Antidepressant-Induced Neurogenesis in the Hippocampus of Adult Nonhuman Primates

Abstract

New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the hypothesis that induction of neurogenesis is a necessary component in the mechanism of action of antidepressant treatments. To date, the effects of antidepressants on newborn neurons have been reported only in rodents and tree shrews. This study examines whether neurogenesis is increased in nonhuman primates after antidepressant treatment. Adult monkeys received repeated electroconvulsive shock (ECS), which is the animal analog of electroconvulsive therapy (ECT), the most effective short-term antidepressant. Compared with control conditions, ECS robustly increased precursor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus in the monkey hippocampus. A majority of these precursors differentiated into neurons or endothelial cells, while a few matured into glial cells. The ECS-mediated induction of cell proliferation and neurogenesis was accompanied by increased immunoreactivity for the neuroprotective gene product BCL2 (B cell chronic lymphocytic lymphoma 2) in the SGZ. The ECS interventions were not accompanied by increased hippocampal cell death or injury. This study demonstrates that ECS is capable of inducing neurogenesis in the nonhuman primate hippocampus and supports the possibility that antidepressant interventions produce similar alterations in the human brain.

A small molecule accelerates neuronal differentiation in the adult rat

“…Although adult NPCs hold substantial promise for neural repair after brain injury, their mobilization is hampered by the lack of knowledge about the molecular mechanisms controlling adult neurogenesis under normal and pathophysiological conditions. Pleiotropic signaling molecules [e.g., retinoic acid (RA), Wnt, and brain-derived growth factor (BDNF)] as well as antidepressant and anticonvulsant drugs (e.g., fluoxetin and sodium valproate) have been implicated in regulating adult NPC proliferation, differentiation, or survival in vivo (2)(3)(4)(5)(6)(7)(8). Therefore, it may be possible to develop neurogenic agents for pharmacological intervention specifically directed at the endogenous NPC pool.…”

Stress coping stimulates hippocampal neurogenesis in adult monkeys

“…Antidepressant-induced hippocampal neurogenesis occurs in bonnet monkeys (33) and antidepressant treatments in rodents appear to enhance emotion regulation by increasing neurogenesis in the ventral hippocampal dentate gyrus (1, 7). The neurogenic effect we observed in squirrel monkeys likewise tended to be greater in the anterior (ventral in rodents) compared with posterior (dorsal in rodents) hippocampal dentate gyrus, but this difference in our sample of six subjects in each housing condition was not statistically significant.…”

Adult Neurogenesis and Psychiatric Disorders

“…A large number of studies have found that antidepressants dramatically enhance adult hippocampal neurogenesis in species ranging from rodents to nonhuman primates to humans ( Fig. 1) (Malberg et al 2000;Malberg and Duman 2003;Santarelli et al 2003;Encinas et al 2006;Perera et al 2007;Boldrini et al 2009;Pinnock et al 2009). For example, SSRI or tricyclic antidepressant (TCA)-treated patient groups with major depression had more NESTIN þ neural progenitor cells and Ki-67 þ dividing cells compared with untreated patients or control groups.…”