Early Deficits in Dentate Circuit and Behavioral Pattern Separation After Concussive Brain Injury
Abstract number :
1.009
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2023
Submission ID :
447
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Andrew Huang, BS – UC Riverside
Susan Nguyen, MS – Molecular, Cellular, and Systems Biology – University of California Riverside; Lucas Corrubia, PhD – Pharmacology, Physiology, and Neuroscience – Rutgers New Jersey Medical School; Mathew Jones, PhD – Neuroscience – University of Wisconsin; Michael Shiflett, PhD – Psychology – Rutgers University; Laura Ewell, PhD – Anatomy and Neurobiology – University of California Irvine; Viji Santhakumar, PhD – Molecular, Cellular, and Systems Biology – University of California Riverside
Rationale: Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Cell intrinsic sparse granule cell firing, and strong feedback inhibition have been proposed as critical to the ability of the dentate gyrus to generate unique representation of similar inputs by a process known as pattern separation. Here we evaluate the impact of brain injury on cellular decorrelation of temporally patterned inputs in slices and behavioral discrimination of spatial locations in vivo one week after concussive lateral fluid percussion injury (FPI) in mice.
Methods: Adult male and female (eight to ten weeks old) C57BL6/J mice underwent lateral fluid percussion injury (FPI) or sham surgery and were examined one week after injury. Slices from sham and FPI mice were stained for ΔFosB, and somatostatin and cell counts quantified using QuPath 0.4.2. Whole-cell patch clamp recordings in acute hippocampal slices (300µm) were used to assess perforant path evoked dentate granule cell (GC) excitability. GC ex vivo pattern separation was assessed by quantifying the correlation of output spike trains evoked by temporally correlated perforant path stimulus trains. Behavioral spatial discrimination was evaluated using a novel object location task.
Results: Similar to previous studies in rats, the amplitude of perforant path evoked excitatory post-synaptic currents was significantly larger in GCs from brain injured mice (in pA, sham: 509.4, n =11; FPI: 759.4, n = 4, p< 0.0001 by t-test). Moreover, the number of GCs expressing ΔFosB, a stable activity-dependent immediate early gene product indicative of persistent increase in excitability, was also enhanced one week after FPI. Despite this sustained increase in excitability, the reliability of GC firing in response to input stimulus trains was not reduced after injury. In response to temporally correlated input trains, GCs continued to produce output trains with greater decorrelation than the inputs. However, the ability of GCs to decorrelate highly similar input spike trains was significantly compromised after FPI. One week after FPI, mice showed reduced preference for exploring an object in a novel location (Discrimination index: sham: 0.28±0.04, FPI: 0.04±0.08, n=8/group, p=0.02 by t-test) in a novel object location test for episodic memory. The total exploration time remained unchanged, indicating impaired location discrimination after FPI. Consistent with the role for dentate inhibition in supporting novel location discrimination, FPI mice euthanized after the behavioral test had significantly fewer somatostatin interneurons in the dentate hilus than sham control mice.
Basic Mechanisms