Neurogenesis, or the generation of new neurons, occurs in the dentate gyrus (DG) of the hippocampal formation (HF) and it is increased by antidepressant treatment (ADT) in adult mammals including humans. Decreased neurogenesis is hypothesized in major depressive disorder (MDD). Neurogenesis occurs together with the generation of new vasculature (angiogenesis) and both are stimulated by trophic factors in rodents. Angiogenesis is necessary for new neurons to differentiate and survive and cerebral blood volume has been proposed as a surrogate in vivo measure of neurogenesis. It has not been examined if trophic factors expression is correlated with neurogenesis and angiogenesis in the human brain. Studies will be carried out in three groups: 1. Patients with Mood Disorder (MDD, n=10) who were on antidepressants (MDDT, five treated with selective serotonin reuptake inhibitors, MDD*SSRI, five treated with tricyclic antidepressants, MDD*TCA) at the time of death;2. MDD patients (n=10) who were not on antidepressants for 3 months and 3. normal, non-psychiatric controls (NC, n=10). The three groups will be matched for sex, age (between 24 and 62 in the whole sample), postmortem interval (PMI) and race. All cases, including controls, will have psychological autopsies according to DSM Axis I diagnosis, neuropathologic examination and toxicological screen. Immunocytochemistry for vascular endothelial growth factor (VEGF), its receptor VEGFR-2, brain derived neurotrophic factor (BDNF), its receptor TrkB will be used to identify their expression in HF cells. Vessels will be stained with nestin and double-labeled with CD31 (marker of endothelial cells). Neural progenitor cells (NPCs) will be identified by nestin stain, dividing cells by Ki-67 stain, mature neurons by neuronal-specific nuclear protein (NeuN) and their dendrites labeled by and neurofilament stain. The rostrocaudal extent of the right HF will be used for the study and series of sections at 2mm intervals will be assayed for each antibody. Stereology will be used to estimate the number of labeled cell in the whole HF, vessel area and volume, neuron size and dendrites length. We will test the hypotheses that: the number of NPCs and mitotic cells in the DG is proportional to the number of cells expressing VEGF, BDNF and their receptors in the HF, which will be greater in MDDT compared to MDD and NC;neuron number, size and dendrite length is proportional to the number of cells expressing VEGF, BDNF and their receptors in the HF and that they will be greater in MDDT vs MDD and NC;vessel area and volume are proportional to the number of cells expressing VEGF, BDNF and their receptors in the HF and that they will be greater in MDDT compared to MDD and NC. These results have implications for understanding the possibility to use trophic factors as ADT in MDD.

Public Health Relevance

Major Depression (MDD) is a serious public health problem and antidepressant treatment (ADT) is not effective in all cases. There is evidence that neuronal replication (neurogenesis) occurs in adult mammals including humans and it occurs together with the generation of new vasculature (angiogenesis). Trophic factors might play a crucial role in support of these phenomena and angiogenesis appears necessary for ADT to work in rodents and therefore, we propose to examine the expression of trophic factors and its correlation with neurogenesis and angiogenesis in MDD patients, with and without ADT, compared to normal controls.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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New York State Psychiatric Institute
New York
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Boldrini, Maura; Butt, Tanya H; Santiago, Adrienne N et al. (2014) Benzodiazepines and the potential trophic effect of antidepressants on dentate gyrus cells in mood disorders. Int J Neuropsychopharmacol 17:1923-33
Wu, Melody V; Shamy, Jul Lea; Bedi, Gillinder et al. (2014) Impact of social status and antidepressant treatment on neurogenesis in the baboon hippocampus. Neuropsychopharmacology 39:1861-71