Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.

https://science.sciencemag.org/content/sci/301/5634/805.full.pdf

Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

A neurotrophic model for stress-related mood disorders.

Mechanisms and functional implications of adult neurogenesis.

https://sites.oxy.edu/clint/physio/article/neurobiologyofdepression.pdf

Neurobiology of depression.

Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.

/pdf/the-molecular-neurobiology-of-depression-19u214boy3.pdf

The molecular neurobiology of depression

Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment.

https://www.jneurosci.org/content/jneuro/22/8/3251.full.pdf

Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression

Neuronal plasticity and survival in mood disorders

The cAMP cascade, including the cAMP response element-binding protein (CREB), is known to play an important role in neuronal survival and plasticity. Here the influence of this cascade on neurogenesis in adult hippocampus was determined. Activation of the cAMP cascade by administration of rolipram, an inhibitor of cAMP breakdown, increased the proliferation of newborn cells in adult mouse hippocampus. In addition, rolipram induction of cell proliferation resulted in mature granule cells that express neuronal-specific markers. Increased cell proliferation is accompanied by activation of CREB phosphorylation in dentate gyrus granule cells, suggesting a role for this transcription factor. This possibility is supported by studies demonstrating that cell proliferation is decreased in conditional transgenic mice that express a dominant negative mutant of CREB in hippocampus. The results suggest that the cAMP–CREB cascade could contribute to the actions of neurotransmitters and neurotrophic factors on adult neurogenesis.

https://www.jneurosci.org/content/jneuro/22/9/3673.full.pdf

Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.

http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Neurogenesis/7ng2002.pdf

Regulation of Adult Neurogenesis by Antidepressant Treatment

Proliferation and maturation of neurons has been demonstrated to occur at a significant rate in discrete regions of adult brain, including the hippocampus and subventricular zone. Moreover, adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors. It has been suggested to play a role in several important neuronal functions, including learning, memory, and response to novelty. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, and drug abuse. As the mechanisms that control adult neurogenesis continue to be identified, the exciting prospect of developing pharmacological agents that specifically regulate the proliferation and maturation of neurons in the adult brain could be fulfilled.

Shin Nakagawa

Papers

Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression

Neuronal plasticity and survival in mood disorders

Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein.

Regulation of Adult Neurogenesis by Antidepressant Treatment

Regulation of adult neurogenesis by psychotropic drugs and stress.