ECON 546 Lecture Notes - Lecture 19: Kynurenine, Gyrus, Doublecortin
27 Jun 2018
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Department
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Professor
Lecture 19: Depression and Suicide II Wednesday, March 21, 2018
Dr. Naguib Mechawar
Mental illnesses are mostly thought to result from the impairment of neuronal (synaptic)
communication and plasticity.
- Not caused by lesions or the loss of cell types
- Mostly abnormal function of limbic circuitry
Trophic Factors and Neuroplasticity
BDNF and Depression
- These factors remain present and are expressed in a mature brain important for
cellular plasticity, vital for healthy circuits and cell survival
- BDNF is important for plasticity and can be modulated by stress, signaling is abnormal in
depression
- BDNF binds to tyrosine kinase receptor B
- Chronic stress decreases BDNF signaling the hippocampus
- Chronic antidepressant treatment increases BDNF-mediated signaling
- Direct injection of BDNF in HC has antidepressant effects
- Decreased HC BDNF signaling in rodents leads to depression-related behaviours and
impairs antidepressant action
- Decreasing HC BDNF and TrkB alterations in postmortem studies of depression
- Alternations in the expression of TrkB in the HC in depressed patients
- Clinical studies measuring concentrations of BDNF in serum of patients have shown that
circulating levels are decreased in depressed patients
oPeripheral BDNF correlates with brain BDNF levels
oWhen treated with antidepressants, levels increase
Other Neurotrophins
- Challenge with neurotrophic factors in the brain other than BDNF GDNF
Hippocampal Volume
- Large body of literature showing that multiple episodes of depression are associated
with a decreased HC volume
- Can be attributed to changes in dendritic plasticity chronic stress leads to shrinkage of
dendritic arbors
- Another theory: decreased neurogenesis in depressed patients, leads to smaller HC
Adult Brain Neurogenesis
- Adult brain neurogenesis: generation and functional integration of newborn neurons in
mature circuitries
oRelatively new field of research (20 years)
find more resources at oneclass.com
find more resources at oneclass.com
- Two main cell types that are produced in adult life: granule neurons in the GCL of
olfactory bulb and granule cells in DG of HC
oTwo reasons:
- Interpretation that became dogma Ramon y Cajal didn’t believe that neurogenesis was
possible in adults
Origin of Neural Stem Cells
- Neural stem cells come from residual radial glial-like cell types that are leftover from
development
- Radial glial cells are important for migration during development, and they have SC-like
abilities
- They remain in the SVZ and SGZ of the DG
- SVZ produces new cells that migrate along the rostral migratory stream to the olfactory
bulb
- New cells produced in the DG migrate only a few microns and remain locally in the DG
Technical Approaches to Visualize Newborn Cells In Vivo
- Used newborn birds learning to sing to characterize neurogenesis
- Wasn’t thought to occur in primates at this time
- (A) method: radioactive thymidine that incorporates into dividing DNA
oTaken up in nucleus, use imaging to localize the radioactive nuclei
oCan follow cells several weeks later to see where they have moved
oFirst characterization of adult neurogenesis
- (B) method: BrdU, a thymidine analogue, is used instead of radioactive thymidine
oCells that are dividing take up BrdU, can be labelled with immunohistochemistry
oDouble labelling can be done cell can also express neuronal markers
- (C) method: use confocal microscopy to image cells that express GFP
Developmental Markers in the Mature DG
- At various stages of development, there is narrow/specific expression of different
markers
- Double-cortin: expressed in post-mitotic neurons, during a narrow window
- Specific molecules can be targeted to identify specific periods of neurogenesis
- Different markers for proliferation, migration, etc.
Distinction between OB and HC Neurogenesis
- Functional difference between OB and HC neurogenesis
- Identified that in the OB, new cells arrive in the bulb and replace older cells that die
oIn rodents, there is a high turnover of olfactory neurons
- In the DG of the HC, there are cells added (not replacing old cells)
What About Humans?
- Animal models are useful because overall architecture is conserved in mammal species
- There are important cellular and molecular differences
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Mental illnesses are mostly thought to result from the impairment of neuronal (synaptic) communication and plasticity. Not caused by lesions or the loss of cell types. These factors remain present and are expressed in a mature brain important for cellular plasticity, vital for healthy circuits and cell survival. Bdnf is important for plasticity and can be modulated by stress, signaling is abnormal in depression. Direct injection of bdnf in hc has antidepressant effects. Decreased hc bdnf signaling in rodents leads to depression-related behaviours and impairs antidepressant action. Decreasing hc bdnf and trkb alterations in postmortem studies of depression. Alternations in the expression of trkb in the hc in depressed patients. Clinical studies measuring concentrations of bdnf in serum of patients have shown that circulating levels are decreased in depressed patients: peripheral bdnf correlates with brain bdnf levels, when treated with antidepressants, levels increase. Challenge with neurotrophic factors in the brain other than bdnf gdnf.
