| Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naive rodents rather than on models that capture the protracted feelings of anhedonia and helplessness, behavioral inflexibility, and diminished goal-directed action that characterize depression.;A history of life stressors acts as a significant predictor for depression, so we first generated evidence that chronic exposure to the major stress-associated adrenal hormone, corticosterone, induces persistent, antidepressant-sensitive helplessness-like and anhedonic-like behavior, as well as decreased instrumental responding for food reinforcement under conditions of diminishing reinforcement availability in mice, modeling amotivation and behavioral inflexibility in depression. Several biological mechanisms of action were next implicated: First, dorsal hippocampal Brain-derived Neurotrophic Factor (BDNF) appeared to be involved in decreased hedonic sensitivity to reward via Extracellular-signal Regulated Kinase 1/2. Next, experiments using selective viral-mediated Bdnf knock-down indicated that BDNF in the medial prefrontal cortex (PFC) also regulates instrumental responding for food and its restoration by antidepressant treatment.;Based on these data, the bdnf+/- mutant mouse might be expected to be a strong candidate transgenic mouse for studying mechanisms of depressive-like behavioral responding. I show, however, that constitutive loss of Bdnf and downstream intracellular signaling relieves an inhibitory influence from the medial orbitofrontal cortex on instrumental responding, rendering the bdnf+/- mouse fundamentally insensitive to reward value.;A history of corticosterone exposure also chronically regulates rodent behavior via several glutamatergic targets: I will conclude this report with evidence that corticosterone impairs fear extinction consolidation---another learning process requiring prefrontal neural integrity---via decreased GluR2/3 and NR2B AMPA and NMDA subunit expression. Moreover, corticosterone increases GluR1 expression in the ventral hippocampus, a major regulator of the nucleus accumbens, and increased glutamatergic activity here may contribute to insensitivity to appetitive reinforcement after corticosterone.;Together, these data point to selective roles for regionally-sensitive patterns of BDNF and AMPA receptor subunit expression after chronic glucocorticoid exposure in: (1) regulating the hedonic responsiveness to, and motivation to acquire, appetitive reinforcement; and (2) interfering with the neural systems that maintain flexible responding under conditions of uncertain environmental outcomes or reward availability. |
