A Bad Start:

1
A Bad Start

• The neuroendocrine consequences of prenatal stress

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Prenatal stress?

• The stressful experiences of a pregnant female
  seem to result in detrimental impacts on the
  offspring.
• While some of these impacts may be linked to
  altered maternal care patterns and lactation,
  some of the alterations seem to happen
  prenatally.
• Gestational timing, sex of fetus, severity of
  stressor, frequency of stress, and kind of
  stressful stimuli seem to affect the outcome.

3
What are its effects?

• Generally, it is associated with
• - hypertension
• - low birth weight
• - sleep disturbances
• - altered sexual function
• - altered HPA axis function
• - decreased immune function
• - impaired learning and memory
• - decreased cell proliferation in brain
• - increased emotional reactivity/anxiety

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What could cause all of this?

• Adrenalectomy of the mother seems to eliminate
  the behavioral, HPA axis, and receptor
  alterations typically seen from prenatal stress
  (Barbazanges, et al. (1996) Zagron Weinstock
  (2006) )
• Adrenal steroids include mineralocorticoids
  (aldosterone), glucocorticoids (cortisol/corticost
  erone), and several sex steroids
• The glucocorticoids seem the most likely
  candidate for many reasons
• - especially since they are a key component
  of the stress response.

5
11ß-Hydroxysteroid Dehydrogenase

• Two forms Type 1 and Type 2
• - Type 2 inactivates endogenous
  glucocorticoids
• - 11ß-HSD2 is found in the kidneys of adults,
  and the brain and placenta of the fetus
• Holmes, et al. (2006) 11ß-HSD2 null mice
• - the offspring of pairs of -/- 11ß-HSD2 mice
  had lower birthweights, spent less time in the
  center of the open field, and less time in the
  open arms of the EPM compared to controls
• - the -/- offspring of pairs of /- 11ß-HSD2
  mice also had lower birthweights and spent less
  time in the open arms of the EPM compared to
  siblings, although time spent in the center of
  the open field was similar (figures on right)

Elevated Plus Maze
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Adrenalectomy and Prenatal Stress

• Barbazanges, et al. (1996)
• - adrenalectomy of some pregnant rats, with
  cort pellet implantation
• - during last week of pregnancy, rats placed
  in retraining tube in bright environment (45 min.
  3x daily) as a stressor
• - at 90d of age, male pups were submitted to
  30 min. of restraint stress and blood levels of
  cort were tracked (figure to right)
• - 2 weeks later, hippocampal corticosteroid
  receptor binding assessed (figure to right)
• - Results pups of non-ADX females submitted
  to prenatal stress had higher levels of cort at
  120 min. after stressor lower Bmax of Type I
  Cort Receptors

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• - some adrenalectomized pregnant rats also
  received injections of either saline or cort
  during same stress treatment
• - again at 90d of age, male pups were
  submitted to 30 min. of restraint stress and
  blood levels of cort were tracked (figure to
  right)
• - 2 weeks later, hippocampal corticosteroid
  receptor binding assessed for these rats (figure
  to right)
• - Results pups of ADX females given cort
  injections along with stressor had higher levels
  of cort at 120 min. after stressor (compared to
  the pups of saline-injected ADX females)
• - lower Bmax of Type I Cort Receptors

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Prenatal Stress and Hippocampus Maturation

• Fujioka, et al. (2006)
• - Dams received either mild or severe stress
  from days E15-E17 30 min. of restraint or 240
  min. of restraint once daily
• - assessments of hippocampus included BrdU
  staining (infant and adult), Golgi staining,
  electrophysiology
• - also assessed affects of MR and GR agonists
  and antagonists on hippocampal cell growth in
  vitro
• - results overall, mild stress enhanced the
  development of hippocampal neurons while severe
  stress suppressed development

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Fujioka, et al. (2006)
10
Fujioka, et al. (2006)
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Assessing MRs vs. GRs - GR agonists and MR
antagonists reduce Brdu/ß-tubilin cell numbers,
branch points, and length - MR agonists and GR
antagonists increase Brdu/ß-tubilin cell numbers
- generally, it seems like MRs enhance the
development of hippocampal cells, while GRs
decrease their development
Fujioka, et al. (2006)
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Fujioka, et al. (2006)
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What are those glucocorticoids doing to the
receptors?

• The MR and GR (corticosteroid receptors) are
  involved in the effects of prenatal stress on the
  brain
• - cort acts on the receptors present in the
  fetus
• - the decreased activation of MRs and/or
  increased activation of GRs may be responsible
  for the cell density deficits found in certain
  brain areas after severe prenatal stress
• - prenatal stress also causes alterations in
  the number of MRs and/or GRs found in certain
  brain structures (Barbazanges, et al. (1996)
  Wilcoxon Redei (in press))
• Ways cortisol/corticosterone might be altering
  receptor expression
• - cort may be directly affecting the
  transcription of the receptor genes cort may be
  affecting the development of other
  neurotransmitter systems (NE, 5-HT, DA), which in
  turn would impact the development and receptor
  expression of target areas and/or cort may be
  affecting the availability of glucose for the
  developing brain
• Now how are these receptor changes likely to
  produce the endocrine and behavioral results seen
  in PNS?

14
Welberg Seckl (2001)
15
?
Welberg Seckl (2001)
16
?
X
Welberg Seckl (2001)
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Other considerations Synthetics

• Synthetic glucocorticoids
• - these include dexamethasone and
  betamethasone
• - they readily bind to GRs, but not to MRs
• - not metabolized by 11ß-HSD2
• More than just an interesting research question
• - these are used clinically to prevent
  respiratory distress in preterm infants, and they
  are also given in repeated doses to mother at
  risk of preterm birth
• - many studies have looked at the use of
  synthetics, and the effects seem similar to PNS,
  although systems like the amygdala may become
  more involved in their effects (for example
  Welberg, Seckl, Holmes (2001))

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Postnatal Handling

• Postnatal handling
• - seems protective against the alterations
  caused by prenatal stress
• Vallee, et al. (1997)
• - Prenatal stress group dams restrained (45
  min. 3x daily) during last week of pregnancy
• - Control group left undisturbed
• - Postnatal handling group pups taken away
  from dam, put in another cage (15 min.), then
  returned to home cage once daily from P1-21

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Vallee, et al. (1997)
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Vallee, et al. (1997)
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- overall results no memory differences between
groups, the PNS group had more locomotor
activity, and PNSgtcontrolgtPNH on anxiety measures
Vallee, et al. (1997)
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More on Postnatal Handling

• Kippin, et al. (2004)
• - prenatal stress was shown to decrease the
  number of neurosphere-forming cells in the
  subependyma of the lateral ventricle throughout
  life
• - stress experienced as an adult did not
  decrease numbers
• - postnatal handling not only increased the
  number of neurosphere-forming cells compared to
  control, but reversed the effects of prenatal
  stress

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Conclusions

• Prenatal exposure to stress can have long-term
  impacts on CNS structure, endocrine function, and
  behavior
• The effect is mostly due to overexposure to
  glucocorticoids
• One brain region that experiences a notable
  alteration after PNS is the hippocampus, and
  those changes include neuron density and
  receptors expressed.
• One or both types of corticosteroid receptors are
  typically altered in number, making the
  hippocampus (and other structures in the negative
  feedback system of the HPA axis) less responsive
  in halting the stress response.
• The effects of PNS can be reduced or reversed by
  early interventions.