Monday, March 5, 2012

Neuroplaticity in the adult hypothalamus

1Main Idea¶

Neuroplasicity, the wiring of brain, explains why some people can easily become fat and can hardly lose their weight. Since, contrarily to popular belief, new neurons continue to be added in adult brain, events in life (such as pregnancy) can rewire the brain and change a person's proneness to obesity.

2Neuroplasicity experiment in rats¶

• high resolution in vivo brain imagingin is done by using chronic window or thining the skull and use time-line imaging to look at flurescently tagged neurons.
  • so usually just at the cortex
• it's showed that triming of viscus (?) induces turnover of neurons of the mouse barrel cortex

3Neuroplasity and oxytoxin¶

• Another example of rewiring of neural projection during different events in life.
• oxytocin neurons are manocellular neurons in paraventiruclar and supraoptic nuclei (PVN and SON),
• during lactation, glial cells's astrocytic processes between SON neurons and around axonal termianls retract, allowing those magnocellular to come in contact, release glutamate on each other and thereby stimulating each other.
  • this is called neuro-glial remodeling
  • lead to release of GnRH and peak fo estrogen right during afternoon of proestrus just before estrous phase (ovulation)
    • during afternoon of proestrus, there's a significant decrease in the surface area of astrocytes in parallel with the increase in LH concentration.
    • surface area of astrocytes returns to similar levesl on estrus, like those on the morning of proestrus.

4Neuroplasicity on ob/ob mice¶

• reminder: ob/ob mice are mice that don't have leptin. They're fat cuz there ain't no leptin to suppress their appetite at the level of ARH and PVN.
  • leptin stimulate POMC neurons, which decrease appetite
  • leptin inhibits NPY/AgRP neurons, which stimulate food intake
  • both POMC and NPY/AgRP nuclei are in Arc and they project to MC3/4R nuclus in PVN.
• synapse types
  • excitatory: asymmetric, presynaptic density is much greater than post synaptic density.
  • inhibitory: symmetric
• leptin deficient(ob/ob mice) differ from wild type mice in the number of excitatory and inhibitory inputs onto NPY and POMC neurons
  • ob/ob mice have more excitatory input and less inhibitory to NPY and opposite for POMC (more inhibitory, less excitatory)
  • when leptin is put into ob/ob, syanptic density becomes like that of wild type (more inhitory on NPY and more excitatory on POMC)
• Dil, a fluorescent lipophilic dye that labels axonal projections, can be used to inject into neuronal bodies and see where their axons and dendrites project to.
  • staining of arcuate nuclei show projections to PVN.
  • experiments show that leptin has to do with neural outgrowth from ARC.
    • leptin deficient mice (ob/ob) show much less fiber density (outgrowth) relatively to that of wildtype.
    • in wild type, there's a lot of outgrowth in ARC and you can even see staining in PVN.
    • when ob/ob is treated with leptin, there's a huge increase fiber ensity in ARC.

5Leptin and Hypothalamus¶

• three actions (as discussed so far)
  • act on neurons of the ARC by binding to their leptin receptor and change their production of NPY, POMC, AgRP.
  • modify ARC neurons' syaptic inputs
  • induce neural projections frmo ARC to PVN.
  • (but we don't know the molecular mechanism to those)
• genetifically built in fatness
  • DIO rats, those that are bred to be prone to diet-induced obesity, have less projection from ARC to PVN comparing to diet resistant rats.
    • detectable even within 12 days of birth, suggesting that even though those rats have the same weight, some are more prone to obesity.
  • because such defect in Arc projections which can be seenearly in first week persists into adulthood.
  • so predisposition for obesity might be wired into the brain from the start....
    • to get around the problem, we look at how to take advantage of neurogensis in adults... CNTF!
• CNTF (ciliary neurotrophic factor) induces "sustained" weigh loss in obese people
  • even after treatment of CNTF, weight loss continues.
  • so it's maybe due to plastic chagne in the brain
    • answer is yes!

6CNTF and brain rewiring¶

• reminder: leptin signals via phosphorylation and activation of STAT3, which dimerize and induces transcription of certain genes.
• CNTF induces cell proliferation (neurogenesis) in the brain as shown using BrdU labeling
  • BrdU: gets incorporating to replication DNA, thus a good indicator of cell proliferation
• result of BrdU staining overlaps with staining of phosphorylated STAT3 in CNTF-treated mice
  • indicating that CNTF induces cell proliferation of the cells that sense leptin.
• experiment using AraC, a inhibitor of cell proliferation, further strenghtens the conclusion of above experiment
  • when AraC is used with CNTF, long term effect of CNTF is abolished.
  • but short term effect of CNTF is not affected.
    • because CNTF mimics effect of leptin in the hypothalamus.
• in summmary, CNTF does two things:
  • short term: act like leptin
    • esp. important when key CNS targets of leptin are less responsive to leptin due to excess body fat.
  • long term: induce growth/proliferation of leptin sensing neurons
    • those new neurons increase weight regulation and effects of leptin
    • maintain weight after CNTF treatment