Comprehensive Notes on Integration: Brain Health, Cognition, and Aging

Integration Unit Overview

  • The purpose of this unit is to connect core material from the first three units.
  • Nature does not adhere to subject areas; disciplines are human constructs.
  • The integration section looks at intersections of life sciences with molecular biology.
  • Practical application: University of Miami requires comprehensive exams for finals.
    • Integration serves to represent material from throughout the course.
    • Students should identify overlaps between Unit 4 and previous units.
    • Skill testing might involve commenting on Unit 4 through the lens of Units 1, 2, or 3.
  • The goal is to practice with information in a complex environment, not separated into sub-disciplines, to make sense of things.
  • Topics covered:
    • Stem cells and development.
    • Cancer biology (development gone awry).
    • Brain health and diseases.

Brain Health and Disease

  • Becoming an educated person has molecular underpinnings.
  • Understanding molecular mechanisms of learning, memory, and brain disease can:
    • Make one a more efficient student.
    • Help preserve cognitive function longer in life.
    • Potentially assist family members with brain-related problems.
  • Brain-related problems are common due to the organ's high activity and mitochondrial activity.
  • Since thinking in this way, learning and memory have become effortless.
  • Training the brain to recognize patterns and relate new information to existing knowledge facilitates genuine knowledge.
  • Avoid cramming for exams; it wastes time and confuses the brain.
  • Material discussed points to potential problems and solutions, some provocative.

Cognitive Aging

  • The old belief that you are born with a fixed set of neurons is false.
  • Like other somatic tissues, the brain undergoes growth and development as needed due to damage, disease, or aging.
  • Stem cells and neural precursor cells in the brain can regenerate nerves.
  • Cognition is an emergent property of the network of connections between neurons.
  • Neurons collaborate and "vote," leading to information encoding and problem-solving.
fMRI Studies
  • Functional magnetic resonance spectroscopy (fMRI) shows brain activity during cognition.
  • Participants are given problems to solve while glucose consumption is monitored.
  • Ethical dilemma example: The train trestle problem explores moral decision-making.
  • Brain imaging shows different areas active, oscillating as glucose consumption changes.
  • Activity patterns entrain themselves and migrate to a single locus before a decision is made.
  • Scientists claim they can predict the person's conclusion by observing the locus and dynamics.
  • Conflicting viewpoints debate, reach consilience, and lead to a verbalized choice.
  • fMRI can also be used to detect lying and understand improvisation in speech and music.

Brain Organization

  • Different levels of organization in the brain are mapped over anatomical features.
  • The hippocampus, particularly the dentate gyrus, is involved in taking on new information.
  • Loss of neurons in the dentate gyrus is associated with age-related cognitive decline and memory loss.
  • Active nerves are identified using staining for transcription factors (e.g., DCX).
  • Neural precursor cells differentiate into cortical neurons.
  • Uncontrolled cell growth in the brain is undesirable due to limited space.
Experiments with Rats and Stem Cells
  • Rats trained to run a maze had portions of their brains damaged, causing them to forget how to solve the maze.
  • Implanted pluripotent stem cells engrafted, differentiated, and the rats remembered how to run the maze.
  • Information storage may be delocalized, and damage affects the capacity to access and process the information.
Restoring Brain Function
  • Individuals with long COVID losing smell or taste might retrain their brains.
  • Repeated visualization combined with distinct smells (e.g., clove oil) can rewire the brain, bypassing damaged areas.
  • Restoring brain function can be intentionally worked by solving puzzles and brain teasers

Aging Systemic Milieu

  • The paper "Aging systemic milieu negatively regulates neurogenesis and cognitive function" explores factors affecting cognitive decline.
  • Experiment basis: Old mice lose cognitive function, young mice do not.
  • Hypothesis: Circulating factors in old mice impair brains, or factors in young mice help them.
  • Focus: Chemokines and cytokines.
Parabiosis Experiment
  • Parabiosis involves stitching an old mouse and a young mouse together to share blood compartments.
  • The experiment assesses how this affects neural markers and behavior.
  • Results: Joining an old mouse to a young mouse decreased neurogenesis in the young mouse and increased it in the old mouse.
  • Heterochronic pairs (young-old) showed the young mouse aging and the old mouse becoming younger cognitively.
  • Isochronic pairs (young-young, old-old) did not show these changes.
  • Plasma from young mice injected into old mice, or vice versa, recapitulated the results of parabiosis.
Cognitive Testing
  • Mice exposed to plasma were tested for learning and memory retention.
  • Older mice exposed to plasma from younger mice showed statistically significant improvement in cognitive abilities.
  • Vice versa was not explicitly shown but implied.
  • The results indicated a soluble factor in the plasma associated with neurogenesis impacts cognition.
Chemokine Analysis
  • Cytokine and chemokine panels were performed to identify specific factors.
  • Stem cells migrate via chemotaxis to repair damaged tissue.
  • Mesenchymal stem cells were coated by gauze and grew arm back.
  • Beckoning molecules instruct cells and modulate the inflammatory response, stimulating cell growth and development.
  • CCL11 was identified as an inhibitory chemokine, interfering with recruitment of stem cells.
  • CCL11 is linked to brain inflammation and decreased cognitive ability.
  • Immunodepleting CCL11 can rejuvenate an old mouse's brain.

Transcription and Cognition

  • Eric Kandel's work demonstrated that interfering with transcription and translation impairs learning and memory.
  • Glucose regulatory transcription factor CREB is involved in acquiring and consolidating long-term memories.
Alzheimer's Disease
  • Normal cognitive decline in aging is possibly due to Alzheimer's disease.
  • Alternative hypothesis: Cognitive decline and amyloid deposition are distinct states.
  • Experiment: Compared entorhinal cortex (EC, where Alzheimer's starts) to dentate gyrus (DG, involved in learning and memory).
  • Transcriptomic study looked for decreasing transcripts in DG compared to EC.
RBAP48
  • A protein called RBAP48, which binds to acetylated lysines on histones, showed a strong correlation with cognitive decline.
  • Creation of dominant negative allele of RBAP48 to test causality.
  • A dominant negative allele is a gain-of-function mutation.
  • A TET ON system was used to regulate the expression of the dominant negative protein.
  • FLAG peptide was fused to the dominant negative allele for protein detection via anti-FLAG antibodies.
  • RBAP48 protein expression was inducible in dentate gyrus to see if affecting cognitive activity.
Discrimination Index
  • The discrimination index tested the animal's ability to differentiate between objects.
  • Expression of the dominant negative RBAP48 caused animals to forget recently acquired information.
  • Older people often remember childhood memories but forget recent events due to dentate gyrus function.

Dendritic Spines and Learning

  • Repetitive motor learning induces coordinated formation of clustered dendritic spines.
  • Axon tickling a dendrite causes an influx of calcium that leads to localized protein synthesis.
  • Molecular staples physically wire the synapse, and maintaining this wiring is crucial for memory.
  • Proteolysis breaks the wiring.
  • New synaptic connections are informed by old ones in the network.
  • Parts of the brain can train newly synthesized parts of the brain.
Associative Learning
  • As new information is acquired, it should be actively compared to existing knowledge.
  • Molecular and cellular basis: Associative learning involves the genesis of new structures called dendritic spines.
  • Multiple axons integrate on a single dendrite, creating a dendritic arbor.
  • Distributed inputs stimulate localized protein synthesis, maintaining the integrity of connections.
  • Dendritic spines are formed, it's a dynamic structure. it comes and goes.
  • Actively engaging in twinned activities in a thoughtful way can reinforce opportunities to create these arbors.
Cappellini Test
  • The Cappellini test gives the animal pasta outside the cage, just outside of reach.
  • This engages motor activities.
Motor Enrichment
  • Motor enrichment leads to an increase in the number of spines formed, but with no longetivity.
  • Focal activities lead to focal accumulation of clustered spines associated with acquiring the information!

Physical Activity and Cognition

  • Physical activity can keep your marbles later in life!
  • Exercise, to the level of elevated heart rate and getting somewhat out of breath, improves cognition and incidence of AA.
High Fat Diet
  • Eating a high fat diet drives brain inflammation and is associated with increased cases of AA.
  • This promotes Alzheimers in this model, but not only. Also to humans!
Amyloid plaque
  • Neprilysin degrades amyloid and degrades phosphorylated tau protein!
Exercising
  • Exercise, first of all, can decrease the effect of fat on APP processing to A beta peptide, which stimulates inflammation.
Hypoxia
  • Hypoxia is associated with stem cell recruitment, thus associated with neurogenesis!

DNA Damage and cognition

  • Thinking can lead to DNA double-strand breaks, and it may be linked to amyloid.
Hemispheres
  • The part of the brain that is being engaged in something complex is experiencing increases in the number of strand breaks.
Non Homologous End Joining for the WIN!
  • Repairs DNA Double Strand Breaks!
Sleeping
  • Sleeping is when you are repairing your brain!
  • Need to sleep on average 8 hours out of the night.
Mitochondria
  • Mitochondria harvest energy, moving electrons which causes action potentials!
    So, novelty/learning creates neural activity!