Introduction
Behavioural endpoints and animal models of MDD
Behavioural endpoints
Anhedonia
Despair
Hopelessness
Apathy
Anxiety
Abnormalities in eating behaviour
Sleep disturbance
Psychomotor agitation or retardation
Irritability
Cognitive impairment
Animal models
Models based on application of stressors
Early life adversity
Stress applied during adulthood
Learned helplessness
Social defeats
Chronic social instability
Predator stress
Unpredictable chronic mild stress (UCMS)
Biological causation
Lipopolysaccharide injection
Bacille Calmette–Guérin (BCG) administration model
Bulbectomy
Corticosterone administration
Genetic models
Optogenetic manipulation
Validity of the classical models of MDD
Models | Core symptoms | Biological alterations | Antidepressant reversal |
---|---|---|---|
Induced by stress | |||
Despair but not anhedonia, sleep disturbances, psychomotor abnormalities | Neurotrophin alteration, hypercorticolemia, inflammation, increased activity in the amygdala, altered noradrenergic neurotransmission | Response to chronic AD | |
Anhedonia, despair, social withdrawal, eating behaviours abnormalities | Increased 5-HT neurotransmission and 5-HT1A receptor desensitisation, neurotrophin alterations, hypercortisolemia | Response to chronic AD | |
Social defeat (Golden et al. 2011) | Social withdrawal and anhedonia, body weight loss, eating behaviour abnormalities, psychomotor abnormalities | Inflammation, hypercortisolemia, corticolimbic alterations, neurotransmission alterations, neurotrophin alterations | Response to chronic AD and to ketamine |
UCMS (Willner 2017) | Despair, anhedonia, apathy, sleep disturbance, psychomotor abnormalities, body weight loss | Inflammation, neurotrophins alterations, hypercortisolemia, corticolimbic alterations, neurotransmission alterations | Response to chronic AD and to ketamine |
Neuroinflamation | |||
Anhedonia and despair | Inflammation, changes in neurotrophins, increased corticosterone, changes in neurotransmission | Response to chronic AD | |
Bulbectomy | |||
Transient anhedonia, despair | Changes in corticolimbic circuits, inflammation, increased corticosterone, changes in neurotransmission | Response to chronic but not acute AD | |
Drinking corticosterone | |||
Despair, sleep disturbance | Increased corticosterone, changes in corticolimbic brain areas, inflammation, changes in BDNF, changes in neurotransmission | Response to chronic AD and ketamine | |
Genetic models | |||
Increased susceptibility, despair | Serotoninergic syndrome (reduced serotonergic cell number and firing rate) | Absence of effects of AD | |
5-HT receptor-KO | |||
Increased anxiety and susceptibility to stress | Increased physiological responses to acute and chronic stress | ||
5-HT1b (Vinkers et al. 2011) | Despair, anhedonia, increased susceptibility | Increased stress-induced autonomic and locomotor responses | |
Higher sensitivity, despair | Changes in neurotransmission (glutamate, GABA) | Effects of acute and chronic AD are abolished | |
HPA axis | |||
FKBP1 KO (Gassen et al. 2014) | Higher sensitivity, despair | Changes in the autophagic pathway | Not tested |
Despair | Increased stress-induced corticosterone levels | Decreased response to chronic AD | |
Anxiety-related behaviours | Affected serotoninergic and noradrenergic system | No response to chronic AD | |
Neurocircuit modifications | |||
BNST inhibition (Johnson et al. 2016) | Increased susceptibility, anhedonia, decreased motivation | Changes in neuronal activity changes in neurotransmission (dopamine, serotonin) | Not tested |
Acc stimulation (Barthas et al. 2015) | |||
Inhibition of spiny cells in Nac (Francis et al. 2015) | |||
Chronic stimulation PFC (Ferenczi et al. 2016) | |||