title: Anxiety- and Depression-Like States Lead to Pronounced Olfactory Deficits and Impaired Adult Neurogenesis in Mice.
abstract: Numerous clinical reports underscore the frequency of olfactory impairments in patients suffering from major depressive disorders (MDDs), yet the underlying physiopathological mechanisms remain poorly understood. We hypothesized that one key link between olfactory deficits and MDD lies in hypercortisolemia, a cardinal symptom of MDD. Corticosterone (CORT) is known to negatively correlate with hippocampal neurogenesis, yet its effects on olfactory neurogenesis and olfaction remain unknown. Here we used a rodent model of anxiety/depression-like states, which is based on chronic CORT administration and studied the effects of the antidepressant fluoxetine (FLX) on behavior, olfaction, and adult neurogenesis in the dentate gyrus (DG), olfactory bulb (OB), and the olfactory epithelium (OE). Chronic CORT had no effect on cell proliferation in the OE or on olfactory sensory neurons projecting to the OB, but induced pronounced deficits in olfactory acuity, fine discrimination of odorants and olfactory memory. These alterations were accompanied by a significant decrease in the number of adult-born neurons in both the DG and OB. Remarkably, FLX not only reversed depression-like states as expected, but also improved olfactory acuity, memory, and restored impaired adult neurogenesis. However, fine olfactory discrimination was not restored. Morphological analysis of adult-born neurons in both the DG and the OB showed that dendritic complexity was not significantly affected by CORT, but was increased by FLX. These findings demonstrate an essential role for glucocorticoids in triggering olfactory impairments in MDD and highlight a novel therapeutic effect of FLX.
  
  
  CONCLUSIONS
  Increasing clinical reports show that major depression is characterized by pronounced olfactory deficits, yet the underlying mechanisms remain unknown. In this work, we used an endocrine model of depression to study whether hypothalamic-pituitary-adrenal axis perturbation could be sufficient to provoke olfactory impairments. We found that chronic corticosterone not only induces marked deficits in olfactory acuity, fine discrimination and olfactory memory, but also significantly decreases bulbar and hippocampal neurogenesis. Importantly, the antidepressant fluoxetine restores both adult neurogenesis and depressive states, and improves most olfactory functions. Our data reveal that impairment of hypothalamic-pituitary-adrenal axis during depression can lead to olfactory deficits and that the neurogenic effects of selective serotonin reuptake inhibitor antidepressants can successfully restore certain olfactory functions.
authors.affiliation: Institut Pasteur, Unité Perception et Mémoire, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3571, F-75015 Paris, France.
authors.forename: Eleni
authors.initials: E
authors.lastname: Siopi
authors.affiliation: Institut Pasteur, Unité Perception et Mémoire, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3571, F-75015 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Denizet
authors.affiliation: Institut Pasteur, Unité Perception et Mémoire, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3571, F-75015 Paris, France.
authors.forename: Marie-Madeleine
authors.initials: MM
authors.lastname: Gabellec
authors.affiliation: Institut Pasteur, Unité d'Analyse d'Images Quantitative, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2582, F-75015 Paris, France, and.
authors.forename: Fabrice
authors.initials: F
authors.lastname: de Chaumont
authors.affiliation: Institut Pasteur, Unité d'Analyse d'Images Quantitative, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2582, F-75015 Paris, France, and.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivo-Marin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1178, Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry F-92296, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.affiliation: Institut Pasteur, Unité Perception et Mémoire, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3571, F-75015 Paris, France, pmlledo@pasteur.fr lazarini@pasteur.fr.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Lledo
authors.affiliation: Institut Pasteur, Unité Perception et Mémoire, F-75015 Paris, France, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3571, F-75015 Paris, France, pmlledo@pasteur.fr lazarini@pasteur.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lazarini
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000633:toxicity; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001007:Anxiety / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D003345:Corticosterone / Q000633:toxicity; D003863:Depression / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000627:therapeutic use; D006120:Grooming / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D000857:Olfaction Disorders / Q000209:etiology* / Q000473:pathology*; D009831:Olfactory Mucosa / Q000378:metabolism / Q000473:pathology; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000473:pathology; D011930:Reaction Time / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D018687:Antidepressive Agents, Second-Generation; D005473:Fluoxetine; D003345:Corticosterone
keywords: corticosterone; dentate gyrus; olfactory bulb; olfactory epithelium; serotonin; subventricular zone