The Neurobiology of Depression Flashcards
Which systems are dysfunctional in imaging of brains of depression patients and which areas do these include?
Emotional processing and reward seeking - amygdala and NAc
Emotional regulation - ventral hippocampus, mPFC, ACC
Cognition - PFC
Define stress
State of perturbed homeostasis - following perceived danger - that evokes adaptive reactions
What are the steps of the HPA axis?
Hypothalamus releases CRH/AVP
Anterior pituitary releases ACTH
Adrenal cortex releases glucocorticoids - inhibit CRH and ACTH release
Which test is used to measure HPA function?
Dexamethasone suppression test
What does the dexamethasone suppression test involve?
Administer dexamethasone (GR agonist) and CRH
Dexamethasone inhibits cortisol release - CRH increases cortisol release
Measure cortisol levels
Which NT is involved in regulating GR transcription?
5HT
How does 5HT regulate GR transcription?
5HT projections to hippocampal neurons - stimulate 5HT7Rs - coupled to cAMP
cAMP activation - increases NGF1-A expression (transcription factor) - activates Nr3c1 (GR gene) promoter
What is the effect of high-licking mothering on pups?
Demethylation of Nr3c1 (GR gene)
Increased 5HT levels
Increased GR expression
Relaxed
What does the MA theory of depression suggest?
Depression due to low MA levels in brain
Which NTs are MAs?
5HT, DA, NA
What is the effect of most antidepressants?
Prevent MA (5HT, DA, NA) reuptake - increase MA levels - particularly in limbic system (emotional brain)
Where does the NAergic pathway originate?
Locus coeruleus
Where does the 5HTergic pathway originate?
Raphe nuclei
What is the evidence against MA theory of depression?
Clinical effect of antidepressants requires 3-4 weeks - despite 5HT/NA increase within 24hrs
Low rates of treatment response - multiple antidepressant drugs usually tried
What are the 3 types of validity that a rodent model of anxiety and depression must have?
Construct validity
Face validity
Predictive (pharmacological) validity
What is construct validity of a rodent model of anxiety/depression?
Exposed to well-known environmental risk factor/disease-causing agent - e.g. stress, cold water swimming
What is face validity of a rodent model of anxiety/depression?
Has key anatomical, biochemical, neuropathological, behavioural features of human disease - e.g. neurogenesis, anhedonia
What is predictive (pharmacological) validity of a rodent model of anxiety/depression?
Responds to treatment in way that predicts effects in humans
How can animals be stressed to form an anxiety/depression model and how does this affect phenotype?
Forced swim test - reduced time until giving up
Chronic mild stress - grooming, sucrose preference
Fear conditioning - freezing
Early-life stress (e.g. maternal separation) - sociability, resilience to stress
How can animals models be tested for anxiety?
Elevated plus maze
Time spent exploring novel item in environment
Open field test - anxious animal avoids centre
What is the novelty suppressed-feeding test (NST)?
Only test sensitive to chronic antidepressant treatment - not acute
Platform with food in centre of arena
Measure time for animal to reach food
What does the neurogenesis theory of depression suggest?
Adult hippocampal neurogenesis buffers stress response - increases capacity to distinguish similar patterns of stimulation
Which 2 sites do adult neuronal progenitors originate from and where do they integrate?
SVZ of lateral ventricles - to olfactory bulb
SGZ of dentate gyrus - into hippocampal circuitry - as granule cells - project to CA3
What happens at week 2 of neuronal precursor cell maturation?
Processes develop - synapse with GABAergic interneurons - promote differentation
