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The rodent hippocampus generates new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is a striking form of neural plasticity that occurs in the brains of numerous mammalian species. Direct evidence of adult neurogenesis in humans has remained elusive, although the occurrence of this phenomenon in the human dentate gyrus has been demonstrated in seminal studies and recent research that have applied distinct approaches to birthdate newly generated neurons and to validate markers of adult-born neurons. Our data point to the persistence of AHN until the 10th decade of human life, as well as to marked impairments in this process in patients with Alzheimer's disease. Moreover, our work demonstrates that the methods used to process and analyze postmortem human brain samples can limit the detection of various markers of AHN to the point of making them undetectable. In this Dual Perspectives article, we highlight the critical methodological aspects that should be strictly controlled in human studies and the robust evidence that supports the occurrence of AHN in humans. We also put forward reasons that may account for current discrepancies on this topic. Finally, the unresolved questions and future challenges awaiting the field are highlighted. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, TauVLWmice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female TauVLWmice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn TauVLWDGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of TauVLWmice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1+ DGCs in TauVLWmice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of TauVLWmice and FTD patients. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by a loss of neurons in the frontal and temporal lobes of the brain. Tau protein is encoded by MAPT gene and its mutations cause FTD‐Tau, FTD variant. TauVLW mice carries three mutations, G272V (V), P301L (L), and R406W (W) on MAPT, increasing the susceptibility of Tau to be phosphorylated. TauVLW mice show anatomical alterations in the hippocampus as well as behavioural impairments. Importantly, the hippocampus gives rise to new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), converges in the functional integration of mature dentate granule cells (DGCs) into the trisynaptic hippocampal circuit. AHN is altered in patients with Alzheimer´s disease and in animal models of distinct neurodegenerative diseases, including FTD. Methods: To perform an in‐depth characterization of newborn DGCs of TauVLW mice we used a combination of trail‐blazing retroviral approaches. We used Red‐Green‐Blue (RGB) retroviruses to address the morphological maturation of these neurons. We also used retroviruses that encode either PSD95:GFP or Synaptophysin (Syn):GFP, together with monosynaptic retrograde rabies virus tracing to study the connectivity of these cells. Finally, we tested the effects of the selective chemoactivation of newborn DGCs using a retrovirus that encodes the excitatory Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) H3Dmq, as modulator to counteract the alterations. Results: These innovative approaches revealed that the newborn DGCs of TauVLW mice exhibit marked morphological and functional alterations. Importantly, similar morphological alterations are observed in DGCs of FTD patients. Newborn DGCs of TauVLW mice show impaired afferent and efferent connectivity. Moreover, they are disconnected from distal brain regions and exhibited a predominance of local inhibitory innervation. Therefore, a reduced number of activated egr‐1+ DGCs were observed. On the other hand, chemoactivation led to a complete reversal of the morphological alterations and partial reversal of the alterations in the connectivity of these cells. Conclusions: DGCs are disconnected from distal brain regions and local sources of excitatory innervation in a mouse model of FTD. These cells exhibit remarkable similarities with those of FTD patients. Significantly, the functional defects observed in TauVLW newborn DGCs are reversed by chemoactivation. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common type of dementia. This devastating disease is characterized by progressive memory impairments and other behavioral alterations. The hippocampus is one of the brain areas mostly affected by AD progression. Importantly, the hippocampus hosts a unique phenomenon that occurs in the mammalian brain, namely the addition of new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is involved in hippocampal‐dependent memory and confers an extraordinary degree of plasticity to the entire hippocampal circuitry. AHN has been extensively characterized in rodents and other mammalian species during the last decades. Determining the occurrence of AHN during physiological and pathological aging in humans has an unquestionable therapeutic potential. Method: We studied AHN in a collection of post‐mortem hippocampal samples obtained from 13 neurologically healthy subjects and 45 AD patients distributed among the six neuropathological Braak stages of the disease. We quantified the presence of various sub‐populations of immature neurons in the hippocampal dentate gyrus (DG) of these subjects. Importantly, we tightly controlled tissue processing methodologies and used state‐of‐the‐art histological procedures. Result: Thousands of immature neurons positive for the gold‐standard marker Doublecortin (DCX) were identified in the DG of these subjects up to the tenth decade of life. In contrast, we observed an early and sharp decrease in the number of new neurons in patients with AD. Strikingly, the number of cells further decreased as the disease progressed, even though the number of mature neurons positive for the neuronal nuclei (NeuN) remained unchanged. Accordingly, specific decrease in the ratio between immature/mature neurons was observed along the progression of the disease. Importantly, AHN impairments occurred before the generalized presence of neurofibrillary tangles or senile plaques in the DG. Conclusion: Our data demonstrate the persistence of AHN during physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits that occurs in AD. Therefore, the putative detection of AHN impairments by non‐invasive techniques might turn this phenomenon into a relevant biomarker for AD progression. [ABSTRACT FROM AUTHOR]

Background: Alzheimer´s disease (AD) is a devastating neurodegenerative disorder. The hippocampus, one of the brain areas primarily affected by disease progression, hosts one of the most unique phenomena that occur in the adult mammalian brain. This phenomenon, named adult hippocampal neurogenesis (AHN), encompasses the addition of new neurons throughout life, is crucial for hippocampal‐dependent learning, and confers an unparalleled degree of plasticity to the entire hippocampal circuitry. During AHN, in rodents, newborn dentate granule cells (DGCs) go through different maturation stages before acquiring the properties of a fully mature DGC. In this study, we aimed to determine whether immature DGCs at distinct maturation stages can be identified in the human dentate gyrus (DG) and whether the differentiation process of these cells is altered in AD patients. Method: We used a unique collection of hippocampal samples obtained from 13 neurologically healthy control subjects and 45 AD patients distributed among the 6 neuropathological Braak‐Tau stages of the disease. These samples were obtained under tightly controlled conditions and state‐of‐the‐art tissue processing methodologies and histological protocols were applied. Result: We studied the maturation of DGCs that expressed the gold standard marker of immature neurons, doublecortin (DCX) in the DG of these subjects. For that purpose, we co‐localized DCX with markers that characterize distinct maturation stages during AHN. These markers included calretinin for the most immature neurons or calbindin for neurons at more advanced stages of maturation. We observed remarkable morphological differences among these cell populations in control subjects, which suggested remarkable similarities between AHN in rodents and humans. Strikingly, the maturation of DCX+ DGCs was blocked at multiple levels in AD patients, as shown by the reduced percentage of DCX+ DGCs that expressed markers of mature neurons in these patients. Conclusion: Our data do not only support that human AHN exhibits remarkable similarities with that of rodents, but also demonstrate that this process is blocked at different levels during AD. Given that AHN is regulated by lifestyle habits in rodents and these manipulations have a positive impact on cognition, modulating AHN in humans emerges as a potential therapeutic target for AD or other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The hippocampus hosts the continuous addition of new neurons throughout life-a phenomenon named adult hippocampal neurogenesis (AHN). Here we revisit the occurrence of AHN in more than 110 mammalian species, including humans, and discuss the further validation of these data by single-cell RNAseq and other alternative techniques. In this regard, our recent studies have addressed the long-standing controversy in the field, namely whether cells positive for AHN markers are present in the adult human dentate gyrus (DG). Here we review how we developed a tightly controlled methodology, based on the use of high-quality brain samples (characterized by short postmortem delays and ≤24 h of fixation in freshly prepared 4% paraformaldehyde), to address human AHN. We review that the detection of AHN markers in samples fixed for 24 h required mild antigen retrieval and chemical elimination of autofluorescence. However, these steps were not necessary for samples subjected to shorter fixation periods. Moreover, the detection of labile epitopes (such as Nestin) in the human hippocampus required the use of mild detergents. The application of this strictly controlled methodology allowed reconstruction of the entire AHN process, thus revealing the presence of neural stem cells, proliferative progenitors, neuroblasts, and immature neurons at distinct stages of differentiation in the human DG. The data reviewed here demonstrate that methodology is of utmost importance when studying AHN by means of distinct techniques across the phylogenetic scale. In this regard, we summarize the major findings made by our group that emphasize that overlooking fundamental technical principles might have consequences for any given research field., (© 2022 The Authors. Hippocampus published by Wiley Periodicals LLC.)