Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecular mechanisms underlying the regulation of stem/progenitor cell proliferation, survival, maturation, and differentiation have not been completely unraveled. We have studied hippocampal neurogenesis in NF-B p50-deficient mice. Here we demonstrate that in absence of p50, the net rate of neural precursor proliferation does not change, but some of the steps leading to the final neuron differentiation status are hampered, resulting in ϳ50% reduction in the number of newly born neurons in the adult mutant hippocampus. Additionally, in p50 Ϫ/Ϫ mice, we observed a selective defect in short-term spatial memory performance without impairment of hippocampal-dependent spatial long-term memory and learning. Our results highlight the role of NF-B p50 in hippocampal neurogenesis and in short-term spatial memory.

In the present study, we have coupled the chronic mild stress (CMS) protocol with Affymetrix microarray technology to screen the rat genome for gene changes in the frontal cortex. The aim of our work was to assess whether the CMS protocol could be a useful experimental model to provide insights into the molecular basis of depression. Under our experimental conditions, 59 transcripts changed by more than +/-1.5-fold between naïve and anhedonic rats and showed significantly altered expression levels (P < 0.05). Among these, 18 were upregulated (fold change range +1.509 to +3.161) and 41 were downregulated (fold change range -1.505 to -2.659). To confirm the data obtained with microarrays, we used real-time reverse transcription polymerase chain reaction (RT-PCR). The results confirmed the downregulation of Itga6, Camk2a, Plcb1, Cart, Gad1, Homer1 and Th and the upregulation of Egr2 and Ptgs2 observed in the DNA microarray analysis. Moreover, the fold change data of the nine validated transcripts from microarray analysis and real-time polymerase chain reaction showed a good correlation (r = 0.863, 7 d.f., P < 0.01; slope = 0.976). It is of great interest that prostaglandin-endoperoxide synthase 2, tyrosine hydroxylase, Cart, Homer1 and glutamate decarboxylase have already been implicated in affective disorders by different approaches in previous reports. In conclusion, our findings indicate that the CMS paradigm is a useful preclinical model with which to investigate the molecular basis of anhedonia and to help in the discovery of novel targets for antidepressant drugs.

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We have shown that chronic QTP treatment prevented anhedonia and reversed, at least in part, the changes of gene expression induced by CMS in the rat frontal cortex. We have also identified and confirmed by two different methods that 11 genes, representing molecular targets of QTP, are presumably the effectors of its clinical efficacy.

The role of atypical antipsychotics as add-on treatments and as primary mood stabilizers in different phases of bipolar disorder is an important current research area. Although in bipolar patients the main therapeutic indication of quetiapine (QTP) is the management of acute mania, several observations suggest that this agent may exert antidepressant as well as antimanic effects. However, in our knowledge, there are no preclinical studies supporting this hypothesis. Thus, the main goal of the present work was to evaluate the putative antidepressant effect of QTP (0.4, 2.0, or 10 mg/kg/day), in comparison to amitriptyline (AMI) (2 or 5 mg/kg/day), in rats exposed to acute or chronic stress. The administration of QTP, 2 mg/kg/day, prevents the onset of anhedonia in rats exposed to a 6-week chronic mild stress (CMS) protocol. The effect of QTP has a slow onset, beginning at week 5, and causes a complete recovery from anhedonia. In this respect, the effect of QTP is similar to that obtained after chronic administration of AMI 2 or 5 mg/kg/day. Our findings also indicate that a 6-week administration of QTP, 2 or 10 mg/kg/day, has protective effects against the onset of anhedonia caused by the exposure to an acute subthreshold stressful event in rats that have previously experienced the CMS procedure. The results suggest that QTP is able to prevent both the transient mood depression caused by acute stress and the long-lasting anhedonic state induced by exposure, over a period of weeks, to a variety of unpredictable mild stressors.

The present findings demonstrate that the pro-cognitive effect of thioperamide is probably due to the modulation of post-acquisition memory processes through an action on the cholinergic basal forebrain. Our results indicate also that H3-antagonists may provide a useful approach for improving spatial recognition memory.

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