Neural Circuit Mechanisms of Stress-Impaired Social Reward

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Abstract Alzheimer's disease (AD) is characterized by neurodegeneration of the brain that is associated with intraneuronal neurofibrillary tangles, extracellular neuritic plaques and neuroinflammation. Synaptic alteration or dysfunction is increasingly viewed as one of the earliest events in the initiation of AD-type cognitive decline preceding neuronal loss. Aside from cognitive and memory impairments, AD is also commonly associated with social behavioral abnormalities and psychological symptoms. It is estimated that approximately 80-90% of dementia patients suffer from behavioral disorders that include apathy, depression, irritability, agitation, anxiety, social withdrawal, social disinhibition, aggression and agitation. These behavior problems can have a huge impact on the quality of life of the patients and their caregivers. While the mechanisms of comorbid neuropsychiatric symptomswith AD are not well known, it is postulated that neurodegeneration in AD disrupts the brain circuitries involved in social behavior and emotion. Under the parent R01, my lab has been investigating the neural circuitries mediating chronic stress-induced social behavior alteration. We have shown that social stress induces occlusion of social reward and preference in stress susceptible mice and it is associated with aberrant activation of neurotensin (NT)-positive GABAergic neurons in the lateral septum (LS). We also found that chemogenetic activation of LSNT neurons promotes social avoidance behavior and reduced social reward in stress resilient mice, suggesting LSNT neurons plays an important role in determining responses to social rewards. In several genetic mouse models that recapitulate aspects of AD neuropathology, impairments in social behavior have also been observed. In a well-established 5xFAD mouse model of AD-related pathology, we confirm that these mice exhibit deficits in social reward. Thus, in this supplement, we propose to longitudinally examine the activity of LS circuit during social interaction in the 5xFAD mice to determine whether AD-associated reduced social preference is driven by LSNT neurons. Moreover, as it is well established that social stress exacerbates neuropsychiatric symptoms in AD, we will also test the effect of social defeat stress on LS circuit activity and social behavior in 5xFAD mice.