Maternal aggression (protection of offspring) provides a nexus for understanding two important mental health issues: emotional changes that occur during the postpartum period and fierce reactive aggression. Maternal aggression (also called maternal defense) is a powerful form of reactive aggression that is produced in the defense of offspring and is highly conserved in mammals ranging from humans to mice. Our long-term goal is to understand the functional neuronal circuitry of maternal aggression. The objective of this application is to determine how beta adrenergic and GABA A receptor signaling in lateral septum (LS) act to regulate maternal aggression. The central hypothesis of the application is that lowering of beta adrenergic receptor signaling in LS is a key step for elevating maternal aggression, while lowering GABA A receptor signaling in LS is a key step in reducing aggressive output. LS contains a large number of GABA-positive neurons, many of which project outside of LS, and we propose that these GABA-positive projection neurons contain and are regulated by beta adrenergic and GABA A receptors in LS. The rationale for the proposed research is that once the mechanisms by which beta adrenergic and GABA A receptors regulate maternal aggression in LS are known, we will gain important insights into neuronal changes during lactation that shed light on postpartum mood disorders. We will also gain information on the basis of fierce reactive aggressive outburst in humans that is expected to provide insights into new interventions. Consequently, the proposed research is relevant to NIH's mission to reduce the burden of mental illness and behavioral disorders. Guided by strong preliminary data, the hypothesis will be tested by pursuing two specific aims: 1) Identify the key receptors that act in LS to regulate maternal aggression;and 2) Identify the neuronal population in LS that is regulated by beta adrenergic and GABA A receptors. Under the first aim, site-specific injection approaches will be used to modulate beta adrenergic and GABA A receptor activity and test effects on maternal aggression. Established Western blotting and real-time PCR techniques will be used to determine the extent to which these receptors show altered expression in association with changes in aggression. Under the second aim, gene expression approaches will be used to identify changes in GABA synthesis that occur in LS in association with changes in aggression. Double/triple labeling approaches along with anterograde and retrograde tracing will be used to determine the extent to which GABA-positive neurons in LS contain GABA A and beta adrenergic receptors and to identify the downstream brain regions that are targets of the GABA-positive projection neurons in LS. The proposed work is innovative because it combines an array of behavioral, pharmacologic, neurobiological, and neurochemical methods to examine an important, but understudied area of maternal aggression. The proposed research is significant, because it will provide critical missing information on how fierce reactive aggression is produced and provide insights into mood changes during the postpartum period.

Public Health Relevance

The proposed studies are on maternal aggression, an important and under-investigated area that has potential applicability to understanding two mental health issues. One benefit of this research is that it is expected to provide insights into neurobiological and emotional changes that occur within the postpartum period and promote new ideas for treatments of postpartum mood disorders. Another benefit of this research is that it is expected to provide insights into the production of maladaptive fierce reactive aggression and open avenues for developing interventions to reduce aggression in humans.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Simmons, Janine M
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Saul, Michael C; Stevenson, Sharon A; Zhao, Changjiu et al. (2018) Genomic variants in an inbred mouse model predict mania-like behaviors. PLoS One 13:e0197624
Driessen, Terri M; Zhao, Changjiu; Saenz, Marissa et al. (2018) Down-regulation of fatty acid binding protein 7 (Fabp7) is a hallmark of the postpartum brain. J Chem Neuroanat 92:92-101
Gammie, Stephen C; Driessen, Terri M; Zhao, Changjiu et al. (2016) Genetic and neuroendocrine regulation of the postpartum brain. Front Neuroendocrinol 42:1-17
Saul, M C; Zhao, C; Driessen, T M et al. (2016) MicroRNA expression is altered in lateral septum across reproductive stages. Neuroscience 312:130-40
Zhao, Changjiu; Gammie, Stephen C (2015) Metabotropic glutamate receptor 3 is downregulated and its expression is shifted from neurons to astrocytes in the mouse lateral septum during the postpartum period. J Histochem Cytochem 63:417-26
Zhao, Changjiu; Gammie, Stephen C (2014) Glutamate, GABA, and glutamine are synchronously upregulated in the mouse lateral septum during the postpartum period. Brain Res 1591:53-62
Driessen, Terri M; Eisinger, Brian E; Zhao, Changjiu et al. (2014) Genes showing altered expression in the medial preoptic area in the highly social maternal phenotype are related to autism and other disorders with social deficits. BMC Neurosci 15:11
Zhao, Changjiu; Eisinger, Brian; Gammie, Stephen C (2013) Characterization of GABAergic neurons in the mouse lateral septum: a double fluorescence in situ hybridization and immunohistochemical study using tyramide signal amplification. PLoS One 8:e73750
Saul, Michael C; Stevenson, Sharon A; Gammie, Stephen C (2013) Sexually dimorphic, developmental, and chronobiological behavioral profiles of a mouse mania model. PLoS One 8:e72125
Eisinger, Brian E; Saul, Michael C; Driessen, Terri M et al. (2013) Development of a versatile enrichment analysis tool reveals associations between the maternal brain and mental health disorders, including autism. BMC Neurosci 14:147

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