There is an increased risk for abnormal social behavior in individuals suffering from psychiatric disorders. Unfortunately, while many therapeutic strategies exist to treat such disorders, success rates are surprisingly low regardless of the psychiatric diagnosis. Perhaps less surprising, social disorders such as depression and autism often share common affective symptomatology, including misattributed or maladaptive aggressive behavior, yet it is unclear what neural circuits underlie this shared behavioral feature. Several disparate lines of research now suggest that maladaptive aggression may be caused by dysregulation of brain reward circuitry. Further, even in its non-pathological form, it i accepted that aggression itself can be reinforcing. Despite this evidence, our current understanding of the neurobiological basis of the rewarding component of aggressive behavior is limited. The broad objective of this proposal is to investigate how brain reward circuitry modulates aggression reward. This research will focus on the nucleus accumbens, a key node in brain reward circuitry, which has previously been implicated in regulating social reward and aversion. In order to directly address the connection between aggression and reward we will use a novel behavioral model that is based on aggression conditioned place preference (CPP). In this model, aggressive repeated inter-male social interactions with subordinate intruders in a distinct context lead to th development of aggression CPP to the aggression-paired context. Through a multidisciplinary research plan that utilizes molecular techniques, awake-behaving deep-brain calcium imaging, and chemogenetic manipulations, we will explore the role of the nucleus accumbens direct pathway (dopamine receptor type 1 expressing medium spiny neurons) and indirect pathway (dopamine receptor type 1 expressing medium spiny neurons) projections in regulating aggression reward. We hypothesize that these molecularly defined subpopulations within the NAc are differentially recruited for encoding aggression reward, and that the indirect pathway may be preferentially engaged within aggressive mice exhibiting CPP behavior. Preliminary data demonstrate that the nucleus accumbens is activated by intruder presentations in aggressive, but not non-aggressive, mice; further, expression of aggression CPP is modulated in aggressive mice by a Drd2- anatognist. This series of studies seeks to mechanistically identify how these distinct neuronal populations are differentially recruited for encoding aggression reward, and how these neurons mediate the long-lasting effects on aggression reward experience.
Many neuropsychiatric disorders exhibit abnormal social behavior, including maladaptive aggression. This aggression is believed to be modulated, in part, by brain reward systems. However, our understanding of the circuitry modulating the rewarding component of aggressive behavior is limited. By using a novel mouse model of aggression reward in combination with molecular techniques, awake-behaving deep-brain calcium imaging, and chemogenetic manipulations, we will examine how brain reward neurocircuitry is recruited for, and modulates, aggression reward processing.
| Golden, Sam A; Takahashi, Aki (2018) Combinatorial Psycho-Pharmacological Approaches for the Treatment of Abnormal Aggression. Neuropsychopharmacology 43:233-234 |
| Heshmati, Mitra; Aleyasin, Hossein; Menard, Caroline et al. (2018) Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci U S A 115:1111-1116 |
| Golden, Sam A; Shaham, Yavin (2018) Aggression Addiction and Relapse: A New Frontier in Psychiatry. Neuropsychopharmacology 43:224-225 |
| Golden, S A; Aleyasin, H; Heins, R et al. (2017) Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice. Genes Brain Behav 16:44-55 |
| Golden, Sam A; Heins, Conor; Venniro, Marco et al. (2017) Compulsive Addiction-like Aggressive Behavior in Mice. Biol Psychiatry 82:239-248 |
| Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan et al. (2016) Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534:688-92 |
