Saturday, November 23, 2024
11/23/2024
Abstract Cortical circuits, comprising specialized neuron subpopulations and their selective synaptic connections, send output to long-distance cortical and subcortical targets via two distinct classes of projection neurons: intratelencephalic (IT) neurons that project primary within and across cortical hemispheres, and pyramidal tract (PT) neurons that project to deep subcortical targets (e.g., the thalamus and brainstem). Cortical circuits are regulated by a variety of modulatory neurotransmitters, such as serotonin (5-HT) and acetylcholine (ACh), that optimize circuit performance for different cognitive tasks. Indeed, disruption of serotonergic or cholinergic signaling in the cortex impairs cognition and normal behavior, and both transmitter systems are implicated in a range of psychiatric diseases. Therefore, revealing the physiological mechanisms by which 5-HT and ACh influence cortical processing will enhance our understanding of normal cognition, and will advance the development of novel therapeutic strategies for psychiatric patients. In the mouse prefrontal cortex (PFC), 5-HT and ACh act via G-protein-coupled receptors to reciprocally regulate the postsynaptic excitability of IT and PT neurons. 5-HT promotes IT neuron output, but suppresses PT neurons. Conversely, ACh preferentially excites PT neurons, but has limited impact on IT neurons. Regardless of neuromodulatory state, action potential generation in IT and PT neurons requires excitatory synaptic drive that may also be regulated, at the presynaptic level, by 5-HT and/or ACh. Our pilot studies suggest that 5-HT and ACh act differentially to regulate key excitatory afferents to IT and PT neurons. This current project will test the overarching hypothesis that 5-HT and ACh bias the “throughput” of cortical circuits via coordinated pre- and postsynaptic regulation of specific combinations of excitatory afferent and cortical projection target neuron subtype. Our first aim is to map the relative targeting, and functional excitatory drive, of IT and PT neurons by key extrinsic excitatory afferents to the mouse medial PFC. Our second aim is to test for afferent-specific presynaptic regulation by 5-HT and ACh, thereby determining whether pre- and postsynaptic neuromodulation is coordinated to facilitate specific combinations of afferent input and cortical projection output. Our third aim is to test whether 5-HT and/or ACh regulate local circuit communication between IT and PT neurons in a manner consistent with the opposing postsynaptic impacts of these modulators on excitability. Completion of these aims will establish a rigorous, circuit-based framework for understanding cholinergic and serotonergic regulation of cognitive function, and will provide insight into how disruptions of neuromodulatory circuits contribute to psychiatric disease.
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