Saturday, May 31, 2025
5/31/2025
Role of opioid-glutamate interactions in intrinsically rewarded social behaviors - The proposed studies will uncover components of a core neural system that underlies affiliative, rewarding, non-sexual social communication. In cases of depression, anxiety, and autism spectrum disorders, social interactions that are typically rewarding can become aversive. Deficits can also be context-specific. For example, some autistic individuals are able to make directed requests (e.g., for food) that can be extrinsically reinforced (e.g., by receipt of food) but exhibit profound deficits in affiliative communication (e.g., nonsexual, chitchat) that promotes social bonds and is rewarding but does not result in an immediate, obvious extrinsic reinforcer. Many studies focus on mechanisms underlying goal-directed, extrinsically rewarded behaviors (e.g., food-, mate-, or drug-directed); however, these mechanisms appear to differ from those underlying intrinsically rewarded, affiliative social behaviors, leaving a critical gap in basic knowledge about mechanisms underlying non-sexual, affiliative communication. Studies taking advantage of the unique communication properties of songbirds reveal a previously unappreciated role for the medial preoptic nucleus (mPOA) and in particular mu opioid receptors (MORs) in the mPOA in both facilitating and rewarding a form of non-sexual, affiliative singing behavior. Preliminary RNAseq data reveal for the first time a complex of glutamatergic genes in mPOA to be tightly associated with this type of song. The objective of this application is to integrate findings related to the essential role of glutamate and glutamate-MOR interactions in reward to identify foundational, understudied biological mechanisms that underlie affiliative, rewarding communication. The central hypothesis is that glutamate-related genes and MOR-glutamate interactions in the mPOA play critical roles in affiliative communication and other social interactions. The rationale is the need for basic, mechanistic information on core social circuits that underlie behaviors disrupted by mental illness. Based on past and preliminary data, two specific aims are proposed: 1) Determine selective contributions of glutamate-related genes in mPOA to affiliative song, social motivation, and reward; 2) Explore the role of MOR-glutamate interactions in mPOA in affiliative song and reward. In Aim 1 shRNA will be used to knockdown glutamate-related genes SHANK2, GRM5 or GRIN1 in mPOA or a control region, and affiliative song, other social behaviors, social motivation, and social reward will be tested. In Aim 2 effects of the same manipulations on the ability of pharmacological MOR stimulation to facilitate affiliative song as well as reward will be tested. The approach is innovative because it advances the understanding of intrinsically-rewarded social behavior in songbirds with the goal of identifying fundamental, conserved mechanisms. The proposal is significant because it will elucidate the role of glutamate-related genes and MOR-glutamate interactions in non-sexual, affiliative social behaviors and provide insight into core neural circuits that may be disrupted by mental illness in humans.
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