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Project 1

The Locus Coeruleus Catecholaminergic System as a Modular Regulator of Brain Network Dynamics and Animal Physiology

The locus coeruleus (LC), a small brainstem nucleus with widespread projections throughout the brain, modulates cognitive and physiological processes such as attention, learning, arousal, and autonomic regulation. LC neurons primarily release noradrenaline (NA) and can co-release other neurotransmitters like dopamine (DA), which influence brain activity via G-protein-coupled receptors (GPCRs) in target regions. While the LC was traditionally thought to generate a uniform arousal signal, it is now hypothesized to act in a modular fashion, producing distinct effects in different brain areas. In this project, we aim to determine whether LC neurons exhibit distinct physiological and molecular properties based on their projection targets, thereby exerting specific local effects on neuronal, glial, and vascular functions, or whether these effects are shaped by regional differences in GPCR expression and neurotransmitter uptake dynamics. Using state-of-the-art methods – including projection-specific optogenetics, advanced genetically encoded, fluorescent catecholamine sensors, functional ultrasound imaging, two-photon microscopy, and fiber photometry, combined with pharmacological interventions – we will investigate these mechanisms across the whole brain, with a focus on the dorsal hippocampus (dHC), medial prefrontal cortex, and thalamus. Specifically, we will first characterize projection-specific LC neurons at molecular and functional levels. Next, we will study how these neurons drive NA and DA modulation in their target regions. The study will also assess how NA directly influences astrocytes and blood flow, decoding their roles in shaping local brain activity. Using two-photon imaging, we will focus on the dHC to visualize these effects at high spatial resolution and examine their impact on behavior. Finally, we will evaluate the influence of projection-specific LC neurons on sympathetic heart control. By unraveling the interplay between neurotransmitter release and GPCR activation within a projection-specific context, this research aims to elucidate how LC neurons achieve modular control of brain function, advancing our understanding of neuromodulatory mechanisms linking brain-wide signaling to physiological states like arousal.


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