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In this essay, changes in the human hippocampal volume and function induced by stress, depression and physical exercise are examined. Hippocampus is crucially involved in the acquisition and retrieval of episodic and spatial memory, and hippocampal volume correlates with episodic and spatial memory performance. Hippocampus has substantial plasticity and changes with age, but also in response to experiential factors across life. Stress and, under at least some circumstances, also depression have negative effects on hippocampal volume and memory function. The negative effects are believed to accelerate age-related decline in volume and function, mediated by exaggerated cortisol levels and dysfunction in the HPA-axis. Physical exercise is examined from two perspectives; aerobic and strength exercise. Aerobic exercise increases hippocampal volume across various ages and decelerates age-related hippocampal degeneration, whereas support for strength exercise-induced effects are mixed and need to be studied further. The positive effects are believed to be mediated by increased BDNF levels and regional cerebral blood volume. Although hippocampal volume normally correlates with hippocampus-dependent memory, studies on exercise-induced changes in human hippocampus-dependent memory have reported inconsistent results. Animal studies have observed both the negative and positive effects on hippocampal volume to relate to changes in neurogenesis, cell proliferation, and dendritic complexity. The negative and positive effects on hippocampal volume have been observed to be non-permanent, suggesting that physical exercise may prevent, attenuate and possibly reverse hippocampal degeneration induced by stress and depression. Further, more studies on sex and age differences, exercise intervention designs and functional values of physical exercise would be of value.

Indiana University-Purdue University Indianapolis (IUPUI) / New neurons are generated throughout adulthood in two regions of the brain, the dentate gyrus of the hippocampus, which is important for memory formation and cognitive functions, and the sub-ventricular zone of the olfactory bulb, which is important for the sense of smell, and are incorporated into hippocampal network circuitry. Disruption of this process has been postulated to contribute to neurodegenerative disorders including Alzheimer’s disease [1]. AD is the most common form of adult-onset dementia and the number of patients with AD escalates dramatically each year. The generation of new neurons in the dentate gyrus declines with age and in AD. Many of the molecular players in AD are also modulators of adult neurogenesis, but the genetic mechanisms influencing adult neurogenesis in AD are unclear. The overall goal of this project is to identify candidate genes and pathways that play a role in neurogenesis in the adult brain and to test the hypotheses that 1) hippocampal neurogenesis-related genes and pathways are significantly perturbed in AD and 2) neurogenesis-related pathways are significantly associated with hippocampal volume and other AD-related biomarker endophenotypes including brain deposition of amyloid-β and tau pathology. First, potential modulators of adult neurogenesis and their roles in neurodegenerative diseases were evaluated. Candidate genes that control the turnover process of neural stem cells/precursors to new functional neurons during adult neurogenesis were manually curated using a pathway-based systems biology approach. Second, a targeted neurogenesis pathway-based gene analysis was performed resulting in the identification of ADORA2A as associated with hippocampal volume and memory performance in mild cognitive impairment and AD. Third, a genome-wide gene-set enrichment analysis was conducted to discover associations between hippocampal volume and AD related endophenotypes and neurogenesis-related pathways. Within the discovered neurogenesis enriched pathways, a gene-based association analysis identified TESC and ACVR1 as significantly associated with hippocampal volume and APOE and PVLR2 as significantly associated with tau and amyloid beta levels in cerebrospinal fluid. This project identifies new genetic contributions to hippocampal neurogenesis with translational implications for novel therapeutic targets related to learning and memory and neuroprotection in AD.

Introduction : Issus des données animales, les modèles neurotrophiniques du mécanisme d’action des médicaments antidépresseurs pourraient permettre d’identifier chez l’Homme des biomarqueurs prédictifs de la réponse et de la rémission sous antidépresseurs. Nous évaluons l’intérêt clinique, chez les patients souffrant de trouble dépressif caractérisé unipolaire, de 11 biomarqueurs : polymorphismes nucléotidiques simples (SNP) du Brain Derived Neurotrophic Factor (BDNF) et de son récepteur, le Récepteur Tyrosine-Kinase B (TRKB), taux plasmatiques de BDNF et volume hippocampique sur la réponse/rémission sous antidépresseurs. Méthode : Les données originales de ce travail sont issues de la cohorte METADAP. Il s’agit d’une cohorte, prospective, multicentrique incluant 624 patients présentant un épisode dépressif caractérisé dans le cadre d’un trouble dépressif caractérisé unipolaire et nécessitant l’introduction d’un traitement antidépresseur. Le traitement antidépresseur est prescrit de façon naturaliste (tous antidépresseurs commercialisés en France). Les patients sont évalués 1, 3 et 6 mois après l’introduction du traitement antidépresseur. Les biomarqueurs étudiés sont les polymorphismes Val66Met du BDNF et 8 SNP du TRKB et les dosages de BDNF plasmatiques. Une étude ancillaire est menée à partir de 63 patients ayant bénéficié d’Imagerie par Résonnance Magnétique cérébrale réalisée en pratique courante à l’inclusion de cette cohorte afin d’évaluer les volumes hippocampiques. Résultats : 1) Une revue de la littérature met en évidence une association entre la réponse aux antidépresseurs et 12 SNP du BDNF/TRKB sur 242 étudiés, ainsi qu’une association entre allèle Met du polymorphisme Val66Met du BDNF et meilleure réponse sous antidépresseurs chez les patients asiatiques. 2) Nos données ne mettent pas en évidence d’impact de 8 SNP du TRKB sur la réponse/rémission après traitement antidépresseur, mais un effet différentiel du Val66Met du BDNF selon la classe de traitement antidépresseur. 3) L’étude des dosages de BDNF plasmatiques n’est pas concluante. 4) Concernant les volumes hippocampiques, notre méta-analyse montre que des volumes hippocampiques moindres prédisent une moindre réponse/rémission après traitement antidépresseur. 5) Concernant les liens entre les biomarqueurs étudiés, nous ne mettons pas en évidence d’association. Conclusion : Sur les 11 biomarqueurs étudiés, seuls 2 pourraient présenter une utilité en pratique clinique. Si nos travaux étaient répliqués, le polymorphisme Val66Met du BDNF et le volume hippocampique pourraient conduire à orienter le choix des antidépresseurs dans le traitement des épisodes dépressifs caractérisés. Malgré une littérature cohérente chez l’Animal, nous n’avons pas mis en évidence, dans l’échantillon étudié, de lien entre les biomarqueurs génétiques étudiés et les volumes hippocampiques. Nous poursuivons ce travail d’évaluation des biomarqueurs neurotrophiniques et neurogéniques avec des méthodes d’évaluations nouvelles : séquençage nouvelle génération pour la génétique et imagerie multimodale (acquisition répétée d’IRM structurelle, fonctionnelle et de diffusion) de l’hippocampe. Nous évaluerons également de nouveaux biomarqueurs. / Introduction: developed with Animal preclinical approachs, neurtrophinic and neurogenic models of antidepressant mechanism of action lead to identify biomarkers in Human which could be predict antidepressant response and remission in depressed patients. We assess the clinical benefit of 11 biomarkers in depressed patients: Brain Derived Neurotrophic Factor (BDNF) and its receptor Tyrosine Receptor -Kinase B (TRKB), Plasma BDNF and Hippocampal volumes to predict antidepressant response/remission. Methods: The original research data of this work are from METADAP cohort. It is a prospective, multicentric cohort including 624 patients with a diagnosis of major depressive disorder and a current major depressive episode at the start of the index antidepressant treatment. Antidepressant treatment is prescribed in naturalistic conditions (all commercialized antidepressant in France). Patient are assessed 1, 3 and 6 months after the start of antidepressant treatment. Studied biomarkers are BDNF Val66Met polymorphism, 8 TRKB SNP and plasma BDNF. Ancillary study are done with 63 patients which benefit in clinical practice of Magnetic Resonnance (MRI) at the inclusion of the cohort. Results: 1) A review of literature reports associations between antidepressant efficacy and 12 BDNF/TRKB SNP on 242 studied SNP and an association with Met allele of Val66Met BDNF polymorphism and a best antidepressant efficacy in Asian patients. 2) Our original data show no impact of 8 TRKB SNP on antidepressant response remission but a differential effect of Val66Met BDNF polymorphism depending on antidepressant treatment class. 3) Plasma BDNF study is not conclusive. 4) Concerning hippocampal volumes, our meta-analysis show that smaller hippocampal volumes predict lower response/remission rate after antidepressant treatment. 5) No association is found between studied biomarkers. Conclusion: 2 of the 11 studied biomarkers could be useful in clinical practice. After replication of our results, Val66Met polymorphism could lead to personalized antidepressant prescription in major depressive disorder. Although the animal prelinical littérature appar strong, we dont report association between genetic biomarker and hippocampal volume in ours ample. We will assess neurotrophinic and neurogenic biomarkers with new methods: next generation sequencing for genetic, multimodal imaging (repeated structural, functional and diffusion MRI) of hippocampus. We also will assess new biomarkers.