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EXP NEURO > Translation to clinical neuro > Flashcards

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
Q

schizophrenia: rodent models- pharmacological

A
  • glutamate NMDA receptor antagonists

- repeated psychostimulant (meth) admin

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26
Q

schizophrenia: rodent models- genetic

A
  • alterations impacting dopamine/glutamate transmission, or genes thought to induce susceptibility for schizophrenia
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27
Q

schizophrenia: rodent models- neurodevelopmental

A
  • pre/perinatal insults (MAM)
  • lesions of hippocampus
  • infection during gestation w LPS or poly (I:C)
  • maternal deprivation/ social isolation
28
Q

schizophrenia: rodent models- once made schizophrenic, performance deficits can be treated w (2)

A
  • genetic

- pharmacology

29
Q

schizophrenia: rodent models- tasks (3)

A
  • 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
Q

schizophrenia: rodent models- novel object recognition task?

A
  • 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
Q

schizophrenia: rodent models- novel conspecific discrimination task

A
  • 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
Q

schizophrenia: rodent models- 5-CSRTT

A
  • cognitive speed and accuracy

- if goes to correct stimulus light will get treat, if too slow/wrong lights out

33
Q

schizophrenia: why limited treatment?

A
  • need to better understand underlying changes in neurobio that occur w disorder
  • heterogenous disorder: manifests in many diff ways
34
Q

PTSD: causes/symptoms (4)

A
  • 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
Q

PTSD: brain regions effected

A
  • hippocampus increased
  • less input from PFC to amygdala
  • amygdala dom info from from hippocampus -> exacerbation of -ve emotion linked to memory of event
36
Q

PTSD: anxiety- pituitary gland role

A
  • secretes hormones into blood (ACTH)

- adrenal gland = cortisol

37
Q

PTSD: anxiety- hypothalamus role

A
  • regulates peripheral ANS
38
Q

PTSD: cortisol on hippocampus effect

A

stimulates hippocampus - inhibits hypothalamus more - ACTH not released

39
Q

PTSD: increased amygdala effect

A
  • hippocampus less efficient in inhibiting ACTH release, amygdala dom (more ACTH = more cortisol)
  • cortical control of amygdala also lost (PFC -> amyg)
40
Q

PTSD: models (3)

A
  • 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
Q

PTSD: models now focus on

A
  • biological markers (circuit, molecular) hoping to improve translation (increase construct validity)
42
Q

PTSD: (4) requirements

A
  • 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
Q

PTSD: biological phenotypes (6)

A

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
Q

PTSD: best models used rn (6)

A
  • predator stress
  • single prolonged stress
  • unpredictable variable stress
  • foot shock stress
  • immobilisation stress
  • social defeat stress
45
Q

PTSD: models- social defeat stress (SDS) experiment

A

resident - confronted w intruder mouse - then have sensory contact for 24hrs

46
Q

PTSD: models- SDS shows

A
  • 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
Q

PTSD: models- unpredictable variable stress (UVS) experiment

A
  • 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
Q

PTSD: models- UVS shows

A
  • shows symptoms of depression
  • increased activity of amyg, damaged neurons in PFC
  • increased cortisone and CRF lvls, reduced hippocampal vol
49
Q

PTSD: models- UVS does NOT show

A
  • avoidance of cues assoc w trauma
50
Q

PTSD: models- predator stress experiment

A
  • unprotected exposure (10min)
  • protected exposure (in box for 10min)
  • predator scent over days
51
Q

PTSD: models- predator stress shows

A
  • avoidance of cues assoc w trauma
  • reduced connectivity btw PFC and amyg
  • increased corticosterone lvls
  • reduced dendritic length + spine density in hippocampus
52
Q

PTSD: models- predator stress does NOT show

A
  • no symptoms of depression
53
Q

PTSD: models- which models best?

A
  • all show good biological/behavioural phenotypes
  • may see more translation
  • bench to bedside 10-20yrs
54
Q

drug addiction: models

A
  • for drug reward

- self admin model is best

55
Q

drug addiction: models steps of drug taking behaviour- (4)

A
  • maintenance
  • motivation
  • extinction
  • relapse (triggered by drug, cue, stress)
56
Q

drug addiction: experiment

A
  • rats trained to self admin drug eg. meth, IV

- reinstated by meth via peripheral injection into intraperitoneal space

57
Q

drug addiction: how many drug users become addicted?

A

15%

58
Q

drug addiction: deroche-gamonet model

A
  • behavioural phenotyping
59
Q

drug addiction: limtiations

A
  • 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
Q

translation of NT: which NT has potential for addiction therapy?

A

oxytocin but does it translate from rat to human?

61
Q

translation of NT: oxytocin?

A
  • 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
Q

translation of NT: best rat models investigate neurobiology? (4)

A
  • fear
  • learning
  • stress
  • social behaviour
63
Q

translation of NT: due to deviation of oxy btw rodents/humans, best model to use for translating?

A
  • models of stress (drug addiction can be considered stressor)
  • food intake
  • pair bonding
64
Q

ultrasonic vocalisation (USV) w behaviour:

A
  • using ultrasonic sound recorders can ‘hear’ rats talking

- help us understand behaviour, improve translatability

65
Q

USV: how does it help model human behaviour?

A
  • social dysfunction can be measured by deficits in social communication
  • but need to understand communication for ‘normal’ function
66
Q

USV: reality

A
  • lot of research data to analyse, takes time

- could transform understanding of behaviours in rodent models

EXP NEURO (10 decks)

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