Lectures 20, 21, 22, & 23 Flashcards
What is an engram?
Physical trace of an experience; neural substrate for storing and recalling memories
What are the four properties of the engram?
Persistence
Ecphory (essentially retrieval)
Content
Dormancy
I remember being PECD by a bird
An engram has the potential for ecphory, what does this mean?
It may be expressed behaviorally through interactions w/ retrieval cues
What are the requirements for concluding that neurons belong to an engram?
Cells must be active at time of learning and time of memory test
Activation of cells must correlate w/ the generation of the appropriate memory
Direct activation of these cells generate the appropriate behavior
Inhibiting or ablating the specific cells prevent the occurrence of the appropriate behavior Inhibiting
To accomplish labeling engrams, researchers took advantage of what molecular mechanisms?
Immediate early gene activation and protein synthesis
Neuronal depolarization activates the expression of which immediate early genes?
C-fos and Arc
How can immediate early genes be used to mark a neuron activated by an experience?
Increased expression is a giveaway that a neuron is activated by an experience
What does “TetTag” refer to?
Combining tetracycline-controlled transcriptional activation and activity dependent tagging of neurons
What does the Tetracycline-Controlled System allow for?
Conditional gene expression based on the presence/absence of a tetracycline antibiotic (ex. Doxycyline)
How can TetTag control temporal expression of the LacZ cell tag?
Whenever DOX is present, tTA cannot control LAC promotion, however whenever its absent tTA expression promotes LAC transcription
If DOX is introduced, removed, then returned again, LAC will no longer be expressed but the previously tagged cells stay tagged
How did cells that were exposed to fear conditioning in the absence of DOX show expression of 3 days after fear conditioning? How about during dissection?
Immediately early gene ZIF expression was high
Dissection found cells tagged with LAC & IEG marker ZIF were considered the engram cells
How did freezing time and LAC+ZIF cells compare in a fear conditioned group of mice versus a control group of mice?
Control had far less freezing and less LAC+ZIF cells
What is a limitation of using IEG markers?
They are limited and some last only a few minutes
What did Guzowski et al. Figure out using IEG Arc mRNA?
Labeled Arc mRNA at different time points after an experience
immediately: expression seen in the nucleus
Delayed: outside of the nucleus in the nucleus
Describe the optogenetics activating engram cells protocol?
ChR2 inserted virally into DG along w/ optic fiber
Mice are habituation to Context A w/ DOX
Mice are then conditioned (shock) in Context B w/ NO DOX
Mice are returned to Context A and tested with blue light to activate engram cells and activate the behavior from the conditioning
What did Opsin-induced inhibition do to freezing?
Decreased freezing
What did opsin-induced excitation do to freezing?
Increased freezing
What neurons are primed to become engram neurons?
Neurons with increased intrinsic excitability
Inhibitory neurons are important to determining engram size
What happened to memory after ablation of random neurons?
Nothing
What happened to memory after ablation of engram neurons?
Decreased memory
How do we know synaptic strength was increased in engram cells?
Higher AMPA/NMDA ratio after 1 day of training
Greater connectivity between pre and post synaptic engram cells
Increase in the number and size of spines
Are engram cells likely in a single area or distributed throughout the brain?
Distributed to support different aspects of an experience
What is a silent engram?
Engrams that cannot be retrieved by natural retrieval cues but can be retrieved w/ experimental
What happens if you block protein synthesis immediately after an experience (which leads to amnesia one day later) but reactivate an engram neuron (silent engram) afterwards?
You can recover the memory
What makes silent engram neurons unique regarding physiological and structural alterations?
Weaker physiological and structural alterations
What is mimicry?
The creation of false memory/formation of false episodic memories
How can false memories be formed?
When a biologically important event occurs while an animal is retrieving a previously formed memory, the two stimuli can be associated to form a new false episodic memory
What aspects of cognition decline with aging?
Long term memory
Working memory
What happens to the brain with age?
Decreased brain weight and enlarged ventricles
Significant longitudinal tissue loss for both ___ & ___ ____ even in healthy adults
Gray
White matter
Do elderly people have widespread neuronal loss?
NO! Most areas have minimal neuronal loss
What are the structural alterations that occur in both neurons and glia due to aging?
- changes in complexity of dendrites
- changes in the number of dendritic spines
- myelin changes on axons
- changes in the balance of excitatory and inhibitory neurotransmitter systems
What happens to dendritic spines density as we age?
It decreases
What is a longitudinal study?
Same people studied over a period of time
What is a cross sectional study?
People of varying ages studied simultaneously
What is a problem with longitudinal studies?
They require funding to last the entirely of the study length
What is a problem with a cross sectional study?
Only shows a screenshot of time of different patients
Do cross sectional and longitudinal studies yield the same results?
nope
What is considered normal aging and cognitive decline?
learning at a slower pace, difficulty mastering new things, creativity declines
What happened to old mice when they were given a running wheel for 35 days (sweet spot)?
Increased spatial learning
What are common characteristics of Neurodegenerative Diseases?
- tend to occur during later years of the lifespan
- time of onset not well defined
- processes well underway by time of diagnosis
- accumulation of abnormal protein deposits
What aspects of cognitive function does Alzheimer’s Disease affect?
- memory
- decision making
- reasoning ability
- verbal fluency
What are the hallmarks of Alzheimer’s Disease?
plaques and tangles
How are amyloid beta and Tau related to Alzheimer’s disease?
aggregation, changes in conformation and buildup of Abeta initiate AD pathogenesis and damage the brain
tau pathology also contributes to AD progression
What are the main takeaways of the Oliveira et al. paper?
AD brains have increased eIF2alpha-P which leads to protein synthesis dysregulation
System treatment with a compound that increased eIF2alpha prevented memory impairment and decreased plaques in AD models
