Anxiety and Depression II animal models Flashcards
what is a model
small measure
a simplified representation used to explain the workings of a real system
why do we use models
understand functions of the specific pathways/processes
study genetic/environmental factors
understand intervention/treatment
prevention
animals used for models
worms
zebrafish
fruit flies
non-human primates (unethical and expensive)
rodents (phylogeny shows close relation to humans)
similarities and differences between rodent/human brains
size
cortex is smooth
smaller cortex in rodents
larger have larger OB (more genes encode ORs)
immemorial association between humans and rodents
commensal relationship
mice benefit from humans/humans are unaffected (sharing of food)
neolithic transition - nomadic hunters (farmers)
same environmental influences on man/mouse
behaviour vs activity
behaviour = observed animal activity
activity = voluntary/involuntary movements made by conscious/unrestrained animals
what does current behavioural research use
skinnerian (operant conditioning ) and ethological approach (animals in their natural environment)
skinner - little opportunity to use natural behaviour (trained)
ethological/spontaneous - use innate behaviour of animals (exploration of novel environment)
fear vs anxiety
fear = response to an actual threat, move away from stimulus (triggers fight or flight)
anxiety = response to a potential threat, move towards the stimulus
anxiety tasks with no conditioning
open field area (more locomotion=less anxiety, locomotor activity is confound for all behavioural tests)
light-dark box (anxiety = avoids light)
elevated plus maze
activity tasks
running wheel
home cage
telemetry
fear tasks with conditioning
give electric shock (threat)
response/freeze to a stimulus
cognitive task (emotional memory)
map anatomical pathways involved in fear conditioning
social behaviour tasks with no conditioning
social dominance
social interaction test
exhibit behaviours: boxing/kicking/nosing/wrestlin/biting/anhedonia
depression tasks with conditioning
learned helplessness (Seligman & Maier, 1967) inescapable shock, fail to escape when able, acute antidepressants increase escape
limitation: unethical, severe stress, strain differences, short lasting, not all animals develop helpless behaviour
depression tasks with no conditioning
tests helplessness - how long until give up
Porsolt swim test/tail suspension test
limitation: unethical
assessing validity of behavioural tasks
construct validity - how well the model reflects the theoretical assumptions
predictive validity - how well manipulation predicts performance in the condition being modelled
face validity - degree of similarity between the responses observed in the model and the disorder it stimulates
confounding factors
health and physical ability
sensory abilities
locomotor activity and anxiety
motivation and drive
sex/age
test environment
factors to consider for drug screening tests
efficiency - minimal time and effort expended in providing data
economy - minimal financial cost of animals, recording equipment and personnel training
reproducibility - consistency of results obtained
analytical facility - sustainability of the data by use of statistical methods
Genetic models
based on biology not GWAS
monoamine hypothesis - depletion of tryptophan (reduces 5-HT), typical antidepressants increase monoamines
dysregulation of the HPA axis - increased cortisol in depression, poor negative feedback, antidepressants improve feedback
neurogenesis hypothesis - stress causes hippocampal neuronal death, antidepressants increase neurogenesis
other - circadian clock, inflammation
Cryan & Sweeney 2011
monogenic approach
5HTT KO causes increased anxiety in light-dark box/elevated maze
identify genes (BALB/C)
future models
combine genetic and environmental manipulations
double hit
distal (early life) proximal (adult life)
consider individual susceptibility
form for sophisticated and sensitive tests
challenges of models
MURIDAE
modalities for understanding, recording, and integrating data across early life
chronic unpredictable mild stress model
Wilner et al., 1992
repeated exposure to mild stressors, type and durations of stressors
poor reproducibility
strain selection
physical and psychosocial stressors
maternal separation model
separate pups from mother
day 2-14 pups - 3hr separation
day 9 pups - 24hr separation
poor reproducibility
selected strain (susceptible)
physical and psychosocial stressors
social defeat
continuous contact with aggressor for 10-20 days
long lasting social aversion
increase anxiety/immobility - downregulation of BDNF transcripts
reversed by chronic antidepressant
poor reproducibility
unethical
strain selection
olfactory bulbectomy
removal of the olfactory bulb (used in limbic-hypothalamic axis)
sensory deprivation
hyperactivity in novel environment (increase noctural hyperactivity)
passive avoidance defeat
deficits in spatial memory
poorly understood
altered monoamine NTs - reversed by chronic antidepressants
