An Enriched Environment Restores Normal Behavior

Neuroscience 164 (2009) 929 –940

AN ENRICHED ENVIRONMENT RESTORES NORMAL BEHAVIOR WHILE PROVIDING CYTOSKELETAL RESTORATION AND SYNAPTIC CHANGES IN THE HIPPOCAMPUS OF RATS EXPOSED TO AN EXPERIMENTAL MODEL OF DEPRESSION
L. SIFONIOS,a* M. TRINCHERO,a M. CERESETO,a A. FERRERO,a M. L. CLADOUCHOS,a G. F. MACEDO,a A. REINÉSa,b AND S. WIKINSKIa,c
a Instituto de Investigaciones Farmacológicas(ININFA-UBA/CONICET), Junín 956, 5° piso, (1113) Ciudad de Buenos Aires, Argentina

Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 5° piso, (1113) Ciudad de Buenos Aires, Argentina Primera Cátedra de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2051, 15° piso, (1113) Ciudad de Buenos Aires, Argentina
c

bAbstract—The exposure of rats to an enriched environment (EE) has several effects in common with the administration of antidepressants. However, there is still little information about the molecular underpinnings of these effects on rats subjected to experimental models of depression. The aim of this research was to evaluate the effects of EE on rats exposed to the learned helplessness paradigm (LH), awellknown model of the disease. We found that a 21 day exposure to EE reverts helplessness behavior to normal in LH animals. Inmunohistochemical labeling showed that this effect was accompanied by normalization of two structural proteins of hippocampal neurons to control values: the light neurofilament subunit (NFL) and the postsynaptic density 95 (PSD-95) protein, which were decreased in LH animalshoused in standard cages. The decrease in the presynaptic protein synaptophysin (SYN) observed in LH animals remained unchanged after exposure to EE. There was no increase in neurogenesis as measured by quantification of double-labeled cells with 5-bromo-2=-deoxyuridine (BrdU) and the neuronal marker -tubulin class III. These results show that EE may have behavioral and synaptic effects on animalsexposed to an experimental model of depression, and that such actions seem to be independent from neurogenesis. © 2009 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: major depression, plasticity, cytoskeleton, synaptogenesis, stress.
*Corresponding author. Tel: 54 11 49 61 59 49; fax: 54 11 49 63 85 93. E-mail address: lsifonios@ffyb.uba.ar (L. Sifonios). Abbreviations: ANOVA,analysis of variance; BDNF, brain-derived neurotrophic factor; BrdU, 5-bromo-2=-deoxyuridine; CA3, Ammon’s horn 3; C group, control group; CEE group, control-enriched environment group; DG, dentate gyrus; EE, enriched environment; GZ, granular zone; I, intensity; IF, immunofluorescence; IHC, immunohistochemistry; LH group, learned helplessness group; LHEE group, learned helplessness-enriched environmentgroup; NFL, light neurofilament subunit; O. D., optical density; PBS, phosphate buffer saline; PSD-95, postsynaptic density 95; Pyr, pyramidal cell layer; SL, stratum lucidum; SR, stratum radiatum; SYN, synaptophysin; TBS, tris-buffer saline; TUJ-1, -tubulin class III.

In recent years, clinical research has provided a growing body of evidence of the efficacy of psychosocial interventions for thetreatment of psychiatric diseases. The STAR-D trial series, for example, has demonstrated that cognitive behavioral therapy is as effective as medication for the recovery of treatment resistant depressive patients (Thase et al., 2007). However, the use of environmental interventions in psychiatric treatments has not been accompanied by an understanding of the neurobiological changes underlyingtheir efficacy and data on how the brain responds to different psychotherapeutic approaches is still scarce. When applied to naive animals, enriched environment (EE) has proved to be efficacious at inducing plastic changes, i.e. rearrangement of mossy fiber connectivity (Galimberti et al., 2006; Li et al., 2006) or promotion of signaling pathways that control LTP (Li et al., 2006). Thus, this...