Translation to clinical neuro Flashcards
why use animal models? (7)
- not all procedures can be used on humans
- systematic manipulation of variables
- sometimes easier conceptualise ideas in non-human sys (findings extrapolated)
- analyses of cause + effect
- easier to study in simple sys (animal less neurons)
- rodent + human brains hav similar neuronal sys
- all vert exp must be worthwhile + approved by institutional animal ethics committee
preclinical models: list neurobiology of disorders done on animals (7)
- neurosci in general
- schizophrenia (psychoses, cognitive dysfunction)
- anxiety
- depression
- AD
- abuse potential substances
- drug addiction
preclinical models: which rodent more common and other species?
- mice most common
- zebra fish
- monkeys
preclinical models: translation means?
- sci advances using animals will impact human health
- bigger the sys, more chance variation btw species
- molecular vs behavioural
validity of behavioural models: list (3) main forms
- predictive
- face
- construct
validity of behavioural models: predictive validity
- does model accurately reflect disorder
- can drug treat human disorder + also model?
validity of behavioural models: face validity
- does model show same symptoms as human disorder (subjective)
validity of behavioural models: construct validity
- how well does test measure what its supposed to measure?
- quality of model, piece of puzzle (neurobiological construct)
publication bias: features
- journals only publish +ve results, -ve ones never seen = repetition of experiments not working
- failure to replicate other findings not published
- more funding given to +ve lab (might not use correct approach)
- publication of poor design, execution, analyses
publication bias: what aims to maximise quality of study published
- peer reviews
publication bias: which more important? fundamental sci or practical application studies?
fundamental sci > practical application studies
rats share % genes w humans? and other features
93%
- almost all genes involved in human diseases found in rat
- anatomical similarities of brain
chimps share % genes w humans?
96%
rat differences:
- some behaviour/neurochem not
- models should focus on pieces of larger disease/disorder puzzle
- using pieces we understand disorder better
- complete models of human diseases in animals unlikely, nor rep day to day experience of human
schizophrenia: translation model
- meds not changed for yrs
- +ve, -ve and cognitive symptoms
- psychosis dom, (often overlooked)
- cont to long term disability
- cognitive symptoms core features
- cognitive repair -> increase in global functioning of patient
schizophrenia: hypofrontality PFC
- cognitive deficits
- -ve symptoms
schizophrenia: increased dopamine NAc
- +ve symptoms (psychoses)
- euphoria at beginning
schizophrenia: which sys involved?
mesocorticolimbic dopamine sys (A10)
schizophrenia: glutamate- phencyclidine (PCP) induced psychosis antagonist for? like what other drug?
- NMDA receptors
- like ketamine
schizophrenia: glutamate- PCP induces
- psychosis in humans (1 dose)
- auditory hallucinations
- paranoid delusions
- cognitive impairement
schizophrenia: glutamate- rodent use?
- rats as locomotor activity, stereotypes
- used to screen antipsychotics prior to clinical trials
schizophrenia: MATRICS? (NIMH)
- measurement and treatment research to improve cognition in schizophrenia
- national institute of mental health
schizophrenia: (7) cognitive domains altered MATRICS
- working memory
- attention/vigilance
- problem solving
- social cognition
- reasoning and problem solving
- visual learning and memory
- verbal learning and memory
schizophrenia: can we use rodent models? MATRICS
- yes, must be schizophrenic first
schizophrenia: rodent models- pharmacological
- glutamate NMDA receptor antagonists
- repeated psychostimulant (meth) admin
schizophrenia: rodent models- genetic
- alterations impacting dopamine/glutamate transmission, or genes thought to induce susceptibility for schizophrenia
schizophrenia: rodent models- neurodevelopmental
- pre/perinatal insults (MAM)
- lesions of hippocampus
- infection during gestation w LPS or poly (I:C)
- maternal deprivation/ social isolation
schizophrenia: rodent models- once made schizophrenic, performance deficits can be treated w (2)
- genetic
- pharmacology
schizophrenia: rodent models- tasks (3)
- novel object recognition (visual memory)
- novel conspecific interaction (social cognition)
- touchscreen for neuropsych testing (CANTAB) speed of processing + attention (5-CSRTT) 5 choice serial reaction time task
schizophrenia: rodent models- novel object recognition task?
- rats exposed to 2 same objects
- ## then rat exposed to 1 known, 1 novel object= rats w correct visual memory will spend more time at novel object
schizophrenia: rodent models- novel conspecific discrimination task
- social cognition
- rat exposed to 1 rat (enclosed)
- rat exposed to 1 known (enclosed) and 1 novel (enclosed) rat
= rats w intact social cognition should spend more time w new rat
schizophrenia: rodent models- 5-CSRTT
- cognitive speed and accuracy
- if goes to correct stimulus light will get treat, if too slow/wrong lights out
schizophrenia: why limited treatment?
- need to better understand underlying changes in neurobio that occur w disorder
- heterogenous disorder: manifests in many diff ways
PTSD: causes/symptoms (4)
- exposed to extremely traumatic situation (rape, war combat, sudden loss fam member/friend)
- memories + assoc fear v difficult to suppress
- can be triggered by surroundings
- leads to intense anxiety ‘inability to extinguish conditioned cues’
PTSD: brain regions effected
- hippocampus increased
- less input from PFC to amygdala
- amygdala dom info from from hippocampus -> exacerbation of -ve emotion linked to memory of event
PTSD: anxiety- pituitary gland role
- secretes hormones into blood (ACTH)
- adrenal gland = cortisol
PTSD: anxiety- hypothalamus role
- regulates peripheral ANS
PTSD: cortisol on hippocampus effect
stimulates hippocampus - inhibits hypothalamus more - ACTH not released
PTSD: increased amygdala effect
- hippocampus less efficient in inhibiting ACTH release, amygdala dom (more ACTH = more cortisol)
- cortical control of amygdala also lost (PFC -> amyg)
PTSD: models (3)
- 20+ self reported symptoms, not all linked to empirical evidence/neurosci models
- have relied on face, predictive validity so may not translate
- not ‘one size fits all’ model- data need to be interpreted/ symptom/ model- so specific mechanisms (constructs) more useful and translatable for clinic
PTSD: models now focus on
- biological markers (circuit, molecular) hoping to improve translation (increase construct validity)
PTSD: (4) requirements
- symptoms must occur/ last longer than 1 week after trauma/stress
- 1+ behavioural outcome measured related to PTSD
- results must be replicated across diff labs >1
- use variable stressors to prevent habituation, to better model PTSD
PTSD: biological phenotypes (6)
changes to
- circuitry involving amyg, PFC, hippocampus
- physical changes to structure/morphology of hippocampus
- HPA axis function
- neuroinflammation (cell distress in brain)
- sleep disturbances
- reversal of symptoms w pharmacotherapies (SSRI)
PTSD: best models used rn (6)
- predator stress
- single prolonged stress
- unpredictable variable stress
- foot shock stress
- immobilisation stress
- social defeat stress
PTSD: models- social defeat stress (SDS) experiment
resident - confronted w intruder mouse - then have sensory contact for 24hrs
PTSD: models- SDS shows
- shows avoidance of cues assoc w trauma, symptoms of depression
- reduced control of amyg by PFC, increase PFC activity w defeat
- reduced hippocampal vol
- increased corticosterone
PTSD: models- unpredictable variable stress (UVS) experiment
- daily exposures to various stressors (randomly) over 1-8wks
- damp/no bedding/ cage tilting
- light/dark cycle shifts
- forced swimming
- social stress
- noise/light stimulus
- overcrowding
- restraint stress
- food/water deprivation
- predator scent
- inescapable shocks
- thermal stimuli
etc.
PTSD: models- UVS shows
- shows symptoms of depression
- increased activity of amyg, damaged neurons in PFC
- increased cortisone and CRF lvls, reduced hippocampal vol
PTSD: models- UVS does NOT show
- avoidance of cues assoc w trauma
PTSD: models- predator stress experiment
- unprotected exposure (10min)
- protected exposure (in box for 10min)
- predator scent over days
PTSD: models- predator stress shows
- avoidance of cues assoc w trauma
- reduced connectivity btw PFC and amyg
- increased corticosterone lvls
- reduced dendritic length + spine density in hippocampus
PTSD: models- predator stress does NOT show
- no symptoms of depression
PTSD: models- which models best?
- all show good biological/behavioural phenotypes
- may see more translation
- bench to bedside 10-20yrs
drug addiction: models
- for drug reward
- self admin model is best
drug addiction: models steps of drug taking behaviour- (4)
- maintenance
- motivation
- extinction
- relapse (triggered by drug, cue, stress)
drug addiction: experiment
- rats trained to self admin drug eg. meth, IV
- reinstated by meth via peripheral injection into intraperitoneal space
drug addiction: how many drug users become addicted?
15%
drug addiction: deroche-gamonet model
- behavioural phenotyping
drug addiction: limtiations
- greater access to drug (long/short access)
- more female studies needed
- diff age groups needed
- many rats used for small addicted sample - better ethical model?
translation of NT: which NT has potential for addiction therapy?
oxytocin but does it translate from rat to human?
translation of NT: oxytocin?
- oxytocin evolved alot
- similar location of cells, but diff receptor location
- rodent: large effect on auditory processing and olfaction
- humans: alters visual attention, shifts in eye gaze
- evolutionary change in recognition of conspecifics or threats (smell/hearing vs visual)
- fundamental diff in sensory processing
translation of NT: best rat models investigate neurobiology? (4)
- fear
- learning
- stress
- social behaviour
translation of NT: due to deviation of oxy btw rodents/humans, best model to use for translating?
- models of stress (drug addiction can be considered stressor)
- food intake
- pair bonding
ultrasonic vocalisation (USV) w behaviour:
- using ultrasonic sound recorders can ‘hear’ rats talking
- help us understand behaviour, improve translatability
USV: how does it help model human behaviour?
- social dysfunction can be measured by deficits in social communication
- but need to understand communication for ‘normal’ function
USV: reality
- lot of research data to analyse, takes time
- could transform understanding of behaviours in rodent models
