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NIH grant 1DP2NS155225-01: Selective inhibitory connectivity in cortical circuits revealed by high-throughput electron tomography
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Aaron Kuan. Award: $798395.
Start: 2026-09-05T00:00:00.
Project Summary:
Selective inhibitory connectivity in cortical circuits revealed by high-throughput electron
tomography
This proposal’s objective is to unravel complex brain circuits at the level of individual
neuronal connections (synapses) to understand how different brain regions support diverse
functions like sensory perception and decision-making. Mapping brain connectivity at the
synapse level is a formidable technical challenge that requires advanced electron microscopy
techniques, which are difficult to apply at scale across many samples. Here, we will develop a
novel high-throughput electron tomography platform that overcomes critical technical
challenges to allow scalable and routine mapping of brain circuits. This will make it possible to
compare connectivity across multiple brain regions and individuals, pinpoint the circuit roles of
diverse cell types, and reveal relationships between circuit structure and function.
We will apply this transformative technology to investigate how cortical circuits support
diverse and flexible functions. Since all cortical circuits share the same basic architecture, it is
not clear how each cortical region supports specialized function. Recent evidence suggests that
inhibitory interneurons selectively prefer synaptic connections with certain partners based on
their functional roles, and this selective inhibitory connectivity can only be detected with
comprehensive nanoscale circuit mapping. Our central hypothesis is that these selective
connectivity rules vary across cortical brain regions and play a crucial role in supporting region-
specific cortical function. To investigate this, we will map synaptic connectivity for genetically
defined subpopulations of interneurons in multiple cortical circuits involved in sensory
processing and perceptual decision-making. These data will provide the first detailed
comparisons of inhibitory connectivity across multiple cortical regions at the level of individual
synapses and reveal insights into how selective inhibition contributes to behavior and cognition.
The expected outcomes of this proposal include both technical and conceptual
advances. Technically, we will develop a novel automated electron tomography system that
enables robust and scalable mapping of multiple cortical circuits and provide new datasets of
microcircuit connectomes from multiple cortical areas. Conceptually, we will identify detailed
rules of connectivity for interneuron subtypes and determine how these connectivity motifs vary
across cortical regions and support specific functional roles. These results are expected to have
a positive impact because they will clarify the functional role of inhibition in cognitive tasks and
could help identify new therapeutic targets for brain disorders.document fetched 2026-09-13 02:45