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What are IEGs?
First group to be expressed in neurons following the specific extracellular signals "learning"(ex: synaptic activation of NMDA receptors).
Immediate early genes encode a range of proteins like regulatory transcription factors, structural proteins, growth factors, enzymes, etc.
Their expression is extremely low but is rapidly increaed following a specific neural activity associated with the induction of synaptic plasticity and neural activity.
Name different IEGs.
How are they induced and how quickly?
- Zif268 : regulates target genes downstream induces transcription of another gene. In dentate gyrus.
- CREB: phosphorylation of CREB allows it to activate other pathways that converge down stream.
: Early IEG that induces other IEGS.
:induced by shock of cells and some behavioral event
What is catFISH and how is it used?
It's an image analysis software package that accepts multispectral microscope images that can channel one or more IEG images and show the signal associated with each nuclear component and the amount in the area around it. It's an effective way to look at/ trace IEGs and map neural circuits.
What is the role of Npas4? Which stimuli induces it?
nPas4 is an IEG that induces other IEGS. It's a switch of transcription and is induced by
What does Npas4 regulate?
It regulates the activity-dependent pathway of inhibitory neuronal connections and transcription in the CA3 required for long term fear memory.
Which area of the brain was studied in the Npas4 papers?
Go over images in npas4 paper
What mental diseases can be modeled by context vs. cued fear conditioning?
General anxiety disorders
- Anxiety disorders
- PTSD can be modeled through cued fear conditioning.
can be modeled through contextual fear conditioning.
can be modeled through innate fear conditioning.
What mouse modeled disorders can be made?
Through KOs mice can model PTSD, General anxiety disorder (defecient fear memories), panic attacks (pup retrieval) and phobia (innate fear).
What is the main behavioral symptom in autism?
- Repetitive movements/behavior, cerebellum related.
- Lack of social brain (fails sallyann task), amygdala related.
Which symptoms of schizophrenia can be modeled in mice? Which symptoms cannot be or are difficult to analyze?
Positive symptoms (disordered thought, hallucinations, delusions) are DIFFICULT to analyze.
- Some negative functions can be studied
- 1. working memory deficits (PFC)
- 2. attention deficits (striatum; sensory motor gaiting)
Which mental disorders are easier to study? Why?
- Schizophrenia is hard to model in mice (hard to model positive symptoms).
- Autism is mostly diagnosed with behavioral symptoms that are hard to model in mice (social behaviors) and can't be modeled in one single mouse line.
Schizophrenia has a genetic predisposition.
What is the Dopamine hypothesis of schizophrenia?
- 2 DA systems are disturbed in schizo.
- 1. Increase in activity of the mesolimbic pathway (subcortical- amygdala, striatum) would account for the POSITIVE SYMPTOMS.
- 2. Decreased activity of the mesocortico connections in the PFC accounts for NEGATIVE SYMPTOMS.
Which 2 ways are used to study schizophrenia in mice?
- 1. Target the PFC and isolate specific genes
- 2. Target the dopaminergic system and: overexpress D2 receptor in striatum, inactivate the D1 recepto, inactivate NMDA receptors to reduce D1 responsiveness.
Which gene is affected in Rett syndrome? Which cellular processes are affected by this gene?
- Caused by defect at the nucleus
- Methylation of cytosine causes a disruption of MeCP2 and transcription is blocked- change of signalling pathway.
- Causes lots of genes to shut down via methylation (when genes develop they demethylate- stops development).
What are presenilins?
- forms the active site of complex that produces amyloid beta.
- over expression causes accumulation of amyload beta into plaques.
What are two major neuropaththliologies in the brain associated with AD?
- 1. overexpression of APP/Presinilin/Tau causes accumulation of amyload B which causes plaques that form in the neocortex, hippocampus and amygdala.
- 2. Hyperphosphorylated tau into neurofibrillary tangles. Density correlates with disease duration and severity of dementia.
What is the main behavioral symptom in AD?
- Memory loss!
- Also disorientation, impairment of judgement and problem solving, deterioration of language abilities, motor complications, dementia.
What is the age for early and late onset AD?
- Early onset is before 65.
- Late onset is after 65.
What kind of neurons are mostly affected in AD?
Principal neurons are most affected by plaques and tangles.
What is the Amyloid cascade hypothesis of AD?
Altered amyloid processing and aggregation constitute the key pathogenic factor of the disease and the rest result from amyloid induced changes.
What percent of AD result from autosomal inheritance?
About 1% result from autosomal dominant inheritance of an age dependent trait.
What is the function of presenilins in AD?
They form the active site on the complex that produces amyloid beta.
Why Apolipoprotein E (ApoE) gene polymorphisms are a risk factor?
ApoE is involved in deposition and clearance of plaques. Polymorphisms are a risk because 2 of the 3 are dysfunctional and if it's not working properly plaques will accumulate.
What type of a gene is Cox-2 in terms of its activity-dependent induction?
- IEG/transcription factor
- It is a synaptically induced enzyme. Glutamate activates NMDA receptors that allow Ca2+ flow which eventually induces Cox2.
- Induced by synaptic activity (neural activity/learning)
What promoter was used in the Andreasson et al. paper? Why was it used?
Thy1 promoter was used because it is shown postnatally and avoids potential developmental deficits.
An antibody was used because it will show human and murine cox2 expression and demonstrates continued high expression of TG cox2 in aged animals.
From what species Cox-2 was used in the Andreasson et al. study? What is the age of mice used? Why?
hCox-2results found can be 'applied' to humans as well. One long-term goal of this type of work is to one day devise pharmaceuticals to prevent problems (in this case AD). These must work in humans so it is best to test all biochemical/molecular models with the human protein. Another more practical answer is that by using the human protein you can easily tell where it is being (over)expressed because of that one antibody they had that would bind only the human protein.
Older mice were used, to relate tests to the human model as efficiently as possible (AD prevalent in older people).
What control measurements can be used in the Morris water maze study? What for?
- Speed of swimming (no physical deficits)
- Straight alley
- Visual discirmination (normal sight)
- To eliminate any possible outlying reasons for results. To prove that it is the mental deficit that was performed causing the results.
More _________ excites neurons.
Less depolarization ________ neurons.
ChR2 responds to what?
- 470nm blue lights, activated with Cre recombinase on site
- Na+ pump activated
NpHR responds to what?
- 580nm yellow light
- Cl pump activated
What is optogenetics?
- Optogenetics – using light and opsin proteins to control neuronal activity in vivo
- Done with high precision