The design, application and relative strengths and limitations of depression models have been discussed in several reviews (1
). Without definitive knowledge of pathophysiological processes, these models are often evaluated for their face, construct
and pharmacological validity
), as are models of other clinically defined neuropsychiatric syndromes, such as autism and schizophrenia. Face validity
judges a model’s symptomatic homology to human depression. Today’s depression models achieve this goal considerably: rodent and primate models have successfully recapitulated states of social withdrawal, hypophagia and weight loss, anhedonia, circadian changes and abnormalities of the HPA (hypothalamic-pituitary-adrenal) axis, although these phenotypes are often transient and not all present simultaneously. The more challenging construct validity
requires a model to honor etiological factors implicated in depression, which are themselves not entirely understood. Most paradigms utilize some form of stress (of a physical or a psychosocial form), given the known association between independent stressful life events and depressive episodes (38
). More recently, there has been a greater emphasis on recapitulating both environmental (such as stressful life events) and genetic risk factors (although these remain largely unknown) in the same model.
or predictive validity
is met when a model’s depression-like behaviors are reversed by currently available antidepressant modalities, and several models in use today display this type of predictability with the therapeutic delay that characterizes antidepressant responses in humans. However, given that all available pharmacological agents are monoamine modulators and only a minority of patients remit following first-line therapies (28
), the requirement for pharmacological reversibility is perhaps desirable but not mandatory. Since the mechanisms underlying the delayed antidepressant effects of medication and non-medication treatments (including exercise, electroconvulsive seizures, etc.) remain largely unknown, there have been several attempts to employ animal models to dissect these mechanisms (i.e., models of antidepressant action
), with the caveat that these therapies are applied to laboratory animals that generally lack depression-like behavior or any particular genetic vulnerability to depression. A potential fourth criterion that has received considerably less attention is pathological validity
, whereby depression-related physiological, molecular and cellular abnormalities in animals are validated by demonstrating identical changes in postmortem brain samples from depressed humans. This is a genuinely difficult requirement, but has been gaining increasing popularity with the more widespread access to postmortem samples (12
). Ideally, this criterion might be better addressed through functional imaging studies with depressed patients, but this will require substantial improvements in molecular imaging capabilities.
From an evolutionary perspective, depression may be an analog of the involuntary defeat strategy
(IDS), occurring when an animal perceives defeat in a hierarchical struggle for resources (39
). Hyperarousal, psychomotor retardation, reduced motivation and sleep alterations in the setting of losing
are postulated to have an adaptive advantage in that they serve to protect losers
from further attack and focus cognitive resources on planning ways out of complex social problems (40
). Most behavioral endpoints in depression models aim to quantitatively assay some type of experimentally induced defeat
(), even though this aspect of mammalian behavior is likely physiological
(i.e., adaptive) rather than pathological
. Additionally, while despair behavior is often extrapolated as being depression-like, it is clearly a huge inference to make from rodent models, and most stressors also produce anxiety-like changes that are exaggerated manifestations of the fight or flight response
(reduced exploration, freezing, stress-induced hyperthermia, HPA axis activation, etc.). For example, repeated social subordination in mice (social defeat) leads to a long-lasting phenotype of reduced social interaction with other mice. This impairment in sociability can be interpreted as a reduced motivation to interact (an abnormality of reward
) or as a heightened avoidance of novel social stimuli (a pathological anxiety
response). Distinguishing between these alternative hypotheses is difficult and may even be irrelevant, particularly given the poorly defined neurobiological distinctions between anxiety and depression and their highly variable clinical presentation. In either case, the model employs a naturalistic social stress-induced behavior that is quantifiable and amenable to experimental manipulation (12
Common behavioral endpoints in rodent depression studies
The forced swim and tail suspension tests (FST, TST) are the simplest and most widely utilized models of depression and antidepressant action (). While these approaches have been rightly criticized for involving acute stress and acute antidepressant responses, they have permitted the rapid behavioral screening of novel chemical antidepressants and the phenotyping of genetically altered mutant mice. In certain instances, they have directed the field towards fundamentally novel molecular hypotheses. For example, an antidepressant-like phenotype on the FST (decreased immobility and greater struggling/swimming) was observed in mice deficient in ASIC-1a (acid sensing ion channel 1a), a pH sensitive ion channel expressed in the brain (51
). Subsequent studies have shown that ASIC-1a expressed in the amygdala participates in eliciting a fear response to a variety of aversive cues culminating in acidemia (51
), implicating inhibitors of ASIC-1a (a previously unappreciated target) as potential therapeutics against anxiety and depressive disorders. Analogous approaches have identified several other novel molecular targets, including p11 (a calcium binding chaperone molecule that promotes serotonin signaling through the 5HT1B receptor subtype (15
)), TREK-1 (a distinct type of potassium channel that is enriched in depression-related limbic brain regions (53
)) and ghrelin (a stomach-derived endocrine mediator of energy homeostasis (45
)), among many others.
In the following sections, we focus on neurobiological themes that exhibit therapeutic promises. The two main values of utilizing rats and mice to study depression are: 1) the ability to describe and characterize neuroplasticity with exquisite spatial and temporal precision, and 2) the opportunity to utilize molecular innovations to demonstrate the causative effects of those neuroplastic changes on assays of depression- and antidepressant-like behavior.