Schmidt HD, Duman RS. The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18: 391-418
Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Department of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA. Behavioural Pharmacology
(Impact Factor: 2.15).
10/2007; 18(5-6):391-418. DOI: 10.1097/FBP.0b013e3282ee2aa8
Major depressive disorder (MDD) is characterized by structural and neurochemical changes in limbic structures, including the hippocampus, that regulate mood and cognitive functions. Hippocampal atrophy is observed in patients with depression and this effect is blocked or reversed by antidepressant treatments. Brain-derived neurotrophic factor and other neurotrophic/growth factors are decreased in postmortem hippocampal tissue from suicide victims, which suggests that altered trophic support could contribute to the pathophysiology of MDD. Preclinical studies demonstrate that exposure to stress leads to atrophy and cell loss in the hippocampus as well as decreased expression of neurotrophic/growth factors, and that antidepressant administration reverses or blocks the effects of stress. Accumulating evidence suggests that altered neurogenesis in the adult hippocampus mediates the action of antidepressants. Chronic antidepressant administration upregulates neurogenesis in the adult hippocampus and this cellular response is required for the effects of antidepressants in certain animal models of depression. Here, we review cellular (e.g. adult neurogenesis) and behavioral studies that support the neurotrophic/neurogenic hypothesis of depression and antidepressant action. Aberrant regulation of neuronal plasticity, including neurogenesis, in the hippocampus and other limbic nuclei may result in maladaptive changes in neural networks that underlie the pathophysiology of MDD.
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- "While it has long been postulated that adult DG neurogenesis contributes to the behavioral improvement seen after antidepressant administration, and reduced adult DG neurogenesis contributes to depressive-and anxiety-like behavior, as detailed below data from preclinical studies are conflicting, and more work is needed to test the proposed causal relationship. Preclinically, adult DG neurogenesis appears to be required for antidepressant efficacy[15,16,192021222324, and progenitors are a key target of antidepressant drugs25262728. However, preclinical studies do not agree on whether the disruption of neurogenesis (e.g. via ablation of progenitors , neuroblasts/immature neurons, and/or their progeny) leads to depressive-and anxietylike behavior[21,2829303132. "
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ABSTRACT: Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors.
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- "In addition to NF-L, brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal plasticity. BDNF strongly affects synaptogenesis, spine formation , neuronal survival , long-term potentiation, neuronal excitability , and adult hippocampal neurogenesis . The transcription of several genes, such as BDNF, is stimulated by activating the phosphorylation of cAMP response element-binding "
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ABSTRACT: Adverse early life experiences can negatively affect behaviors later in life. Maternal separation (MS) has been extensively investigated in animal models in the adult phase of MS. The study aimed to explore the mechanism by which MS negatively affects C57BL/6N mice, especially the effects caused by MS in the early phase. Early life adversity especially can alter plasticity functions. To determine whether adverse early life experiences induce changes in plasticity in the brain hippocampus, we established an MS paradigm. In this research, the mice were treated with mild (15 min, MS15) or prolonged (180 min, MS180) maternal separation from postnatal day 2 to postnatal day 21. The mice underwent a forced swimming test, a tail suspension test, and an open field test, respectively. Afterward, the mice were sacrificed on postnatal day 31 to determine the effects of MS on early life stages. Results implied that MS induces depression-like behavior and the effects may be mediated partly by interfering with the hippocampal GSK-3
-CREB signaling pathway and by reducing the levels of some plasticity-related proteins.
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- "The chronic unpredictable stress (CUS) model has been shown to produce a chronic depressive-like phenotype in rats that is responsive to long-term (3 weeks), but not acute or shortterm , antidepressant treatment (Schmidt and Duman, 2007). CUS also causes atrophy of neurons in rodent prefrontal cortex and hippocampus (Radley and Morrison, 2005; Goldwater et al., 2009), effects that could contribute to the decreased volume of these regions reported in brain imaging studies of patients with major depressive disorder (Drevets et al., 2008; Cole et al., 2011). "
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