Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic–pituitary–adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

The brains of sengis (elephant shrews, order Macroscelidae) have long been known to contain a hippocampus that in terms of allometric progression indices is larger than that of most primates and equal in size to that of humans. In this report, we provide descriptions of hippocampal cytoarchitecture in the eastern rock sengi (Elephantulus myurus), of the distributions of hippocampal calretinin, calbindin, parvalbumin, and somatostatin, of principal neuron numbers, and of cell numbers related to proliferation and neuronal differentiation in adult hippocampal neurogenesis. Sengi hippocampal cytoarchitecture is an amalgamation of characters that are found in CA1 of, e.g., guinea pig and rabbits and in CA3 and dentate gyrus of primates. Correspondence analysis of total cell numbers and quantitative relations between principal cell populations relate this sengi to macaque monkeys and domestic pigs, and distinguish the sengi from distinct patterns of relations found in humans, dogs, and murine rodents. Calretinin and calbindin are present in some cell populations that also express these proteins in other species, e.g., interneurons at the stratum oriens/alveus border or temporal hilar mossy cells, but neurons expressing these markers are often scarce or absent in other layers. The distributions of parvalbumin and somatostatin resemble those in other species. Normalized numbers of PCNA+ proliferating cells and doublecortin-positive (DCX+) differentiating cells of neuronal lineage fall within the overall ranges of murid rodents, but differed from three murid species captured in the same habitat in that fewer DCX+ cells relative to PCNA+ were observed. The large and well-differentiated sengi hippocampus is not accompanied by correspondingly sized cortical and subcortical limbic areas that are the main hippocampal sources of afferents and targets of efferents. This points to intrinsic hippocampal information processing as the selective advantage of the large sengi hippocampus.

The hippocampus in fluoxetine-treated mice responds differently with regard to volume and cell numbers under stressful vs enriched conditions. To account for effects specific to defined septo-temporal segments of the hippocampus, dissected hippocampi were straightened (a) and embedded in an egg-albumin-based matrix (see asterisk in c). Systematically collected sections along the hippocampal septo-temporal axis were assigned and analyzed unambiguously for the septal, middle and temporal third. As an example in b, volumetric measurements in the CA1 molecular layer are only decreased in the septal third in fluoxetine-treated animals under stressful conditions. Representative cross sections of the straightened hippocampus are shown in c: top panel: Giemsa-stained hippocampus used for volumetric measurements of the main hippocampal fields and estimation of the resident granule cell population size. Middle panel: immunohistochemistry visualizes the proliferating, Ki67-positive cells in the subgranular layer of the dentate gyrus (arrow and insert). Lower panel: identification of young, doublecortin (DCX)-positive neurons in the subgranular layer (arrow and insert) can significantly be augmented by applying a light hematoxylin counterstain. The embedding matrix (*) picks up unspecific background stain in the immunohistochemical-treated material (middle and lower panels), but this does not compromise the specificity of the antigen labeling in the tissue itself. Scale bar: 250 μm, inset scale bar: 10 μm. For more information on this topic, please refer to the article by Alboni et al. on pages 552-561.