A latent neurogenic program in astrocytes regulated by Notch signalingMagnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EM,Lindvall O, Kokaia Z, Frisén J.

Science. 2014 Oct 10;346(6206):237-41. doi: 10.1126/science.346.6206.237.

Jitesh Doshi [670302401]CS502 Computational BiologyUniversity of Illinois at Chicago

What we’re going to look at?

Overview of Neurogenesis and Notch signaling

Goal of the presented work Approach Results Conclusions Questions I thought could be relevant If you have any questions References

BRAIN

NEURON

ASTROCYTES

NOTCH SIG.

A highly complex organ specialized in reasoning and logic imparting cognitive abilities and senses

A center of all actions we perform originative or as a response to stimuli

Predominantly composed of neuronal sense as a means of transport of signal

STRIATUM

BRAIN

NEURON

ASTROCYTES

NOTCH SIG.

An electrically excitable cell which can process and transmit information

Also help in memory development

Do not divide further (G0 phase)

* Fundamental principle of Neural Networks

STRIATUM

BRAIN

NEURON

ASTROCYTES

NOTCH SIG.

Star shaped cells

Helps in metabolism, migration, response to injuries and many more functions

Dysfunction may cause aberrant neuronal circuitry

Thus involved in neurodevelopmental disorders

STRIATUM

BRAIN

NEURON

ASTROCYTES

NOTCH SIG.

Evolutionary conserved signaling pathway

Regulates cell-fate determination during development

Maintains adult tissue homeostasis

Regulates neurogenesis

STRIATUM

BRAIN

NEURON

ASTROCYTES

NOTCH SIG.

STRIATUM

Subcortical part of fore-brain

Involved in movement and motivation

And some other cognitive functions

Not known to have neurogenic abilities

Neurogenesis

Generation of neurons Very active and occurs widely during infant

stages Restricted in adult brains to some parts of

the brain Neither exchanged or replaced in

pathological conditions Play a very important role in learning and

memory Associated with many diseases

Aim of the study

To explore in vivo neurogenic potential of astrocytes A long-held scientific theory says that the

nervous system is fixed and incapable of regeneration

Recent research have shown that neurogenesis is present in some parts of the brain

This study throws light on neurogenesis in astrocytes

Approach

Induced neurogenesis in a transgenic mice (Connexin-30-CreER) with a reporter protein (YFP)

Specific recombination using tamoxifen Analysis by identifying biomarkers Validation by cross-replication of

experiments

Methodology

Injection of Tamoxifen Activates Cx-30-CreER

Allows specific recombination in astrocytes and sub ventricular zone

Induction of stroke using transient occlusion of middle cerebral artery causing ischemic lesions

Stroke triggered doublecortin positive (DCX+) recombined cells

After two weeks, astrocytes expressed Ascl1, a pro-neural transcription factor

Results

Results

Results

Recombined cells stopped expressing S100, which is an astrocyte marker

Two weeks – tightly packed clusters of recombined cells

Neuron formation and new synaptic junctions were observed

Validations

Possibility of sub ventricular region being origin of neurogenesis was excluded using local recombination by injecting adenovirus in striatum

Uninjured cells did not show any marker to suggest neurogenesis

Surprisingly, Notch signaling pathway was seen to be significantly downregulated in injured mice

Suggesting that Notch signaling regulates the neurogenesis in astrocytes

Markers for Notch signaling were undetectable at the end of the treatment

Artificial continuation of Notch signaling after stroke – No neurogenesis

Artificial reduction of Notch signaling in absence of stroke - Neurogenesis

Conclusion

Astrocytes do have a neurogenic program encoded in their genome, which requires specific activation

This revelation is very important in treatment of neuro-degenerative diseases like Parkinson’s disease

It ensures an alternative strategy of indigenous neurogenesis than interneuron transplantation

Questions to be asked

Are there any other activators/regulators of such a neurogenic pathway?

Could the neurogenesis in astrocytes be precisely modeled using statistical / computational techniques to perfect the neuron replacement strategies?

Will it have any undesirable consequences at the psychological level in a patient undergoing such treatment?

An interesting extension

Somewhat parallel work going on in Univ. of New Mexico, added a great value to this work

They present two computational models of neurogenesis to investigate possible functional implications One, a spiking, biologically realistic model

Basic growing feedforward model

Could result in an interesting anticipated outcome: Improvement of decision making in no-prior-experience situations

Adult Neurogenesis: implications on Human and Computational Decision making

Any questions, in case?

References

Aimone JB et al, Eur J Neurosci. 2011 Mar;33(6):1160-9. doi: 10.1111/j.1460-9568.2011.07615.x.

Becker S, Hippocampus. 2005;15(6):722-38. Cunio et al Scientific Reports 2, Article number: 735 doi:10.1038/srep00735

Vineyard et al, Lecture Notes in Computer Science Volume 8027, 2013, pp 531-540