Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells

Franjic, Daniel; Škarica, Mario; Ma, Shaojie; Arellano, Jon I.; Tebbenkamp, Andrew T.N.; Choi, Jinmyung; Xu, Chuan; Li, Qian; Morozov, Yury M.; Andrijević, David; Vrselja, Zvonimir; Spajic, Ana; Santpere, Gabriel; Li, Mingfeng; Zhang, Shupei; Liu, Yang; Spurrier, Joshua; Zhang, Le; Gudelj, Ivan; Rapan, Lucija; Takahashi, Hideyuki; Hüttner, Anita; Fan, Rong; Strittmatter, Stephen M.; Sousa, André M. M.; Rakić, Paško; Šestan, Nenad

doi:10.1016/j.neuron.2021.10.036

Cited by 188 publications

(231 citation statements)

References 134 publications

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“…It is important to note that while this review will focus on findings surrounding markers of adult neurogenesis from rodent studies, the prevalence of adult neurogenesis in humans remains an ongoing scientific debate. For example, while doublecortin is a conventional marker of neurogenesis in rodents, recent single-nucleus RNA-seq data question its validity as a comparable marker of adult neurogenesis in humans ( Franjic et al, 2022 ). These findings highlight the center of this debate, which predominantly consists of technical issues in identification and labeling of adult newborn neurons in humans.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

2022

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Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol’s effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol’s effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood.

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Section: Introductionmentioning

confidence: 99%

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

2022

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“…To further characterize the identity and diversity of immature neurons in the EC, we isolated nuclei from snap-frozen samples from the EC at early postnatal ages (33 days to 3 years of age) and performed single-nuclei RNAseq (snRNA-seq). We integrated this developmental dataset with one recently published in the adult EC (50 to 79 years of age) 4 ( Fig. 4a, Extended Figure 9 ).…”

Section: Diverse Interneuron Subtypes Migrate Into the Ec Between Bir...mentioning

confidence: 99%

“…1a–c ). Since DCX can be expressed in more mature neurons 4,12,13 , we characterized these putative migrating DCX cells in more detail. At birth, cells in these dense clusters had ultrastructural features consistent with migratory neurons ( Fig.…”

Section: Extensive Migration In the Infant Temporal Lobementioning

confidence: 99%

“… The entorhinal cortex (EC) is a highly-interconnected hub for multisensory integration and memory processing 1–3 , containing diverse neuronal subtypes 4,5 including subpopulations that are uniquely spatially-tuned 6,7 . Although many spatial and memory functions develop in infancy, it is considered that neurogenesis and neuronal migration to the EC occurs prenatally.…”

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confidence: 99%

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Persistent postnatal migration of interneurons into the human entorhinal cortex

Nascimento

Biagiotti

Herranz-Pérez

et al. 2022

Preprint

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The entorhinal cortex (EC) is a highly-interconnected hub for multisensory integration and memory processing1-3, containing diverse neuronal subtypes4,5 including subpopulations that are uniquely spatially-tuned6,7. Although many spatial and memory functions develop in infancy, it is considered that neurogenesis and neuronal migration to the EC occurs prenatally. Here we show that the postnatal human temporal lobe contains a prominent stream with large chains of young migrating neurons and many individual neurons breaking away directed into the EC. The EC stream forms between the second and third trimesters of prenatal development when the lateral ventricle walls in the temporal lobe collapse, displacing the subventricular zone (SVZ) and dividing radial glia. At birth, the EC stream follows a path of radial glial fibers in the site of the collapsed ventricle. Migratory chains persist up to 11 months postnatally; however, many individually migrating young neurons can still be detected in the EC at 2 years of age and a few isolated cells at 3 years of age. Within the EC at birth, immature neurons are a mixed population expressing markers of the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE), but postnatally rapidly become primarily CGE-derived. Using single-nuclei RNAseq we identified these lineages and found that the MGE-derived neurons matured at earlier postnatal ages compared to those derived from the CGE. The CGE interneurons arriving and maturing the latest included subtypes expressing calretinin (CR), reelin (RELN), and vasoactive intestinal protein (VIP) many of which settle in layer II of the entorhinal cortex. This study reveals that the human EC is still being constructed during the first years of life revealing the largest known postnatal stream of migratory neurons in humans. The protracted postnatal arrival of a diverse population of interneurons could contribute to plasticity8,9 and proper excitation-inhibition balance10,11 within these highly connected brain circuits.

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“…In humans, most reports of adult neurogenesis focus on the hippocampus. The extent, and even the existence, of adult neurogenesis in the human hippocampus is still controversial, however, with recent high-profile papers concluding that it is either "abundant" (Moreno-Jiménez et al, 2019) or "undetectable" (Franjic et al, 2021;Sorrells et al, 2018). Either way, unlike most other cell types, most human neurons cannot be replaced in adulthood (for discussion see Denoth-Lippuner & Jessberger, 2021;Gage, 2019;Lucassen et al, 2020;Oppenheim, 2019), probably because each contains learned information and/or participates in intricate neural networks critical to fitness.…”

Section: Defending the Brain From Pathogensmentioning

confidence: 99%

Homo medicus: The transition to meat eating, increased pathogen pressure, and the constitutive and inducible use of pharmacological plants in Homo

Hagen¹,

Blackwell²,

Lightner³

et al. 2021

Preprint

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The human lineage entered a more carnivorous niche 2.6 mya. A range of evidence indicates this increased zoonotic pathogen pressure. This evidence includes increased zoonotic infections modern hunter-gatherers and bushmeat hunters relative to others living in the same environments, exceptionally low stomach pH compared to other primates, human-specific downregulation in ANTXR2 that would have protected against increased exposure to zoonotic anthrax, exceptional human immune responses to LPS compared to other primates, and other divergent immune genes. These all point to change, and likely intensification, in the disease environment of Homo compared to earlier hominins and other apes. At the same time, the brain, an organ in which inflammatory immune responses are highly constrained, begins to increase, eventually tripling in size. We propose that the combination of increased zoonotic pathogen pressure and the challenges of defending a large brain and body from pathogens across what would eventually become the longest lifespan of any mammal, selected for intensification of the self-medication strategies already in place in apes and other primates, resulting in a variety of plant-based pathogen defenses. In support, there is evidence of medicinal plant use by hominins in the middle Paleolithic, and all cultures today have sophisticated, plant-based medical systems, incorporate plant components high in secondary compounds (spices) into food, and regularly consume psychoactive substances that are harmful to helminths and other pathogens in the CNS and other tissues. The computational challenges of discovering effective plant-based treatments, and the economic challenges of benefiting from costly-to- acquire medical knowledge that would be more often useful to others than oneself, were selection pressures for increased cognitive abilities and unique exchange relationships in Homo. In the story of human evolution, which has long featured hunters, shamans and healers had an equal role to play.

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Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells

Cited by 188 publications

References 134 publications

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

Cholinergic and Neuroimmune Signaling Interact to Impact Adult Hippocampal Neurogenesis and Alcohol Pathology Across Development

Persistent postnatal migration of interneurons into the human entorhinal cortex

Homo medicus: The transition to meat eating, increased pathogen pressure, and the constitutive and inducible use of pharmacological plants in Homo

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