminate the hypothalamic hormone
  production
• Short loop feedback (can be negative or
  positive) from the pituitary to the hypothalamus
  to produce more or less hormone
• Ultra-short loop, within the hypothalamus
  (usually is positive) to produce more hormone
  once its production and release is triggered
• The end organ can be a gland or a non-endocrine
  target, but the same concept is valid

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• There are three important hypoth anterior
  pituit end organ axes that need to be memorized
  for their importance
• Hypothalamus pituitary thyroid (HPT, controls
  metabolic energy production)
• Hypothalamus pituitary gonads (HPG, testicle
  or ovary hormone production)
• Hypothalamus pituitary surrenal gland (HPA,
  glucocorticoid production from the adrenal
  cortex)

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• Example HPT
• 1) The paraventricuar n. of the hypoth. Produces
  the tripeptide TRH (thyrotropin releasing
  hormone)
• 2) TRH is released trough the median eminence
  into the portal vessels system and reaches the
  pituitary
• 3) In the pituitary TRH activates TRH receptors
  on thyrotropes where it induces the production of
  TSH (thyroid stimulating hormone)
• 4)TSH reaches the thyroid where it induces the
  production and release of two thyroid iodinated
  hormones, T3 and T4 (tyroxine), which in turn
  increase general cell metabolism (glucose
  turnover for the production of ATP, the
  biochemical fuel)
• 5) Thyroid hormones returning to the hypothalamus
  turn off the production of TRH (long loop)

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• Other two pituitary hormones are particularly
  important
• Prolactin and growth hormone (GH)
• Prolactin controls lactation (milk ejection after
  newborn suckling)
• GH controls the growth of bones and most bodily
  organ
• Both prolactin and GH have many more functions
  beyond these
• They do not have the three-level production
  control, but they are just controlled by the
  short loop because they act more in a
  distributed manner
• These two pituitary hormones have the important
  property that the hypothalamus can
• Increase their release with a Prolactin releasing
  factor and a growth hormone releasing hormone
  (GHRH), respectively, or (here is the novelty)
• Decrease their release with Dopamine, or
  Somatostatin, respectively

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• Hypothalamic control of behavior and motivation
• Lesions to some hypothalamic n. can induce
  changes in the motivation for certain behaviors
  like
• Eating (hyperphagia or hypofagia)
• Drinking (water)
• Sex (lordotic behavior in females, copulatory
  movements in males)
• The control of this variables and behaviors is
  not straightforward, but great advancements in
  our knowledge have been done in the last decades,
  at least for some of them, like eating control
• The control of food intake is now believed to be
  based on a loop between a weight setting
  pointnucleus, the mediobasal hypothalamus
  producing Neuropeptide Y. the amount of fat
  stored in the adipocytes, the production of the
  hormone leptin in the guts, and a
  leptin-sensitive nucleus in the hypothalamus
  itself, which, when activated decreases the
  desire for food consumption.
• This loop has been relatively well studied only
  in the last decade or so

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• Hypothalamic control of behavior and motivation
  (contd)
• For these reasons many believe that the
  hypothalamus is the core of the motivational
  system, acting in a subconscious manner to impose
  its commanding control obeying, in turn, to a
  complex and strict need to optimize the internal
  environment directly through body reflexes, or
  indirectly through simple behavior (eating,
  drinking sleeping, etc.) or through more complex
  behavior involving possibly many brain areas.
• In this view, the complex function of large parts
  of the brain like the neocortex in humans might
  be considered as an accessory of the
  hypothalamus, which, through the limbic systems
  which controls emotions, imposes its control to
  the whole organism.

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• How to study a neuroendocrine system?
• Through manipulation of a neuroendocrine axis and
  evaluation of the component responses
• Each component has
• -input (feedforward stimulation and, sometimes,
  inhibition)
• -output
• feedback inhibition
• Example the HPA (production of corticoptropins)
• CRH stimulation of production of ACTH can be
  shown in vitro on pituitary cells stimulated
  directly by CRH
• Removal of CRH by hypothalamic lesion,
  immunochelation of CRH, or any other means,
  decreases ACTH production
• Negative feedback can be shown by measuring the
  increment in the production of a hypothalamic or
  pituitary hormone after removal of the end organ
• Removal of gonads (testis or ovaries) yields
  increase in GnRH (hypoth) and gonadotropins
  (pit.)
• Removal of adrenal gland yields increase in CRH
  and ACTH

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Preservation of the milieu interieur sometimes
requires large temporary changes In response to
external or internal stimuli. Important example
HPA axis -An external stimulus increase CRH
production which in turn -Increases ACTH which in
turn stimulates -Glucocorticoid production If
the stress is eliminated the external stimulus
for the activation of the HPA axis disappears and
the axis activation goes back to the basal
level If the stress remains the system is not
able to fully reset itself with a negative
feedback, because there is still an unresolved
level of stress to keep it active. This
prolonged response can have multiple deleterious
long-term consequences on the organism
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Signals activating neuroendocrine
axes Exteroceptive or interoceptive
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• Exteroceptive
• can be
• Pheromonal
• Temperature
• Visual
• Tactile
• Olfactory or gustatory
• Cognitive
• Example 1
• The act of coitus produces stimulation of
  virtually all modalities.
• In turn, such stimulation activates the HPG
  (gonadal) axis, with the production of LH in the
  female, which eventually tends to synchronize
  ovulation with the presence of sperm in the
  ovulatory tract, after which activation goes back
  to basal levels
• Example 2
• Cold temperature activates the HPT axis until
• the ext temp is brought back to a comfortable
  level

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Interoceptive Baroceptors (internal pressure
) Proprioceptors (organ, joint and muscle
movements) Internal thermoreceptors Example A
drop in internal pressure produces the activation
of the HPA axis and the production of vasopressin
inducing vasoconstriction Important for the HPG
axis too
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Cross talk between different neuroendocrine
systems Interactions can be positive Ex.
complementary production of CRH and vasopressin
following stress Or negative Ex. lactating
women may interrupt their cycle, due to the
inhibitory action of prolacting on GnRH (and
gonadotropin release) for obvious reasons
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• Change in homeostatic set points
• The set points in homeostatic regulation change
  during
• Development
• Sexual maturation
• Aging
• Environment (chemical or physical)
• Disease (organic)
• Nutrition
• Stress
• Psychiatric conditions
• Circadian period
• Season

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• Neuroendocrine alterations have invariably major
  health repercussions
• Ex.
• Changes in menstrual cycle
• body energy production misfunction
• Cushing syndrom
• And many others
• In some cases there can be even fatal secondary
  consequences (cancer, autoimmune disease and
  others)
• Primary neuroendocrine dysfunction
• -the end organ is the cause
• Secondary neuroendocrine dysfunction
• -the hypothalamus or the pituitary (or other
  organs) are the cause

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Neuroendocrine reflexes
Acute physiological responses to sensory and/or
somatic signals They are similar to their
neuromotor counterpart, except that While
neuromotor reflexes consist only of neuro-motor
afferent and efferent INPUT MECHANISM OUTPUT
Neuroendocrine reflexes have at least one
component (input or output or both) which is
hormonal
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Two reflexes associated with oxytocin release
1) Nipple suckling Induces oxytocine release,
which induces contraction of the muscles
surrounding the lactation duct, in turn
stimulating lactation 2) Cervix mechanoceptors
are activated during labor inducing the release
of oxytocin which increases uterine contraction
which increases oxytocin release in a positive
feedback until delivery is completed
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Graded reflex. Example vasopressin release

• Increase in plasma osmolarity
• Decrease in blood pressure
• The effect is
• re-absorption of water from kidneys
• (that is why vasopressing is also called
  anti-diuretic hormon)
• And
• 2) Arterial vasoconstriction preventing further
  pressure drop

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• The output is a graded function of the input
• The amount of vasopressin released is
  proportional to the increase in blood osmolarity
  or to the decrease in blood pressure
• Differences between
• Neuroendocrine reflex vs. Homeostatic mechanism
• Controlled and feedback variable is a hormone
• Controlled and feedback variable is a systemic
  variable
• A reflex is usually triggered by a large
  displacement of a system variable outside the
  normal variation range (life-threatening
  situation)
• Homeostasis is part of the physiological control
  of a variable within the physiological range

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Neuroendocrine pulsatility Endocrine neurons are
not qualitatively different from other neurons,
but they have a great propensity, under specific
stimulation, to synchronize their activity and
likewise to release together, in pulsatile
manner, the corresponding hormone. The
mechanisms inducing neuroendocrine pulsatility
are not completely clear, but electrical or
chemical synapses connecting similar hypothalamic
cells, and periodic oscillations in intracellular
CaI (intracellular concentration of Calcium are
supposed to play a role at least in the
synchronization of some groups Corollary of
this fact is that the presentation of continuous
stimuli of hypothalamic hormones is less
effective, or even inhibitory, in releasing
pituitary hormones.
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Example synchronicity (coupling) of LHRH and LH
pulses
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Extracellular signal inducing neuroendocrine
secretion
1) Neuroendocrine pulse generating
mechanisms (cell-cell connectivity and local
signaling) 2) Membrane and Voltage-dependence
modulation 3) Modulation in hormone or receptor
transcription or translation (mRNA production or
protein synthesis) 4) post-translational
processing 5) Stimulus secretion coupling
(presynaptic terminal)
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• Modality of neuroendocrine modulation
• Amplitude modulation
• 2) Frequency modulation
• Explanation
• The amplitude (amount) of hormone released in
  pulses of is a increasing function of the
  stimulus (ex. CRH)
• The frequency of the hormone pulses is
  accelerated as proper stimulus grows its
  intensity
• This frequency is not the frequency of the
  neurons involved in release (time scale of
  neuronal spikes is ms, that of endocrine pulses
  is on the order of magnitude of minutes to hours)
• Pulsatile release has been thoroughly studie in
  the HPG (gonadal axis).
• Due to the absence of inhibitory feedback in
  castrated males, the pulses of GnRH and pituitary
  gonadal hormones are more evident in castrated
  animals (or ovarectomized females, as shown in
  the previous example) .

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LHRH (GnRH) pulsatility
Intact male
Castrated male (no feedback from gonads)
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• Permissive effect of hormones
• Hormones do not create the neural circuit for the
  corresponding activities, they simply activate
  (or inhibit) them
• Example induction of sexual behavior in the
  female by estrogen and progesterone
• Estrogen ? the production of oxytocin receptors
  in the VMN of the hypothalamus
• Progesterone facilitates their cellular
  distribution
• An increased oxytocin response ? the sensibility
  to oxitocin of this nucleus and produces the
  lordotic behavior

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• Cross-talk between different hormones
• Effect of Intracellular cascades
• Although many chemical cascades are sometimes
  compartimentalized (they happen in different
  anatomical regions, cell types, or at least
  different part of the same cell), in most cases
  metabolic cascades are NOT compartimentalized
• Example steroid hormones receptors can be
  activated, or their sensitivity to their
  activators can be increased (or decreased) by
  cAMP and growth factors
• This cross-talk greatly complicates the
  interpretation of neuroendocrine experiments

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Trophic effects of hormones In some important
cases hormones do not just increase the
probability of the activation of a particular
neuronal circuit or behavior, but have also
permanent or long-lasting consequences Example
growth hormone The nature of the signals that
induce the correct body part and histological
attributes is specified by means of hormonal
signaling, at least in a first phase. Hormonal-li
ke communication between tissues of body organs
contributes to finalize the correct build of the
body during development.