Brain-wide Reconstruction of Inhibitory Circuits After Traumatic Brain Injury
Abstract number :
1.047
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2022
Submission ID :
2204572
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Alexa Tierno, BS, MS – University of California Irvine; Jan Frankowski, PhD – University of California, Irvine; Shreya Pavani, BS – University of California, Irvine; Quincy Cao, BS – University of California, Irvine; David Lyon, PhD – University of California, Irvine; Robert Hunt, PhD – University of California, Irvine
This abstract has been invited to present during the Basic Science Poster Highlights poster session.
Rationale: Despite the functional importance of understanding the brain’s wiring diagram, our knowledge of how neuronal connectivity is rewired by traumatic brain injury (TBI) remains remarkably incomplete. A specific subtype of inhibitory interneurons that express somatostatin play a unique role in inhibiting dendrites and regulating the integration of excitatory input to local principal neurons in hippocampus. However, somatostatin interneurons are susceptible to cell death following injury, and those that survive receive more excitatory input, form new synapses, and grow into territories they normally do not occupy. Whether this rewiring occurs on a broader scale throughout the brain remains unknown.
Methods: We used cellular resolution whole-brain imaging to generate brain-wide maps of the input to somatostatin neurons in a mouse model of traumatic brain injury. Using retrograde monosynaptic rabies virus, we traced the inputs to somatostatin interneurons in hippocampus and prefrontal cortex after controlled cortical impact TBI. We then used whole-brain tissue clearing, along with light sheet microscopy, to visualize the local and long-range inputs to these interneurons. Finally, we harvested GABA progenitors from the medial ganglionic eminence of E13.5 mouse embryos, transplanted them into the injured hippocampus and performed whole-brain rabies-based circuit tracing to identify the inputs to these grafted neurons.
Results: In hippocampus, somatostatin interneurons have an increase in local input (e.g., from CA1) but a decrease in long-range inputs after TBI (e.g., from entorhinal cortex). However, there was no neuron loss within the distant input regions themselves. We found similar results in prefrontal cortex, an area far away from the injury site that was not directly damaged by the injury; somatostatin interneurons received more input from the ipsilateral isocortex but long-range connections were reduced (e.g., from thalamus). Interneuron progenitors grafted into the hippocampus established appropriate local and long-range connections but retained the enhanced local input that was seen after TBI.
Conclusions: Our results suggest that focal brain damage has a broader impact on neural circuit function. Our findings uncover a potential strategy to sustain and optimize inhibition after traumatic brain injury that involves spatial reorganization of the direct inputs to inhibitory neurons across the brain.
Funding: NIH R01–NS096012, F31–NS106806, R01–EY024890, UCI Summer Undergraduate Research Program (SURP) fellowships
Basic Mechanisms