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Translation to clinical neuro Flashcards

1
Q

why use animal models? (7)

A
  • 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
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2
Q

preclinical models: list neurobiology of disorders done on animals (7)

A
  • neurosci in general
  • schizophrenia (psychoses, cognitive dysfunction)
  • anxiety
  • depression
  • AD
  • abuse potential substances
  • drug addiction
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3
Q

preclinical models: which rodent more common and other species?

A
  • mice most common
  • zebra fish
  • monkeys
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4
Q

preclinical models: translation means?

A
  • sci advances using animals will impact human health
  • bigger the sys, more chance variation btw species
  • molecular vs behavioural
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5
Q

validity of behavioural models: list (3) main forms

A
  • predictive
  • face
  • construct
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6
Q

validity of behavioural models: predictive validity

A
  • does model accurately reflect disorder

- can drug treat human disorder + also model?

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7
Q

validity of behavioural models: face validity

A
  • does model show same symptoms as human disorder (subjective)
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8
Q

validity of behavioural models: construct validity

A
  • how well does test measure what its supposed to measure?

- quality of model, piece of puzzle (neurobiological construct)

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9
Q

publication bias: features

A
  • 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
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10
Q

publication bias: what aims to maximise quality of study published

A
  • peer reviews
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11
Q

publication bias: which more important? fundamental sci or practical application studies?

A

fundamental sci > practical application studies

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12
Q

rats share % genes w humans? and other features

A

93%

  • almost all genes involved in human diseases found in rat
  • anatomical similarities of brain
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13
Q

chimps share % genes w humans?

A

96%

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14
Q

rat differences:

A
  • 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
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15
Q

schizophrenia: translation model

A
  • 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
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16
Q

schizophrenia: hypofrontality PFC

A
  • cognitive deficits

- -ve symptoms

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17
Q

schizophrenia: increased dopamine NAc

A
  • +ve symptoms (psychoses)

- euphoria at beginning

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18
Q

schizophrenia: which sys involved?

A

mesocorticolimbic dopamine sys (A10)

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19
Q

schizophrenia: glutamate- phencyclidine (PCP) induced psychosis antagonist for? like what other drug?

A
  • NMDA receptors

- like ketamine

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20
Q

schizophrenia: glutamate- PCP induces

A
  • psychosis in humans (1 dose)
  • auditory hallucinations
  • paranoid delusions
  • cognitive impairement
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21
Q

schizophrenia: glutamate- rodent use?

A
  • rats as locomotor activity, stereotypes

- used to screen antipsychotics prior to clinical trials

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22
Q

schizophrenia: MATRICS? (NIMH)

A
  • measurement and treatment research to improve cognition in schizophrenia
  • national institute of mental health
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23
Q

schizophrenia: (7) cognitive domains altered MATRICS

A
  • working memory
  • attention/vigilance
  • problem solving
  • social cognition
  • reasoning and problem solving
  • visual learning and memory
  • verbal learning and memory
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24
Q

schizophrenia: can we use rodent models? MATRICS

A
  • yes, must be schizophrenic first
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25
schizophrenia: rodent models- pharmacological
- glutamate NMDA receptor antagonists | - repeated psychostimulant (meth) admin
26
schizophrenia: rodent models- genetic
- alterations impacting dopamine/glutamate transmission, or genes thought to induce susceptibility for schizophrenia
27
schizophrenia: rodent models- neurodevelopmental
- pre/perinatal insults (MAM) - lesions of hippocampus - infection during gestation w LPS or poly (I:C) - maternal deprivation/ social isolation
28
schizophrenia: rodent models- once made schizophrenic, performance deficits can be treated w (2)
- genetic | - pharmacology
29
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
30
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
31
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
32
schizophrenia: rodent models- 5-CSRTT
- cognitive speed and accuracy | - if goes to correct stimulus light will get treat, if too slow/wrong lights out
33
schizophrenia: why limited treatment?
- need to better understand underlying changes in neurobio that occur w disorder - heterogenous disorder: manifests in many diff ways
34
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'
35
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
36
PTSD: anxiety- pituitary gland role
- secretes hormones into blood (ACTH) | - adrenal gland = cortisol
37
PTSD: anxiety- hypothalamus role
- regulates peripheral ANS
38
PTSD: cortisol on hippocampus effect
stimulates hippocampus - inhibits hypothalamus more - ACTH not released
39
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)
40
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
41
PTSD: models now focus on
- biological markers (circuit, molecular) hoping to improve translation (increase construct validity)
42
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
43
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)
44
PTSD: best models used rn (6)
- predator stress - single prolonged stress - unpredictable variable stress - foot shock stress - immobilisation stress - social defeat stress
45
PTSD: models- social defeat stress (SDS) experiment
resident - confronted w intruder mouse - then have sensory contact for 24hrs
46
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
47
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.
48
PTSD: models- UVS shows
- shows symptoms of depression - increased activity of amyg, damaged neurons in PFC - increased cortisone and CRF lvls, reduced hippocampal vol
49
PTSD: models- UVS does NOT show
- avoidance of cues assoc w trauma
50
PTSD: models- predator stress experiment
- unprotected exposure (10min) - protected exposure (in box for 10min) - predator scent over days
51
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
52
PTSD: models- predator stress does NOT show
- no symptoms of depression
53
PTSD: models- which models best?
- all show good biological/behavioural phenotypes - may see more translation - bench to bedside 10-20yrs
54
drug addiction: models
- for drug reward | - self admin model is best
55
drug addiction: models steps of drug taking behaviour- (4)
- maintenance - motivation - extinction - relapse (triggered by drug, cue, stress)
56
drug addiction: experiment
- rats trained to self admin drug eg. meth, IV | - reinstated by meth via peripheral injection into intraperitoneal space
57
drug addiction: how many drug users become addicted?
15%
58
drug addiction: deroche-gamonet model
- behavioural phenotyping
59
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?
60
translation of NT: which NT has potential for addiction therapy?
oxytocin but does it translate from rat to human?
61
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
62
translation of NT: best rat models investigate neurobiology? (4)
- fear - learning - stress - social behaviour
63
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
64
ultrasonic vocalisation (USV) w behaviour:
- using ultrasonic sound recorders can 'hear' rats talking | - help us understand behaviour, improve translatability
65
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
66
USV: reality
- lot of research data to analyse, takes time | - could transform understanding of behaviours in rodent models

EXP NEURO (10 decks)

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