SUMMARY Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some but not all behavioral paradigms, suggesting both neurogenesis-dependent and independent mechanisms of antidepressant actions. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, β-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that β-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.long-term potentiation ͉ learning ͉ memory N ew neurons are born in the dentate gyrus (DG) of the hippocampus throughout the life of mammals (1) and derive from dividing progenitor cells located in the innermost part of the granule cell layer, a region called the subgranular zone. Young granule neurons integrate into the existing circuitry of the hippocampus, as evidenced by the development of functional synaptic inputs provided by the medial perforant path (MPP) and growth of axons to target cells in CA3 (2). Although a variety of environmental and pharmacological manipulations can affect neurogenesis (2, 3), it is unclear whether adult-born neurons provide a significant contribution to hippocampal function and, ultimately, how it might impact behavior.Recent studies have shown that various strategies to disrupt neurogenesis produce a limited impairment in some hippocampaldependent learning and memory tasks and in responses to antidepressant drugs (4-11). Unfortunately, the lack of spatial and cellular specificity provided by most ablation techniques has made it difficult to ascertain whether the consequent behavioral effects were caused by ablation of neurogenesis or other impairments. To circumvent these problems we have used two independent strategies of ablation. The first is a previously reported x-ray procedure that differs from similar methods in two ways: (i) the x-ray administration is restricted to a fraction of the brain containing the hippocampus and spares neurogenesis in the neighboring subventricular zone; and (ii) mice are allowed to recover for 3 months before testing to allow for the disappearance of markers of inflammation, such as reactive microglia (9). The second method of ablation is a genetic strategy that directly targets dividing progenitors throughout the brain and avoids potential radi...

Environmental enrichment increases adult hippocampal neurogenesis and alters hippocampal-dependent behavior in rodents. To investigate a causal link between these two observations, we analyzed the effect of enrichment on spatial learning and anxiety-like behavior while blocking adult hippocampal neurogenesis. We report that environmental enrichment alters behavior in mice regardless of their hippocampal neurogenic capability, providing evidence that the newborn cells do not mediate these effects of enrichment.

The striatum receives prominent dopaminergic innervation that is integral to appetitive learning, performance, and motivation. Signaling through the dopamine D 2 receptor is critical for all of these processes. For instance, drugs with high affinity for the D 2 receptor potently alter timing of operant responses and modulate motivation. Recently, in an attempt to model a genetic abnormality encountered in schizophrenia, mice were generated that reversibly overexpress D 2 receptors specifically in the striatum (Kellendonk et al., 2006). These mice have impairments in working memory and behavioral flexibility, components of the cognitive symptoms of schizophrenia, that are not rescued when D 2 overexpression is reversed in the adult. Here we report that overexpression of striatal D 2 receptors also profoundly affects operant performance, a potential index of negative symptoms. Mice overexpressing D 2 exhibited impairments in the ability to time food rewards in an operant interval timing task and reduced motivation to lever press for food reward in both the operant timing task and a progressive ratio schedule of reinforcement. The motivational deficit, but not the timing deficit, was rescued in adult mice by reversing D 2 overexpression with doxycycline. These results suggest that early D 2 overexpression alters the organization of interval timing circuits and confirms that striatal D 2 signaling in the adult regulates motivational process. Moreover, overexpression of D 2 under pathological conditions such as schizophrenia and Parkinson's disease could give rise to motivational and timing deficits.