Stephen C. Gammie - US grants

behavioral /social science research tag; laboratory mouse

DESCRIPTION (provided by applicant): To help understand and mitigate human aggression, it is critical to develop appropriate animal models to understand all the different forms of aggression. Maternal aggression is a fierce aggression exhibited towards intruders by lactating female rodents when they are protecting their pups, that may share similarities with other short-lived, but fierce forms of human aggression. The goal of this proposed research, submitted by a new investigator, is to examine the neural basis of maternal aggression in mice. During lactation, decreases in corticotropin releasing hormone (CRH) neurotransmission have been linked to decreases in fear and anxiety. Because maternal aggression is high when fear and anxiety are low, it is possible that decreases in fear are necessary for a dam to be able to attack a normally fear evoking stimulus. Despite a possible link to maternal aggression, no work has systematically examined whether, or how, CRH plays a role in the control of this important social behavior. The studies proposed here test the hypothesis that regulation of CRH during lactation plays a necessary role in switching on maternal aggression. Consistent with this hypothesis we have collected evidence that intracerebroventricular (icv) injections of CRH inhibit maternal aggression and that decreases in endogenous CRH due to developmental intervention increase levels of maternal aggression. The three studies of this proposal will extend these preliminary findings and use multiple approaches to investigate further the role of CRH in maternal aggression. 1) Conduct icv injections of CRH, and a related peptide, urocortin III, and two CRH receptor antagonists to the lateral ventricle to determine the effect on maternal aggression. 2) Examine whether and where levels of CRH mRNA are decreased in mice that exhibit increased levels of maternal aggression due to a developmental intervention. 3) Examine levels of maternal aggression in mice that are missing either the CRH receptor 1 gene, or the CRH receptor 2 gene relative to control mice. Each study will also use indirect markers for neuronal activity, cFOS and FosB, to identify brain regions where CRH may be interacting with maternal aggression circuitry. Many studies have focused on male aggression, but far less is known about the neural basis of female aggression and preliminary results indicate that CRH has the opposite effect on male and maternal aggression. Basic research into sex differences in aggression, then, is important to understanding the biological underpinnings of sex and gender differences in social behavior, health, and disease.

DESCRIPTION (provided by applicant): To help understand and mitigate human aggression, it is critical to develop appropriate animal models to understand all the different forms of aggression. Maternal aggression is a fierce aggression exhibited towards intruders by lactating female rodents when they are protecting their pups, that may share similarities with other short-lived, but fierce forms of human aggression. The goal of this proposed research, submitted by a new investigator, is to examine the neural basis of maternal aggression in mice. During lactation, decreases in corticotropin releasing hormone (CRH) neurotransmission have been linked to decreases in fear and anxiety. Because maternal aggression is high when fear and anxiety are low, it is possible that decreases in fear are necessary for a dam to be able to attack a normally fear evoking stimulus. Despite a possible link to maternal aggression, no work has systematically examined whether, or how, CRH plays a role in the control of this important social behavior. The studies proposed here test the hypothesis that regulation of CRH during lactation plays a necessary role in switching on maternal aggression. Consistent with this hypothesis we have collected evidence that intracerebroventricular (icv) injections of CRH inhibit maternal aggression and that decreases in endogenous CRH due to developmental intervention increase levels of maternal aggression. The three studies of this proposal will extend these preliminary findings and use multiple approaches to investigate further the role of CRH in maternal aggression. 1) Conduct icv injections of CRH, and a related peptide, urocortin III, and two CRH receptor antagonists to the lateral ventricle to determine the effect on maternal aggression. 2) Examine whether and where levels of CRH mRNA are decreased in mice that exhibit increased levels of maternal aggression due to a developmental intervention. 3) Examine levels of maternal aggression in mice that are missing either the CRH receptor 1 gene, or the CRH receptor 2 gene relative to control mice. Each study will also use indirect markers for neuronal activity, cFOS and FosB, to identify brain regions where CRH may be interacting with maternal aggression circuitry. Many studies have focused on male aggression, but far less is known about the neural basis of female aggression and preliminary results indicate that CRH has the opposite effect on male and maternal aggression. Basic research into sex differences in aggression, then, is important to understanding the biological underpinnings of sex and gender differences in social behavior, health, and disease.

Aggression is found in a wide range of species. Reactive aggression is triggered by a perceived threat to oneself or one's resources and accounts for high levels of aggression across species. Maternal aggression (also called maternal defense) is a powerful form of reactive aggression that is produced in the defense of offspring. It is found in species ranging from humans to mice and is notable because females can be peaceful and nurturing one moment and then fiercely aggressive the next. An understanding of how fierce aggressive outbursts can occur in an otherwise peaceful individual is still missing and maternal aggression therefore provides an excellent model for understanding the biological basis of this form of aggression. This project will examine the neurobiological basis of maternal aggression and will focus on the neurotransmitter neurotensin. This work is expected to provide novel insights into the regulation of aggression because, until recently, no studies had linked neurotensin to aggression. It is expected that the results from these studies will determine where and how neurotensin acts in the brain to regulate maternal aggression. Behavioral, pharmacological, and biochemical approaches will be used in a mouse model system. Because this research examines aggression during reproduction, another possible benefit is that the research will provide insights into emotional changes that occur during the postpartum period. These studies will provide training opportunities in neuroscience for undergraduate, graduate students, and postdoctoral fellows. Underrepresented minority high school and undergraduate students will participate in these projects as part of programs that promote the involvement of underrepresented minorities in science. The studies will also strengthen links within and outside the scientific community and results from studies will be disseminated to a broad audience via press releases and other media outlets.

DESCRIPTION (provided by applicant): 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.

? DESCRIPTION (provided by applicant): Social deficits are characteristic of most major mental health disorders, including depression, bipolar disorder, schizophrenia, and autism. In many cases, social interactions that were once rewarding become aversive and individuals become withdrawn. Despite the negative impact that social withdrawal has on the individual and family, the mechanisms are unknown and treatments are lacking. The proposed research will fill this important gap by identifying neural mechanisms that naturally promote social interactions, which can be used to develop treatment options. The research turns to novel insights from the postpartum brain and applies them to non- parental adults. Naïve prepartum female mice find social interactions with mouse pups to have low valence; however, postpartum females find social interactions with pups to be intensely rewarding. It is possible that the reward mechanisms altered in mothers may represent fundamental mechanisms that promote sociability across social contexts. Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) (also known as Rev erb alpha) is of great interest because striking and reliable decreases in Nr1d1 expression occur in postpartum (i.e., prosocial) compared to prepartum mice in multiple brain regions regulating reward, including nucleus accumbens (NAC). Nr1d1 is a transcription factor involved in circadian rhythm regulation, but recent work suggests a key role for Nr1d1 in reward-related processes as well as disorders with social deficits, such as depression. Depression is associated with dysregulation of reward pathways and Nr1d1 may be the link between reward, social behavior, and depression. Recent work indicates that Nr1d1 in NAC interacts with and possibly regulates numerous reward-related genes. Still, the role of Nr1d1 in NAC in social reward is not known. The long- term goal is to understand the basis of changes in sociability with the possibility of opening avenues for devel- oping treatments to improve social deficits in humans. The objective here is to determine how decreases in Nr1d1 in NAC regulate social reward. Our central hypothesis is that decreases in Nr1d1 in NAC will improve social reward in a non-reproductive context. The rationale is that the findings will contribute key, missing information on the role of Nr1d1 in NAC on modulating social reward. In order to test the central hypothesis and accomplish the objective of the application, the following two specific aims are proposed. 1. Identify effects of decreasing Nr1d1 in NAC on social reward-related behaviors. 2. Identify effects of decreasing Nr1d1 in NAC on CNS processes using microarrays and bioinformatics approaches. Bioinformatics analysis will highlight pathways related to addiction/reward, mental health, neuronal activity, transcriptional regulation, and circadian rhythms. The approach is innovative as is the concept that Nr1d1 is a critical trigger for social reward. This work is significant because it will provide novel insights into new approaches on how to improve sociability. These studies will provide specific information about how Nr1d1 functions in adults to regulate social reward and could provide insights for understanding dysregulation in adults.