ABSTRACT
Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.
Subject(s)
Bone Morphogenetic Proteins/metabolism , Bone Morphogenetic Proteins/physiology , Animals , Anti-Anxiety Agents/metabolism , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Anxiety/drug therapy , Anxiety/metabolism , Bone Morphogenetic Protein 4/metabolism , Bone Morphogenetic Protein 4/physiology , Cell Proliferation/drug effects , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Depression/drug therapy , Depressive Disorder/drug therapy , Fluoxetine/pharmacology , Gene Expression Regulation/drug effects , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Neural Stem Cells/metabolism , Neurogenesis/physiology , Neurons/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Signal Transduction/drug effects , Stem Cells/metabolismABSTRACT
The prefrontal cortex is a higher brain region that regulates thought, behavior, and emotion using representational knowledge, operations often referred to as working memory. We tested the influence of protein kinase C (PKC) intracellular signaling on prefrontal cortical cognitive function and showed that high levels of PKC activity in prefrontal cortex, as seen for example during stress exposure, markedly impair behavioral and electrophysiological measures of working memory. These data suggest that excessive PKC activation can disrupt prefrontal cortical regulation of behavior and thought, possibly contributing to signs of prefrontal cortical dysfunction such as distractibility, impaired judgment, impulsivity, and thought disorder.
Subject(s)
Memory/physiology , Prefrontal Cortex/physiology , Protein Kinase C/metabolism , Adrenergic alpha-Agonists/pharmacology , Alkaloids , Animals , Benzophenanthridines , Carbolines/pharmacology , Electrophysiology , Enzyme Activation , Female , Imidazoles/pharmacology , Lithium Carbonate/pharmacology , Macaca mulatta , Male , Memory/drug effects , Neurons/drug effects , Neurons/physiology , Phenanthridines/pharmacology , Prefrontal Cortex/enzymology , Protein Kinase C/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-1/physiology , Signal Transduction , Stress, Physiological/physiopathology , Tetradecanoylphorbol Acetate/pharmacology , Valproic Acid/pharmacologyABSTRACT
BACKGROUND: Stress exacerbates many neuropsychiatric disorders associated with prefrontal cortical (PFC) dysfunction. Stress also impairs the working memory functions of the PFC. Although stress research has focused on dopaminergic mechanisms, stress also increases norepinephrine (NE) release in PFC, and intra-PFC infusions of NE alpha-1-adrenoceptor agonists impair working memory. The current study examined whether NE alpha-1-adrenoceptor actions in PFC contribute to stress-induced deficits in working memory performance. METHODS: Rats were treated with a pharmacological stressor, FG7142 (30 mg/kg) or vehicle 30 min before testing on a test of spatial working memory, delayed alternation. The alpha-1-adrenoceptor antagonist, urapidil (0.1 microgram/0.5 microL), or saline vehicle, was infused into the PFC 15 min before delayed alternation testing. RESULTS: As observed previously, FG7142 significantly impaired the accuracy of delayed alternation performance, and induced a perseverative pattern of responding consistent with PFC dysfunction. FG7142 also slowed motor response times. Infusion of urapidil into the PFC completely reversed the FG7142-induced impairment in delayed alternation performance, but did not alter the slowed motor responding. CONCLUSIONS: These findings indicate that alpha-1-adrenoceptor stimulation in the PFC contributes to stress-induced impairments in PFC cognitive functions. These neurochemical actions may contribute to symptoms of working memory impairment, poor attention regulation, or disinhibited behaviors in neuropsychiatric disorders sensitive to stress exposure.
