Neurology Pharmacology Flashcards
What is the societal impact of cognitive disorders?
28% of disease burden is mental health
1 in 4 affected each year
£70-100 billion is costs/year
There is few effective treatment options but extensive health and social impacts
How are AMPA and NMDA receptors implicated in memory?
If apply APV (blocks NMDA receptor), this would block the induction of long-term potentiation
When AMPA cells are blocked only a small amount of LTP is produced but then it decays. AMPA cells are key to memory trace formation
The drug stopped the synapses from changing in strength, however it did not stop communication between pre and post synapses
This is because AMPA cells are also involved- depolarise the neurone and unblock the Mg2+
Once NMDA have been activated, Ca2+ flows through and triggers a pathway that trafficks additional AMPAR to the membrane and a stronger connection is formed
What is the synaptic tagging hypothesis?
Synaptic tagging suggests that, following learning, certain synapses are marked or tagged in a way that sequesters plasticity proteins and so enables the specificity of persistence
In weak stimulation still get tag but no proteins upregulated and thus the memory trace is not created
If a protein synthesis inhibitor (anisomycin) is added the LTP dissapears
What is optogenetics?
A neuroscience technique that involves using light to control cells that have been genetically modified to express opsins (light sensitive channels that response to specific wavelengths of light)
- Channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) are examples of opsins used in optogenetics.
- ChR2 responds to blue light by allowing positive ions to enter the cell, leading to depolarization, while NpHR responds to yellow light by allowing negative ions to enter, leading to hyperpolarization.
What does fear conditioning do to AMPA receptors?
Drives AMPA receptors into the synapse of a large fraction of postsynaptic neurones in the lateral amygdala, a brain structure essential for this learning process
How are NMDA receptors involved in short and long term memory?
Using an NMDA receptor blocker AP5 on rats in a watermaze, it was found that short term memory for spatial information is independent of NMDA receptors and the rapid consolidation of spatial information into long-term memory requires activation of hippocampal NMDA receptors.
How can the Cre-Lox procedure be used for conditional gene deletion?
Cre is an enzyme derived from the bacteriophage P1. Cre recognises and acts on a specific DNA sequence called ‘LoxP sites’
The gene of interest is modified to induce loxP sites flanking critical regions
The gene is still functional when both loxP sites are present
Cre recombinase is placed under the control of a tissue specific or inducible promoter. This ensures cre is only expressed in specific cells or specific conditions
Cre recomination results in the exicision of the floxed region, allowing for conditional gene deletion
How can GFP be used in a molecular process?
GFP family can be used to label cells or cellular structures
Green fluorescent protein is a naturally occuring protein derived from a jellyfish
It has become a widely used molecular tool due to its fluorescence ability and its compatibility with living cells
To label cells with GFP, the gene encoding GFP is genetically fused to the gene of interest.
This fusion gene is then introduced into cells using various methods, such as transfection, viral transduction, or microinjection.
When exposed to specific wavelengths of light, GFP absorbs photons and emits green fluorescence. This fluorescence allows researchers to visualize he localization of the protein within the cell.
Allows visualisation of processes such as cell division, migration
What is FRET?
Fluorescence resonance energy transfer
When the donor and the acceptor fluorphores are in close proximity (typically within 1-10 nanometers) the energy from the excited donor is transfered
FRET can be detected by changes in the fluorescence properties of the donor and acceptor.
By attaching donor and acceptor fluorophores to specific molecules of interest, FRET can be used to study protein-protein interactions, cellular signalling, molecular conformation changes and DNA.
What is calcium imaging?
A technique used to visualise and monitor changes in intracellular calcium within living cells
Calcium imaging relies on the use of fluorescent calcium indicators. These are molecules that exhibit changes in fluorescence intensity or colour in response to binding with calcium ions.
Calcium imaging is typically performed using fluorescence microscopy. The fluorescent signals emitted by the calcium indicators are captured and recorded in real-time.
Common types of calcium indicators include small molecule dyes (such as Fluo-4, Fura-2, and Rhod-2) and genetically encoded calcium indicators (GECIs) like GCaMP (Genetically Encoded Calcium Indicator
What is chemogenetics?
The engineering of proteinn receptors to respond to previously unrecognised small molecules
- Chemogenetics often involves the use of designer receptors, which are engineered versions of naturally occurring receptors. These receptors are designed to respond selectively to synthetic ligands that do not interact with endogenous receptors.
- Genetically engineered to be introduced into the target cell
- To target specific cell populations the receptor gene is placed under the control of a tissue specific promoter
How can neurones be activity tagged?
c-Fos is a immediate early gene that is rapidly expressed in neurones in response to activation.
This can be flurorescently labelled
c-Fos is placed under the control of the tet-on or tet off promoter, so can only be expressed when DOX is given or removed.
Cells that were activated in a time window can be identified
What is the problem with activity tagging of neurones using tet on/off systems and how could this be overcome?
Tagging window is large so there is plenty oppurtunity for different memories to be formed and the wrong neurones tagged
Can use all optical interrogation of neural circuits. This detects activity of cells based on Ca2+ imaging, although this does not work on freely moving animals
What is the financial and personal burden of mental health?
28% of disease burden is mental health with 1 in 4 people affected each year. Costs an estimated £70-100 billion each year
What drugs are amnesic agents?
- Procedures or chemicals that cause memory impairment.
- Examples are electroconvulsive shock (ECS), beta-adrenergic receptor antagonist (propranolol), protein synthesis inhibitors (anisomycin), anaesthetics (MS222)
How many propanolol be used in neurology?
The beta-adrenergic blocker propranolol given within hours of a psychologically traumatic event reduces physiologic responses during subsequent mental imagery of the event- PTSD
Oral propanolol administered prior to nictotine unconditioned stimulus induced memory (i.e. being reexposed to nicotine) decreased craving in humans
What is general cognitive function (measured within labs) useful for?
There is a correlation between general cognitive function and job performance
There is an increased risk of mortality for all diseases inversely linked with cognitive ability
Laboratory cognitive tests were found to strongly relate to everyday knowledge tasks such as knowledge about medication and memory for household items
What are the pros and cons of studying aging in a cross section vs longitudional study?
- Can measure a wide range of people of all ages once- cross sectional.
- However aging is a dynamic within-person phenomenon
- And cohort differences (Flynn effect- over the last century people have performed better on cognitive tests than previous generations)
- Or can follow a group of people in a
longitudinal- Nonrandom attrition (bias against people less healthy)
- Practise effects of remembering previous tests given over the lifetime
What is the lothian birth cohort?
The lothian birth cohort 1936 is a longitudinal research project that focuses on individuals born in Edinburgh
Participants in the LBC1936 underwent a battery of cognitive tests to assess various aspects of cognitive function, including memory, processing speed, reasoning, and other domains. These assessments were conducted at multiple time points, allowing researchers to track changes in cognitive abilities over time (started age 11)
In addition to cognitive assessments, the LBC1936 collected various biomedical and genetic data from participants. This includes information on health, lifestyle, and genetic factors, providing a comprehensive dataset for researchers to analyze.
Some participants in the LBC1936 underwent structural and functional brain imaging, such as magnetic resonance imaging (MRI). Brain imaging data contribute to a better understanding of the neural correlates of cognitive aging.
What are the statistics for depression?
4% global average
It is second in global health burden (after heart disease), and the 4th leading cause of mortality in younger people.
It also varies by socioeconomic status- higher in those with low socioeconomic status.
What is depression?
Depression is a common but serious mood disorder. It causes severe symptoms that affect how a person feels, thinks, and handles daily activities, such as sleeping, eating, or working.
To be diagnosed with depression, the symptoms must be present for at least 2 weeks.
Symptoms include depressed mood, lack of motivation, change in appetite, isomnia, fatigue and poor self esteem
What is thought to cause depression?
Monoamine dysfunction- deopamine, norepinepherine and seronin.
Dopamine is involved in reward and motivation, norepinephrine in alertness and serotonin in mood
Also different theories such as lower BDNF levels, impaired synpatic function and plasticity
Also strong links between inflammation and depression- direction unknown however increased levels of TNF-alpha have been associated with depressive behaviour in animal studies
What is the first line treatment for depression, what is the evidence and what are side effects?
SSRIs- selective serotonin reuptake inhibitors
Reduce the reuptake of serotonin from the synapse thus making more serotonin available in the synapse.
Recent evidence shows in mice treated with LPS, SSRIs administration leads to decreased serum levels of TNF-alpha and IL-10
Do have side effects that need to be considered- gastrointestinal problems, sleep disturbances and sexual dysfunction
What can PET scans be used for in neurology?
Can measure and track synapse loss using a tracer that binds to the synaptic vesicle glycoprotein
Anti-body tracers also been developed- can visualise the build up of pathology (amyloid beta or tau for example) in the brain.
What are the 5 cardinal signs of inflammation?
Heat, pain, redness, swelling, loss of function
Where do the immunotherapies against AD bind to?
Donanemab, lecanemab and aducanumab
