Neuroplasticity and Neurogenesis in Depression

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Neuroplasticity and Neurogenesis in Depression

• Chris Clark

Mentors Dr. Craig Stockmeier Dr. Javier
Miguel-Hidalgo
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Neuroplasticity Neurogenesis

• Neuroplasticity changes occurring in brain as a
  result of learning, stress, disease or drugs
• Challenges hypothesis that ideas and circuits are
  hardwired from birth
• Presents possible explanation for some
  psychiatric illnesses, as well as potential
  treatment for neurological or psychiatric
  disorders
• Leads to such breakthroughs as Brain-Machine
  Interface
• Neurogenesis Literally, birth of new neurons
  glia
• Occurs in two places in brain
• Subventricular Zone Important in olfactory
  system
• Dentate Gyrus of Hippocampus What were
  interested in
• Is there neurogenesis in humans and is it dynamic
  in mental illness?
• Yes (Gage et al.) and unclear

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Major Depressive Disorder (MDD)

• Thought to be affected by changes in certain
  neurotransmitter levels/activity (i.e. Serotonin,
  Norepinephrine, GABA?)-e.g. reserpine depletes
  monoamines and can cause depression.
• Changes in neurons and glia density/number within
  the hippocampus and prefrontal cortex found in
  patients having MDD -Rajkowska et al., 1999
  Stockmeier et al., 2004

• Symptoms include
• Depressed mood
• Loss of interest or pleasure
• Inability to concentrate or make decisions
• Appetite and sleep disturbances
• Fatigue
• Psychomotor agitation or retardation
• Inappropriate guilt
• Thoughts of death or suicide
• (DSM-IV, APA, 1994)

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Hippocampus

• Named after sea horse (Greek Hippos horse
  Kampi curve)
• Located bilaterally within the temporal lobe
• Involved in formation of memory, spatial
  navigation
• Patients with MDD have reduction in hippocampal
  volume
• Dentate Gyrus, a region exhibiting adult
  neurogenesis, may be involved in depression

Dentate Gyrus
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Neurogenesis and MDD

• Animal models (e.g., learned helplessness)
  suggest that neurogenesis may be suppressed in
  major depression
• Neurogenesis in these models is restored or
  increased by efficacious treatments for
  depression e.g., SSRIs, electroconvulsive
  treatment (enriched environment, voluntary
  physical exercise)
• The therapeutic response to SSRIs in depression
  may involve neurogenesis
• Is neurogenesis altered in humans with major
  depression?

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Is neurogenesis in the Hippocampus affected in
MDD?

• In particular
• Is there a change in proliferation of cells
  (neurons and/or glia) in MDD?
• Do subjects with more than one depressive episode
  exhibit a greater reduction in proliferation of
  new cells than subjects with one episode or
  controls?
• Is a change in neurogenesis a cause or effect of
  MDD? (state or trait?)
• Ultimately, how can we use this knowledge to form
  more effective treatments?

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Hypothesis

• Based on animal studies which may model some of
  the symptoms of depression, we hypothesize a
  reduction in neurogenesis in subjects with
  depression, and that
• Subjects with gt1 depressive episode will have the
  greatest reduction in neurogenesis

Depression
Neurogenesis
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Ki-67

• Ki-67 is a protein that is expressed in cells
  that are actively involved in the cell cycle
• Used extensively in IHC for the detection of
  cancer (due to increased proliferation of cells)
• Most neurons are arrested in the G0 phase
• Cells immuno-positive for Ki-67 represent neurons
  or glia recently undergoing neurogenesis

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Materials Methods

• Tissues from 34 subjects were obtained at autopsy
  from the coroners office of Cuyahoga County
  (Cleveland, OH). An ethical protocol approved by
  the Institutional Review Board of the University
  Hospitals of Cleveland was used, and informed
  consent was obtained from the next-of-kin for all
  subjects.
• The Structured Clinical Interview for DSM-IV
  (First et al. 1996) was administered to
  next-of-kin for all subjects. At consensus
  diagnosis, the interview and medical records
  revealed that 17 subjects met criteria for MDD,
  while 17 subjects were psychiatrically normal.
  Most subjects had been prescribed antidepressant
  medications sometime in their lives many were
  noncompliant at time of death.
• There were no significant differences between
  cohorts in age or postmortem interval.
• The hippocampal formation was frozen in
  isopentane cooled by dry ice. Tissue blocks were
  sectioned at 20µm, and adjacent sections were
  stained for Nissl substance.

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Materials and Methods (Cont.)

• The block selected for this study was in the
  rostral body of the hippocampal formation and
  immediately caudal to the lateral geniculate
  nucleus.
• Frozen sections were air dried and processed for
  IHC (Miguel-Hidalgo). The sections were
  incubated with Ki-67, an anti-mouse, monoclonal
  antibody (1200, Zymed). Sections were
  immunohistochemically processed for localization
  of Ki-67 in the dentate gyrus and were visualized
  using the Vectastain Universal Elite ABC kit.

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Immunohistochemistry (IHC)

• Primary antibody binds to specific antigen (i.e.
  proteinin our case Ki-67)
• Secondary antibody binds to primary antibody
• DAB (Diaminobenzidine) binds to secondary
  antibody
• View/quantify immunopositive cells with
  microscope

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IHC Imaging

• Hippocampus
• note dentate gyrus (20x)

b. Ki-67- immunoreactive cells within Granule
Cell Layer of Hippocampus Neutral Red Used as
Counterstain (1000x)
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Further Research

• If neurogenesis is decreased in depression,
  possible future studies include IHC of other
  markers of cell division dual labeling studies
  of neurons and glia to determine cell type that
  changes.
• Then, a detailed mapping of the biochemical
  processes underlying and controlling the rate of
  neurogenesis can be explored, and
• Ultimately, treatments may be developed.
• For example, SSRIs boosting synaptic levels of
  serotonin were based on the observation that
  reserpine decreased serotonin levels in brain and
  caused depression in some.
• Entire new class of drugs may be designed to
  promote healthy cell development/proliferation

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Acknowledgments

• Dr. Craig Stockmeier
• Dr. Javier Miguel-Hidalgo
• Dr. Ian Paul
• Dr. Gouri Mahajan
• Katie ONeill
• Justin A. Cobb
• Victoria Lo Valeria Wanzo
• Anne Dautenhahn
• Catherine Kaime
• UMMC CPN
• NSSP
• RR17701 MH67996