Circuit structure and dynamics in prefrontal-limbic networks

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PROJECT ABSTRACT The lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC) in primates interact with each other, as key components of the executive control network. However, these areas participate in distinct extrinsic circuits and exhibit temporally-distinct activation patterns as they enhance task-relevant and suppresses task-irrelevant information to guide behavior. The LPFC rapidly encodes and transiently stores sensory-motor information for continuous updating of information in “working memory” for the task at hand. As temporal and cognitive- emotional demands increase (i.e., a higher number of temporally distinct motivational variables to consider), the ACC is additionally engaged. The ACC, as part of the limbic network, can integrate emotional and mnemonic information to modulate cognitive tasks that span both rapid and longer timescales. Cortical excitatory and inhibitory synaptic networks determine the spatial and temporal dynamics of signal enhancement or suppression in cognitive tasks. The scientific premise of this proposal is that the key differences in the temporal dynamics of processing in ACC vs LPFC in behavior are due to differences network excitatory-inhibitory (E:I) synaptic balance in these areas, which remain poorly understood. Our recent work suggests that higher inhibitory tone and longer membrane time constant in ACC neurons likely contribute to a longer temporal range for integration. The overall hypothesis of this proposal is that highly distinctive excitatory-inhibitory and neuromodulatory circuits in the ACC and LPFC underlie differential temporal dynamics of signal processing for cognitive-emotional integration by these two areas. Using multi-scale neuroanatomical, in vitro and in vivo electrophysiological, pharmacologic and optogenetic techniques in adult rhesus monkeys (Macaca mulatta), we aim to study the properties of inhibitory circuits that control the temporal dynamics of ACC vs LPFC pyramidal neuron activity, and how limbic input from the amygdala influences communication within the ACC-LPFC network. We will study GABAergic and neuromodulatory influences on these prefrontal networks that are highly implicated in the regulation of stress and emotions. In Aim 1 we will investigate the properties of temporally-distinct inhibitory circuits, using in vitro electrophysiological and pharmacological techniques to isolate fast versus slow inhibitory currents, as well as neuroanatomical techniques to classify inhibitory neurons based on their receptors and innervation patterns. In Aim 2 we will determine whether differential inhibitory signaling in ACC vs LPFC affects capacities for diverse network oscillations in vitro and in vivo. In Aim 3 we will study the properties of ACCamygdala vs ACCLPFC projections and how these neurons receive synaptic input from the amygdala, using optogenetics and 3D electron microscopy. Disruption of the E:I balance and oscillatory dynamics within this ACC-LPFC prefrontal-limbic network is the core neuropathology in cognitive-affective psychiatric disorders. The proposed study will shed light on the underlying circuit mechanisms of normal and disrupted cognitive-emotional integration in primates.