Dysregulation of hippocampal adult-born immature neurons disrupts a brain-wide network for spatial memory

Abstract

SummaryMounting evidence suggests that cognitive deficits associated with various neurological disorders may arise in part from a small population of dysregulated adult-born neurons in the dentate gyrus (DG). How these dysregulated adult-born neurons contribute to brain-wide network maladaptation and subsequent cognitive deficits remains unknown. Using an established mouse model with a small number of time-stamped dysregulated adult-born immature neurons and spatial memory deficits, we performed resting state functional magnetic resonance imaging and found that approximately 500 deficient immature neurons (<0.1% of total DG granule neurons) are sufficient to induce a significant decrease in the functional connectivity between DG and insular cortex (IC), two brain regions without direct anatomical connections. Furthermore, using a combination of rabies-based retrograde tracing and in vivo fiber photometry recording, we demonstrated that dysregulated adult-born neurons induce aberrant activity and synchrony in local hippocampal CA3 and CA1 regions, as well as distal medial-dorsal thalamus and IC regions during a spatial memory process. These results suggest that a few hundred dysregulated adult-born immature neurons can impact brain-wide network dynamics across several anatomically discrete regions and collectively contribute to impaired cognitive functions.

Neuronal dynamics of the default mode network and anterior insular cortex: Intrinsic properties and modulation by salient stimuli

“…We used an fMRI-compatible, spectrally resolved, fiber-photometry platform (Bao et al, 2020; Chao et al, 2022; Das et al, 2021; Meng et al, 2018; Oyarzabal et al, 2022; Zhang et al, 2022b, 2022a) with four recording fibers ( Figure 1A ) to measure neuronal GCAMP activity in the RSC, Cg, PrL, and AI from rats ( Supplementary Figure 1 ). GCaMP activity was combined with whole-brain fMRI recordings in anesthetized rodents to capture concurrent resting-state signals from both modalities ( Figure 1A ).…”

“…A MRI-compatible, four-channel, spectrally resolved, fiber-photometry platform was used (Bao et al, 2020; Chao et al, 2022; Das et al, 2021; Meng et al, 2018; Oyarzabal et al, 2022; Zhang et al, 2022b, 2022a). We used interleaved 488 nm (OBIS Galaxy Laser 1236444, Coherent, Santa Clara, CA) and 405 nm (OBIS Galaxy Laser 1236439, Coherent, Santa Clara, CA) diode lasers for GCaMP signal excitation.…”

“…A MRI-compatible, four-channel, spectrally resolved, fiber-photometry platform was used (Bao et al, 2020;Chao et al, 2022;Das et al, 2021;Meng et al, 2018;Oyarzabal et al, 2022;Zhang et al, 2022bZhang et al, , 2022a. We used interleaved 488 nm (OBIS Galaxy Laser 1236444, Coherent, Santa Clara, mm core/cladding multi-mode patch cable (M200L02S-A, Thorlabs, Newton, NJ).…”

“…Here, to form a comprehensive understanding of neuronal signaling among putative rodent DMN and SN areas in a behaviorally relevant context and build an accurate and translational model of the DMN and its dynamic properties, we concurrently measured neuronal calcium activity in the RSC, Cg, PrL, and AI of Thy1-GCaMP6f transgenic rats (Scott et al, 2018). To enable these measurements, we developed an fMRI-compatible, four-channel, spectrally resolved, fiber-photometry recording system based on the platform used in our previous studies (Bao et al, 2020; Chao et al, 2022; Das et al, 2021; Meng et al, 2018; Oyarzabal et al, 2022; Zhang et al, 2022b, 2022a). We used our novel fiber-photometry platform and recent advances in computational modeling of brain-circuit dynamics to characterize neuronal dynamics of the putative DMN nodes and AI under resting-state and awake, salient stimulus presentation conditions.…”

Nervous system reduction in branched-chain amino acid metabolism disrupts hippocampal neurogenesis and memory

“…The dentate gyrus is an important region for processing spatial information, and newborn neurons are integrated into this network (Clelland et al, 2009; Kee et al, 2007; Toda et al, 2019). A recent study has shown that just a few hundred dysregulated adult-born immature neurons can cause aberrant activity in CA3 and CA1 hippocampus, leading to brain-wide disruptions in neural connectivity that impair spatial memory (Bao et al, 2020). Consistent with this finding, in this study we observed extensive accumulation of DCX+/Neurod1+ immature cells in the GCL of Ppm1k cKO mice that could contribute to disturbances in spatial working memory.…”