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DNA modifications: methylation and methyl-CpG patterns
- C's followed by G's will be methylated. At CG sites gene transcription doesn't occur.
- Need demethylation of DNA for development and learning.
What kinds of histone modifications do you know?
acetylation acetylation, phosphorylation phosphorylation, methylation, ubiquitination, and ADP-ribosylation.
Histone acetyyltransferases (HATs) catalyze the transfer of acetyl groups to histone proteins, whereas histone deacetylases (HDACs) cause the removal of acetyl groups.
Histone methylation is initiated by histone methyltransferases (HMTs) such as G9 G9 , whereas histone demethylases ((HDM HDMs) such as LSD1 remove methylation marks.
The integration ofsignalling at the level of epigeneticsis commonly referred to as the histone code (alters histone tail).
Epigenetic effects on gene activity and disease
changes in histone acetylation and DNA methylation alters specific genes transcription processes and is part of many human cognitive disorders such as AD (APP gene), Rett syndrome (MECP2 gene), schizophrenia (reelin gene).
The role of ERK-mediated regulation of Histone Acetylation and Gene transcription
histone-associated heterochromatin undergoes ERK-dependent regulation and these histone and changes in heterochromatin are necessary for hippocampal LTPand memory formation
MAPK/ERK >CREB ->> CBP brings HAT and may be CBP histone H3 phosphorylation which is associated with changes in behavior and synaptic plasticity
Once ERK is activated it exerts downstream affects such as regulation of excitability and transcription of many genes.
What behavioral control groups can be used and for what purpose?
- 1. Conditioned stimulus and unconditioned stimulus to test for association
- 2. context conditioned stimulus and unconditioned stimulus
- 3. shock unconditioned stimulus
- 4.unpaired CS and UCS, explicitly unpaired or random
- 5. tone (cs)
Ways of testing brain activity during or after behavioral experiment
- 1. IEG studies: cFOS levels after training
- 2. electrodes during experiments
- 3. fMRI, PETscans during training
Affective behaviors (genes in social behaviors)
- Stathmin reveals dissociable roles of the basolateral amygdala in parental and social behaviors
- BLA leads to the positive expression maternal behaviors
- Stathmin somehow effects the positive expression social behaviors
- Stathmin and basolateral amygdala via danger assessment can control in opposite directions maternal and social interactions
- important in pup retrieval (knock out shows deficiency)
- without stathmin social interactions are better (decreases assessment of fear)
The Amygdala and Dentate Gyrus havedifferent roles in maternal behaviors:– the Amygdala controls maternal behaviors both invirggin and p p postpartum mice– the DG controls only in the postpartum phase
Empathy and imitation behaviors
Describe the experiment examining social transfer of fear in mice
Genes and neural circuits involved in maternal behavior (describe the behavioral tests that are used: pup retrieval (PR) in home cage, PR in the open field, nest building and other experiments we discussed)
- Pup retreival task in the home cage: a female is monitored while retrieving 2-5 day old pups to nest for 20 mins (deficits in stathmin affect pup retrieval by lowering efficiency)
- in open field:
- nest building: less efficient without stathmin or without BLA
- bad at danger assessment with KO and lesion
- DG is involved in maternal behavior for postpartum while amygdala invovled for all, as is BLA
Describe four major behavioral abnormalities of autism (social, communication, repetitive and inflexibility) and tests in mice that can be used to examine those
• Social withdrawal (cortex, hippocampus, amygdala)– Can be tested by social interactions, social recognition, ultrasonic vocalizations (pup retrieval), juvenile play
• Repetitive behaviors (cerebellum)
• Unable to read social mind (mirror neurons in the cortex)– Tested by empathy?
• Inflexibility (hippocampus, cortex)– Tested by the reversal of the platform in the Morris water maze
What is the role of amygdala in autistic behaviors? Which behaviors?
- Lack of “social brain” (amygdala-related):
- • The ability to imitate
- • Understand emotions of others
- • Lack of social skills
- • Trustworthiness
Which genes/biochemical pathways are involved or can be potentially involved in autism?
PTEN, MET, MECP2, FMR1 and neurotransmission genes.
Pathways in the amygdala, hippocampal, perirhinal cortex areas
What is a neurotransmitter? Name four criteria.
- 1. synthesized by a neuron
- 2. present in the presynaptic terminal and taken up by the post (local)
- 3. released as a drug and mimics actions of endogenous neurotrans
- 4. specific mechanism for removal exists(transporter)
Two main classes of neurotransmitters
- 1. small molecule
- 2. neuroactive peptide
What mental disorders do involve DA dysfunction?
- Parkinson's Disease (caused by loss of dopamine-secreting neurons in the substantia nigra),
- Schizophrenia (involves elevated levels of dopamine activity in the mesolimbic pathway and decreased levels of dopamine in the prefrontal cortex),
- ADHD (associated with decreased dopamine activity).
- Addiction: drugs of abuse (cocaine, amphetamine, opiates, and nicotine) act as positive reinforcers. They increase the level of DA released at terminals of the projections of the ventral tegmental area (VTA). Cocaine and amphetamine do so by blocking the DA transporter
What brain regions are involved in DA normal function and its dysfunction in schizophrenia?
: two DA systems are disturbed in schizophrenia. First, an increase in activity in the mesolimbic (striatum) pathway (likely through D2, D3 and D4-R) would account for the positive symptoms.
Second, decreased activity of the mesocortical connections in the prefrontal cortex would account for negative symptoms. Thus, unbalance between these two systems, cortical and subcorticaldopaminergic transmission underlies the development of schizophrenia.
What is delayed fear conditioning? What brain regions does it involve?
- Tone and shock at the same time. US & CS paired.
What is trace fear conditioning? What brain regions are involved?
- tone THEN shock. separated (5, 30 60 sec)
- HIPPOCAMPUS, AMYGDALA, CINGULATE GYRUS AND PERIRHINAL CORTEX.
Why is the paper by Liu et al in Nature 2012 entitled “Optogenetic stimulation of a hippocampal engram activates activates fear memory recall fear memory recall” important?
Directly activating a subset of cells through optogenetical stimulation that are involved in the formation of memory is enough to induce the behavioral expression of memory.