[R01] Region-Specific, Inducible Axonal Tract-Tracing in the Brain
Ente: National Institute of Mental Health
Scadenza: 2031-04-30
Importo max: 806.563 EUR
Paese: US
Descrizione
Project Summary/Abstract
This proposal responds to NOFO PA-25-301 and NOSI NOT-MH-25-045, which “encourages computational
approaches in fundamental neuroscience research investigating the molecular and cellular mechanisms that
drive the structure and function of cells and circuits supporting cognitive, affective, and social domains.” It focuses
on developing and applying genetically based tools for accessing and analyzing neurons that contribute to
emergent properties of neural networks, such as attractors, that we have recently discovered to encode scalable
and persistent internal affective states underlying instinctive social behaviors. We wish to adapt technologies
originally developed to genetically access neuronal subpopulations defined by stable molecular markers, to
access computationally defined neuronal subpopulations with specific dynamical properties. We propose to
combine computational tools to identify such subpopulations in large-scale neural data, with new methods to
mark, map and manipulate their constituent neurons with high spatio-temporal resolution, to understand the
neural implementation and causal role in behavior of these emergent network-level mechanisms. Our broad,
long-term objective is to develop and apply methods to tag and perturb computationally identified neuron subsets
that participate in population codes. The central objective of this proposal is to optimize a suite of optical tools to
map the connectivity and test the causal role in behavior of neurons that generate line attractors in a subcortical
nucleus, VMHvl, that controls internal affective states underlying social behaviors. The rationale for this approach
is that understanding the function of population codes such as attractors requires genetic access to neuron
subsets defined by latent factor analysis, which has been difficult to do in mammalian systems. To achieve our
objective, in Aim 1 we will generate and register spatial transcriptomic data to computationally defined “line
attractor neurons” (LANs), identified in 2-photon (2P) calcium imaging data from the VMHvl of head-fixed or
freely behaving mice, to investigate their correspondence with transcriptomic subtypes. In Aims 2 and 3 we will
optimize and apply 2P-based single-cell marking methods to map the local synaptic connectivity ex vivo and
long-range projections in vivo, respectively, of these neurons. In Aim 4 we will develop activity-dependent single-
cell marking methods to express chemogenetic effectors in LANs, to test their causal role in social behavior. This
contribution is significant because it will develop and apply tools to address fundamental questions about the
implementation and function of continuous attractor networks, for the first time in any mammalian system. The
contribution is innovative because it develops a general approach to bridge the current gap between circuit-level
and manifold-level neuroscience, to allow causal tests of theories that invoke emergent network-level
Istituzione: CALIFORNIA INSTITUTE OF TECHNOLOGY
PI: David J Anderson
Progetto: 2R01MH070053-21
Settori: National Institute of Mental Health
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