[F31] The role of activity dependent transcription in navigational decision making

Ente: National Institute of Neurological Disorders and Stroke

Scadenza: 2028-06-30

Importo max: 41.568 EUR

Paese: US

Descrizione

Abstract Effective navigation relies on transforming spatial representations into motor plans to get from A to B, a process involving distributed brain regions including the posterior parietal cortex (PPC). During navigation of a T maze, neurons in the PPC fire in a sequential manner, tiling the mouse’s route along the maze with respect to the choice it makes to turn left or right. Although the nature of these so-called choice specific sequences have been extensively characterized once the mouse has mastered the maze, the mechanisms underlying their formation and maintenance as a mouse learns to navigate remain unclear and understudied. One entry- point into understanding these mechanisms is through activity dependent transcription. The activity-inducible transcription factor Fos has been shown to play a key role in shaping hippocampal plasticity and memory, yet its role in cortical circuits that support goal-directed behavior remains largely unknown. Fos is rapidly expressed in response to neural activity and orchestrates gene programs that modulate synaptic and circuit- level plasticity. However, whether and how Fos contributes to learning-dependent circuit modifications in the cortex, particularly during navigational decision-making, is not understood. To address this, the proposed research will investigate the role of Fos in shaping and stabilizing task-relevant neural sequences in the PPC during a virtual-reality navigation task. In Aim 1, two-photon calcium imaging in Fos-reporter mice will be used to track neural activity and Fos induction as mice learn to associate visual cues with navigational choices. This will reveal whether neurons that highly induce Fos are more likely to participate in stable, choice-specific activity sequences. In Aim 2, a triple conditional knockout strategy targeting Fos, Fosb, and Junb will be used to determine whether Fos is necessary for the formation and maintenance of these cortical sequences. This work addresses a fundamental question in neuroscience: how activity-dependent transcription shapes the formation of learned neural representations. The proposed training plan combines advanced molecular genetics, in vivo imaging, and behavioral neuroscience, providing the applicant with comprehensive research experience in neural circuit mechanisms of learning. The research will be conducted in a highly collaborative and supportive environment, combining expertise in both molecular and systems neuroscience approaches to tackle this question. By uncovering how Fos regulates cortical plasticity during navigation, this work directly supports the mission of NINDS to understand the brain and reduce the burden of neurological disorders through informing mechanisms underlying memory impairment in conditions such as Alzheimer’s disease, autism spectrum disorder, and Rett syndrome. Istituzione: HARVARD MEDICAL SCHOOL PI: Yasmine R Ayman Progetto: 1F31NS149604-01

Settori: National Institute of Neurological Disorders and Stroke

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