Abnormal social behavior, such as maladaptive aggression or social anxiety to a lack of interest in social relationships, is associated with a number of neuropsychiatric disorders including schizophrenia, mood disorders and autism. Such disruptions in social behavior are thought to result, in part, from inappropriate activation of brain reward systems in response to social stimuli. A series of nuclei within the ventral midbrain that control mood and emotion are known to encode certain aspects of aggressive and nonaggressive social interaction; however, little is known about the neural circuit mechanisms that directly modulate the motivational or rewarding component of social behavior. To address this question, we established a mouse behavioral model for investigating individual differences in social behavior. In this model, approximately 70% of outbred mice engage in aggressive behavior with a resident intruder and find such interaction rewarding, whereas the remaining 30% are not aggressive at all and find intruder interactions aversive. The lateral habenula (LHb) is a major hub within the brain's reward circuit and can encode information about positive and negative social stimuli. Interestingly, the LHb is differentially activated by intruder-based social interaction in aggressive and nonaggressive mice and we hypothesize that it plays a critical role in mediating social behavior. Indeed, our preliminary results show that the neuropeptide, orexin (also known as hypocretin) signals directly within the LHb to control initiation of aggressive social behavior and the valence of social interaction during the resident intruder paradigm in aggressive mice. In this application, we will dissect the complex microcircuitry of the LHb using cell type specific molecular tools to control orexin receptor signaling along with in vivo monitoring of neural activity in awake behaving animals to understand LHb function in social behavior. A basic understanding of these circuits is absolutely critical for developing new treatment strategies for social deficits in a range of psychiatric illnesses.

Public Health Relevance

There is an increased risk for abnormal social behaviors in individuals suffering from social phobias, autism spectrum disorders (ASDs), schizophrenia and mood disorders. However, we still have a limited understanding of the neural circuit mechanisms that control aggressive or nonaggressive social behaviors. In this proposal, we define a role for orexinergic signaling within the lateral habenula of mice that controls motivational aspects of aggressive and nonaggressive social interaction.!

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Simmons, Janine M
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Aleyasin, Hossein; Flanigan, Meghan E; Golden, Sam A et al. (2018) Cell-Type-Specific Role of ?FosB in Nucleus Accumbens In Modulating Intermale Aggression. J Neurosci 38:5913-5924
Aleyasin, Hossein; Flanigan, Meghan E; Russo, Scott J (2018) Neurocircuitry of aggression and aggression seeking behavior: nose poking into brain circuitry controlling aggression. Curr Opin Neurobiol 49:184-191
Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S et al. (2018) Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci 12:56
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
Flanigan, Meghan; Aleyasin, Hossein; Takahashi, Aki et al. (2017) An emerging role for the lateral habenula in aggressive behavior. Pharmacol Biochem Behav 162:79-86
Takahashi, Aki; Chung, Jia-Ru; Zhang, Song et al. (2017) Establishment of a repeated social defeat stress model in female mice. Sci Rep 7:12838
Menard, Caroline; Pfau, Madeline L; Hodes, Georgia E et al. (2017) Social stress induces neurovascular pathology promoting depression. Nat Neurosci 20:1752-1760