Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice.

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2-9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3',4'-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

Depletion of adult neurogenesis using the chemotherapy drug temozolomide in mice induces behavioural and biological changes relevant to depression.

Numerous studies have examined links between postnatal neurogenesis and depression using a range of experimental methods to deplete neurogenesis. The antimitotic drug temozolomide (TMZ) has previously been used successfully as an experimental tool in animals to deplete adult neurogenesis and is used regularly on human patients as a standard chemotherapy for brain cancer. In this study, we wanted to evaluate whether TMZ as a model for chemotherapy treatment could affect parameters related to depression in an animal model. Prevalence rates of depression in patients is thought to be highly underdiagnosed, with some studies reporting rates as high as 90%. Results from this study in mice, treated with a regimen of TMZ similar to humans, exhibited behavioural and biochemical changes that have relevance to the development of depression. In particular, behavioural results demonstrated robust deficits in processing novelty and a significant increase in the corticosterone response. Quantification of neurogenesis using a novel sectioning method, which clearly evaluates dorsal and ventral neurogenesis separately, showed a significant correlation between the level of ventral neurogenesis and the corticosterone response. Depression is a complex disorder with discoveries regarding its neurobiology and how it relates to behaviour being only in their infancy. The findings presented in this study demonstrate that chemotherapy-induced decreases in neurogenesis results in previously unreported behavioural and biochemical consequences. These results, we argue, are indicative of a biological mechanism, which may contribute to the development of depression in patients being treated with chemotherapy and is separate from the mental distress resulting from a cancer diagnosis.

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5'-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27(Kip1) and p57(Kip2). In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.