The objective of this application is to test the hypothesis that: 1) early developmental stages are critically important for monoamine oxidase (MAO) A to induce long-term effects on neuroplasticity and aggression through the regulation of serotonin (5-hydroxytryptamine, 5-HT) levels and the activation of 5-HT receptors in forebrain regions;and 2) environmental stress interacts with MAO A to modulate these processes. MAO A is the key enzyme in 5-HT metabolism, and its deficiency results in increased 5-HT levels and increased aggression in humans and mice. 5-HT in forebrain regions (frontal cortex, amygdala and hippocampus) modulates aggression as well as dendrite and spine morphology in pyramidal neurons.
The specific aims are outlined below: 1: To identify which early developmental stages are critical for the effects of 5-HT on aggression and dendritic morphology and spine density in pyramidal neurons of frontal cortex, amygdala and hippocampus in MAO A knockout (KO) mice. MAO A KO mice will be injected with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) during each of the 5 weeks of forebrain 5-HT innervation (E16-P28),to normalize the increased 5-HT levels in their forebrain regions. 5-HT levels will be determined by HPLC. Aggression and other related behaviors will be tested in adult mice (P60). Once we identify the critical stage for 5-HT role in behavior, we will study dendrite and spine morphology of 5-HT-targeted pyramidal neurons in forebrain regions, using light microscopy on Golgi-Cox stained brain sections as well as fluorescence microscopy on sections with 5-HT receptor labels and retrograde label of dendritic processes. 2: To identify what 5-HT receptors mediate the effects of 5-HT on aggression and dendritic morphology in forebrain regions of MAO A KO mice during the critical developmental stages. After treating MAO A KO mice with PCPA at the critical stages, we will quantify 5-HT1A, 5-HT1B and 5-HT2A receptors (mRNA levels) in their forebrain regions, by RT-PCR. To study the role of each receptor in behavior and morphology, we will inject MAO A KO mice with selective antagonists of specific 5-HT receptors during the specific critical stages, and determine which receptor blockade attenuates aggression and morphological alterations at P60. 3: To test the hypothesis that the interaction between MAO A and acute or chronic environmental stress induces specific changes in 5-HT in forebrain regions, which result in increased aggression and altered dendrite and spine morphology. We will study the impact of acute and chronic restraint stress on the behavior and brain morphology of MAO A KO mice. These studies will provide a significant contribution to basic and clinical research, by elucidating the impact of developmental mechanisms and stress on aggression, and shed light on new preventive and therapeutic strategies for aggression and other psychiatric disorders, including alcohol and drug abuse.

Public Health Relevance

This application will study the role of monoamine oxidase (MAO) A during critical developmental stages and in specific forebrain regions on the regulation of serotonin levels, brain morphology and aggressive and related emotional behaviors. The interaction between MAO A and environmental stress and its impact on these phenomena will also be studied. This research will provide critically important findings for the understanding of the molecular bases and the brain circuitry of aggression. It will also shed new light on preventive, diagnostic and therapeutic strategies for aggression and other mental disorders associated with abnormal monoamine neurotransmission.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Nadler, Laurie S
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University of Southern California
Schools of Pharmacy
Los Angeles
United States
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