Uncovering the Role of Astrocyte-Secreted Thrombospondins and Their Neuronal Receptor α2δ-1 in Goal-Directed Actions

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Goal-directed actions (GDAs), the optimal set of actions to achieve an outcome, are voluntary behaviors requiring complex cognitive processes. Cortico-striatal circuits, particularly neuronal projections from the prefrontal cortex to the dorsomedial striatum (DMS), are critical for the establishment and performance of goal-directed behaviors. Synaptogenesis underlies the formation and remodeling of neural circuits that control cognition and behavior. Astrocytes, a major glial-cell type in the central nervous system (CNS), promote synapse formation and remodeling. During development, astrocytes secrete synaptogenic proteins called thrombospondins (TSPs), which act through the neuronal receptor α2δ-1 to induce excitatory synaptogenesis. The role of astrocytes in synapse formation during development is well established. However, it is less clear whether astrocytes promote synaptogenesis in the adult brain to control complex learned voluntary behaviors. Here we used instrumental operant conditioning to investigate the role of adult synaptogenesis in brain regions engaged during GDA training. We discovered that during the establishment of GDAs in adult mice, new excitatory synapses are formed in the Anterior Cingulate Cortex (ACC). The loss of α2δ-1 reduces this training-induced excitatory synapse formation in the ACC and causes a profound persistence of GDA performance, even when the effort required for the reward is drastically increased. Ablation of α2δ-1 only in ACC neurons projecting to the DMS (ACC->DMS) recapitulated the synaptic and behavioral phenotype observed with constitutive loss of α2δ-1. Based on the findings from the loss of α2δ-1, we predicted that astrocyte-secreted TSPs, which bind to α2δ-1, are also required for the proper performance of GDAs. Surprisingly, we found that constitutive loss of TSP isoforms 1 and 2 (TSP1/2) significantly reduced GDA performance as the effort required for reward increased. Interestingly, the absence of TSP1/2 did not impair GDA training-induced synaptogenesis. Ablation of TSP1/2 in developing but not adult astrocytes was able to reduce GDA performance during high-effort tasks. Furthermore, transcriptomic analysis suggested that constitutive loss of TSP1/2 alters the expression of a group of genes associated with inhibitory and cholinergic neurons. Additionally, we found that mice lacking TSP1/2 have increased inhibitory synapse density in the ACC, which is diminished with GDA training. Altogether, my doctoral dissertation research demonstrates that new synapses are formed in adult animals to control complex voluntary behaviors such as GDAs. These findings also reveal novel roles for astrocyte-secreted thrombospondins in controlling brain circuit formation and adult plasticity, which involve a developmental process that controls inhibition in the mouse ACC. Taken together, my findings reveal that synaptogenic signaling between astrocytes and neurons is critical for modulating GDA performance.






Lawal, Oluwadamilola (2023). Uncovering the Role of Astrocyte-Secreted Thrombospondins and Their Neuronal Receptor α2δ-1 in Goal-Directed Actions. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/29106.


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