c. elegans learning
TRANSCRIPT
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The Effect of AMPK Activation on Cognitive FunctionJUAN C. RAMIREZ – AUGUST 4, 2016
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Introduction to Aging and its Implications
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1.1 Increase in Elderly Population and Complex Diseases
In the past century, we have seen a tremendous rise in human lifespan
A Graphic showing recorded and predicted numbers of elderly people in the US (U.S. Bureau of the Census)
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1.2 Aging and Complex Diseases Overview
Aging constitutes the biggest risk factor in the onset of complex diseases and physiological decay
A Graphic showing proportion of elderly population with Alzheimer’s and other dementias (AA)
B Graphic showing proportion of elderly population with single and multiple diseases (CMS)
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Mechanisms of Aging
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2.1 Mechanisms of aging• Single gene mutations and simple interventions have been demonstrated to increase lifespan
•Notable interventions include:• Dietary Restriction (DR)• Mediation of mitochondrial dynamics• Activation of AMPK
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2.2 Dietary Restriction and AMPK in Aging
• DR has been demonstrated to increase lifespan across species, including primates
• Molecular mechanisms mediating DR are a focus area in aging science
• AMP-Activated Kinase Protein (AMPK) has been shown to be upregulated in DR• AMPK has since been well-documented to extend
lifespan
A Graphic showing lifespan data for both well-fed nematodes and those subjected to DR (Win et al. 2013)
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2.2 AMPK and Healthspan Extension
Highly conserved low energy sensor composed of three subunits
Activated AMPK
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Assessing Nematode Cognitive Function
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3.1 Memory Assay Quantify C. elegans learning ability to determine neuronal health in both treated and non-treated animals
Conditioning of worms in both a neutral stimulus (salt) and unconditioned stimulus (starvation) results in conditioned response (repulsion to salt)
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3.2 Conditions
No preference No preference Aversive behavior
-NaCl-Food
+NaCl+Food
+NaCl-Food
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3.3 Quantifying Memory in Nematodes
Chemotaxis Index (CI) measures attraction to salt
Memory Index (MI)
quantifies nematode
learning ability
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3.4 Effect of CA AMPK on Learning
• Hypothesis: CA AMPK will promote higher learning ability in treated worm
• Result: CA AMPK worms demonstrate a nearly two-fold increase in learning ability
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3.5 Effect of DR on Learning• eat-2 worms possess a mutation that prevents normal pharyngeal pumping of food• Mimics DR
•Hypothesis: eat-2 worms will also have greater learning ability than non-DR worms
•Results contradicted hypothesis, with eat-2 worms possessing roughly 50% of wild-type learning ability
•Bias of assay involves sensing of food, that which may not be available to eat-2 mutants
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3.6 Forgetting Assays can provide further insights
•Among the chief hallmarks of aging is progressive memory loss
•A Forgetting Assay can quantify memory loss much like memory formation is assessed in a memory assay
•Progression of memory loss across worm strains, growth conditions, or pharmacological treatments grants insight into time-dependent phenotypes
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Conclusions & Future Directions
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4.1 AMPK supports extended cognitive ability; DR effect on memory remains unclear• Genetic activation of AMPK promotes increased learning in addition to extended lifespan • Suggests an AMPK-promoted maintenance/improvement of cognitive ability
•Dietary restriction provides mixed results, with more repeats necessary to verify conclusion• Development of alternative assay may be necessary
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4.2 Future Directions• In order to further study these effects, we aim to:• Express CA AMPK in specific tissues, singling out
those responsible for lifespan extension and improved neurological function
• Activate AMPK via pharmacological intervention and compare the treated worms’ cognitive functions against recruitment method
• Measure nematode memory retention against time to further assess cognitive function
Phenformin
Activated AMPK
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Mair LabFunding
Lab MembersWilliam Mair Emina TabakovicSydney Brumfield Heather WeirKristopher Burkewitz Yue ZhangSneha Dutta Carlos Silva GarciaCaroline Escoubas Caroline HeintzAnne Lanjuin
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Thank You