Molecular landscapes of human hippocampal immature neurons across lifespan

Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated environmental stimuli. Adult-born neurons can contribute to spatial memory but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we found that mice that were previously housed in an enriched environment, which triggers an increase in neurogenesis, had increased spatial information encoding in the hippocampal dentate gyrus during novel context exposure. Ablating adult neurogenesis by prior focal irradiation of the hippocampus blocked the effect of enrichment and lowered spatial information content, as did the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreased the calcium activity rates of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast to previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves neural representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory.

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“…The copyright holder for this preprint this version posted December 1, 2022. ; https://doi.org/10. 1101/2022…”

Section: Author Contributionsmentioning

confidence: 99%

Adult neurogenesis improves spatial information encoding in the mouse hippocampus

Frechou

Martin

McDermott

et al. 2022

Preprint

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“…Together our observations indicate that the mouse PL forms during embryonic ages and contains a pool of developmentally-arrested neurons that mature at later ages. Interestingly, a similar process of delayed neuron maturation has been proposed 75 as an explanation for the presence of DCX + cells with mature morphologies 76 in the human hippocampus, in the absence of dividing progenitor cells 73,77,78 . A better understanding of the molecular influences on immature neuron maturation arrest and growth might provide a unique angle to understanding the significance of this phenomenon in either brain region.…”

Section: Discussionmentioning

confidence: 65%

Mouse paralaminar amygdala excitatory neurons migrate and mature during adolescence

Alderman

Saxon

Torrijos-Saiz

et al. 2022

Preprint

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The human amygdala paralaminar nucleus (PL) contains immature excitatory neurons that exhibit protracted maturation into adolescence; however, whether a similar population exists in mice is unknown. We discovered a previously undescribed region with immature doublecortin (Dcx)+ excitatory neurons adjacent to the mouse basolateral amygdala, and similar to humans, these neurons mature during adolescence and are distinct from adjacent intercalated cells. Despite their immature features, these neurons are born during embryogenesis, populate the mouse PL prior to birth, and remain in an immature stage of development until adolescence. In the postnatal brain, a subpopulation of these excitatory neurons surprisingly migrate into the neighboring endopiriform cortex, peaking between P21-P28. In humans, cells with the molecular identity of mouse PL neurons populate the PL as early as 18 gestational weeks, and also exhibit migratory morphology into adolescence (13 years). The finding of a similar region in both mice and humans suggests a potentially conserved cellular mechanism for neuron recruitment and migration during adolescence, a key time period for amygdala circuit maturation and behavioral changes.

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“…Assuming neurological substrates of the DG form a molecular fingerprint of fatal suicidality, the question is whether any P2RX7 + nuclei subset(s) could distinguish suicidal phenotypes or consequences. As the presence of P2RX7 + nuclei rapidly decreased with the extension of the PMD, technological approaches that profile transcriptomic alterations at single-cell resolution may provide a feasible alternative for overcoming PMD-dependent protein degradation in postmortem human DG 37 .…”

Section: Discussionmentioning

confidence: 99%

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Zhang

Verwer

Heerikhuize

et al. 2022

Preprint

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Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+ microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

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Molecular landscapes of human hippocampal immature neurons across lifespan

Cited by 160 publications

References 81 publications

Adult neurogenesis improves spatial information encoding in the mouse hippocampus

Adult neurogenesis improves spatial information encoding in the mouse hippocampus

Mouse paralaminar amygdala excitatory neurons migrate and mature during adolescence

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

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