A latent neurogenic program in astrocytes regulated by Notch signaling Magnusson JP, Göritz C, Tatarishvili J, Dias DO, Smith EM,Lindvall O, Kokaia Z, Frisén J. Science Oct 10;346(6206): doi: /science Jitesh Doshi [ ] CS502 Computational Biology University 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

 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 Mar;33(6): doi: /j x.  Becker S, Hippocampus. 2005;15(6): Cunio et al Scientific Reports 2, Article number: 735 doi: /srep00735  Vineyard et al, Lecture Notes in Computer Science Volume 8027, 2013, pp