Sunday, May 11, 2025
5/11/2025
Circuit structure and dynamics in prefrontal-limbic networks - ABSTRACT The ability to regulate when and how emotions are used to guide cognition relies on adaptive and plastic circuits that can integrate internal limbic-visceral and external sensory-motor information for a given behavioral context. The anterior cingulate cortex (ACC) is an area that plays an important role in this process of emotional regulation and multimodal integration, acting as a unique connectional node for the otherwise segregated cognitive, motor and limbic networks. The ACC forms a robust network with the amygdala (AMY), a key limbic structure for emotion and arousal, which exhibits specialized circuit reorganization and plasticity during emotional stress. Our previously funded R01 (MH116008) focused on comparing the ACC with the lateral prefrontal cortex (LPFC), another region implicated in cognition and stress, and on the extrinsic ACC pathways to cognitive/motor and limbic areas. It remains unclear how exactly these multimodal pathways interact across the functionally distinct rostral ‘cognitive’ (a32), ventral ‘limbic’ (a25) and dorsal ‘motor’ (a24) subdivisions of the ACC, which is the focus of this renewal application. Our work in the previous grant period has shown that the robust ACC interconnections with AMY span all ACC areas and are therefore, well-suited for integrating information across these distinct ACC functional domains. Further, compared to ACC projections to cognitive/motor areas in LPFC and dorsal premotor (PMd) cortices, AMY-targeting ACC pyramidal neurons show greater laminar diversity in their distribution, and biophysical, structural, and inhibitory synaptic properties. Computational modeling show that these unique single- cell biophysical and connectional properties contribute to diverse laminar oscillatory dynamics in ACC outputs to AMY, which can support synchrony at low frequencies in L5, but at high frequencies in L3. In contrast, cortico- cortical ACC outputs to PMd are more tuned towards higher oscillatory frequencies in both layers. While we have shown how these extrinsic ACC outputs are diverse at the single cell level, the question remains as to how multimodal information is integrated within the ACC. This renewal focuses on the largely uncharacterized short- range interconnections within and between the functionally distinct ACC areas that are likely important for this multimodal integration. Using anatomical tract-tracing, optogenetics, slice physiology, high-resolution microscopy and computational modeling we propose to assess intrinsic ACC-ACC interconnections in adult rhesus monkeys (5-13Y) with regards to their: excitatory vs inhibitory constituents, neuromodulation of synaptic plasticity, interactions with long-range cognitive (LPFC), motor (PMd) and limbic (AMY) pathways, and contributions to diverse network dynamics. The overall hypothesis is that distinct short-range intrinsic ACC circuits have specialized excitatory, inhibitory and neuromodulatory properties and interactions with long-range cortico-limbic pathways, which endow diverse network oscillatory dynamics and plasticity in the ACC. Novel data from this study will yield new insights into how selective circuit neuromodulation within distinct ACC networks can lead to normal cognitive-affective behavior and its dysfunction in the primate.
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