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Progress in Lipid Research Jul 2023Dentate gyrus of the hippocampus continuously gives rise to new neurons, namely, adult-born granule cells, which contribute to conferring plasticity to the mature brain... (Review)
Review
Dentate gyrus of the hippocampus continuously gives rise to new neurons, namely, adult-born granule cells, which contribute to conferring plasticity to the mature brain throughout life. Within this neurogenic region, the fate and behavior of neural stem cells (NSCs) and their progeny result from a complex balance and integration of a variety of cell-autonomous and cell-to-cell-interaction signals and underlying pathways. Among these structurally and functionally diverse signals, there are endocannabinoids (eCBs), the main brain retrograde messengers. These pleiotropic bioactive lipids can directly and/or indirectly influence adult hippocampal neurogenesis (AHN) by modulating, both positively and negatively, multiple molecular and cellular processes in the hippocampal niche, depending on the cell type or stage of differentiation. Firstly, eCBs act directly as cell-intrinsic factors, cell-autonomously produced by NSCs following their stimulation. Secondly, in many, if not all, niche-associated cells, including some local neuronal and nonneuronal elements, the eCB system indirectly modulates the neurogenesis, linking neuronal and glial activity to regulating distinct stages of AHN. Herein, we discuss the crosstalk of the eCB system with other neurogenesis-relevant signal pathways and speculate how the hippocampus-dependent neurobehavioral effects elicited by (endo)cannabinergic medications are interpretable in light of the key regulatory role that eCBs play on AHN.
Topics: Adult; Humans; Endocannabinoids; Hippocampus; Neurogenesis; Neurons; Signal Transduction
PubMed: 37385352
DOI: 10.1016/j.plipres.2023.101239 -
Frontiers in Neuroscience 2023Neurogenesis ceases in most regions of the mammalian brain before or shortly after birth, however, in a few restricted brain regions, the production of new neurons... (Review)
Review
Neurogenesis ceases in most regions of the mammalian brain before or shortly after birth, however, in a few restricted brain regions, the production of new neurons proceeds into adulthood. Neural stem cells (NSCs) in these neurogenic zones are integrated into niches that control their activity and fate. Most stem cells in the adult brain are mitotically inactive and these cells can remain quiescent for months or even years. One of the key questions is what are the molecular mechanisms that regulate NSC maintenance and differentiation. Notch signaling has been shown to be a critical regulator of stem cell activity and maintenance in many tissues including in the nervous system. In this mini-review we discuss the roles of Notch signaling and the functions of the different Notch receptors and ligands in regulating neurogenesis in the adult murine brain. We review the functions of Notch signaling components in controlling NSC quiescence and entry into cell cycle and neurogenesis.
PubMed: 37457009
DOI: 10.3389/fnins.2023.1179011 -
The Journal of Neuroscience : the... Jul 2023The perforant path provides the primary cortical excitatory input to the hippocampus. Because of its important role in information processing and coding, entorhinal...
The perforant path provides the primary cortical excitatory input to the hippocampus. Because of its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells remains to be characterized. Here, we have used mouse organotypic entorhino-hippocampal tissue cultures of either sex, in which the entorhinal cortex (EC) to dentate granule cell (GC; EC-GC) projection is present, and EC-GC pairs can be studied using whole-cell patch-clamp recordings. By using cultures of wild-type mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared, and differences in short-term plasticity were identified. As the perforant path is severely affected in Alzheimer's disease, we used tissue cultures of amyloid precursor protein (APP)-deficient mice to examine the role of APP at this synapse. APP deficiency altered excitatory neurotransmission at medial perforant path synapses, which was accompanied by transcriptomic and ultrastructural changes. Moreover, presynaptic but not postsynaptic APP deletion through the local injection of Cre-expressing adeno-associated viruses in conditional tissue cultures increased the neurotransmission efficacy at perforant path synapses. In summary, these data suggest a physiological role for presynaptic APP at medial perforant path synapses that may be adversely affected under altered APP processing conditions. The hippocampus receives input from the entorhinal cortex via the perforant path. These projections to hippocampal dentate granule cells are of utmost importance for learning and memory formation. Although there is detailed knowledge about perforant path projections, the functional synaptic properties at the level of individual connected pairs of neurons are not well understood. In this study, we investigated the role of APP in mediating functional properties and transmission rules in individually connected neurons using paired whole-cell patch-clamp recordings and genetic tools in organotypic tissue cultures. Our results show that presynaptic APP expression limits excitatory neurotransmission via the perforant path, which could be compromised in pathologic conditions such as Alzheimer's disease.
Topics: Mice; Animals; Perforant Pathway; Amyloid beta-Protein Precursor; Alzheimer Disease; Dentate Gyrus; Synaptic Transmission; Synapses
PubMed: 37369586
DOI: 10.1523/JNEUROSCI.1824-22.2023 -
Neural Regeneration Research Jan 2024Adult neurogenesis, the process of creating new neurons, involves the coordinated division, migration, and differentiation of neural stem cells. This process is... (Review)
Review
Adult neurogenesis, the process of creating new neurons, involves the coordinated division, migration, and differentiation of neural stem cells. This process is restricted to neurogenic niches located in two distinct areas of the brain: the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle, where new neurons are generated and then migrate to the olfactory bulb. Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells. Interestingly, recent years have seen tremendous progress in our understanding of adult brain neurogenesis, bridging the knowledge gap between embryonic and adult neurogenesis. Here, we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells. In this notion, we talk about the importance of intracellular signaling molecules in mobilizing endogenous neural stem cell proliferation. Based on the current understanding, we can declare that these molecules play a role in targeting neurogenesis in the mature brain. However, to achieve this goal, we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints, which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.
PubMed: 37488837
DOI: 10.4103/1673-5374.375317 -
Journal of Neurochemistry May 2024The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply....
The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI-MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β-hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition.
Topics: Animals; Glucose; Mice; Dentate Gyrus; Mice, Inbred C57BL; Male; Rest; Glycolysis; Energy Metabolism; Female
PubMed: 37929637
DOI: 10.1111/jnc.16004 -
Journal of Neuroinflammation Jun 2023Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is...
BACKGROUND
Neuroinflammation and microglia play critical roles in the development of depression. Cluster of differentiation 200 (CD200) is an anti-inflammatory glycoprotein that is mainly expressed in neurons, and its receptor CD200R1 is primarily in microglia. Although the CD200-CD200R1 pathway is necessary for microglial activation, its role in the pathophysiology of depression remains unknown.
METHODS
The chronic social defeat stress (CSDS) with behavioral tests were performed to investigate the effect of CD200 on the depressive-like behaviors. Viral vectors were used to overexpress or knockdown of CD200. The levels of CD200 and inflammatory cytokines were tested with molecular biological techniques. The status of microglia, the expression of BDNF and neurogenesis were detected with immunofluorescence imaging.
RESULTS
We found that the expression of CD200 was decreased in the dentate gyrus (DG) region of mice experienced CSDS. Overexpression of CD200 alleviated the depressive-like behaviors of stressed mice and inhibition of CD200 facilitated the susceptibility to stress. When CD200R1 receptors on microglia were knocked down, CD200 was unable to exert its role in alleviating depressive-like behavior. Microglia in the DG brain region were morphologically activated after exposure to CSDS. In contrast, exogenous administration of CD200 inhibited microglia hyperactivation, alleviated neuroinflammatory response in hippocampus, and increased the expression of BDNF, which in turn ameliorated adult hippocampal neurogenesis impairment in the DG induced by CSDS.
CONCLUSIONS
Taken together, these results suggest that CD200-mediated alleviation of microglia hyperactivation contributes to the antidepressant effect of neurogenesis in dentate gyrus in mice.
Topics: Animals; Mice; Brain-Derived Neurotrophic Factor; Microglia; Hippocampus; Neurogenesis; Dentate Gyrus
PubMed: 37391731
DOI: 10.1186/s12974-023-02836-4 -
Nature Neuroscience Mar 2024Episodic memories are encoded by experience-activated neuronal ensembles that remain necessary and sufficient for recall. However, the temporal evolution of memory...
Episodic memories are encoded by experience-activated neuronal ensembles that remain necessary and sufficient for recall. However, the temporal evolution of memory engrams after initial encoding is unclear. In this study, we employed computational and experimental approaches to examine how the neural composition and selectivity of engrams change with memory consolidation. Our spiking neural network model yielded testable predictions: memories transition from unselective to selective as neurons drop out of and drop into engrams; inhibitory activity during recall is essential for memory selectivity; and inhibitory synaptic plasticity during memory consolidation is critical for engrams to become selective. Using activity-dependent labeling, longitudinal calcium imaging and a combination of optogenetic and chemogenetic manipulations in mouse dentate gyrus, we conducted contextual fear conditioning experiments that supported our model's predictions. Our results reveal that memory engrams are dynamic and that changes in engram composition mediated by inhibitory plasticity are crucial for the emergence of memory selectivity.
Topics: Mice; Animals; Memory Consolidation; Mental Recall; Neurons; Fear; Memory, Episodic
PubMed: 38243089
DOI: 10.1038/s41593-023-01551-w -
Science (New York, N.Y.) Mar 2024The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells and dendrites of CA3 pyramidal neurons, is a key synapse in the trisynaptic... (Review)
Review
The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells and dendrites of CA3 pyramidal neurons, is a key synapse in the trisynaptic circuitry of the hippocampus. Because of its comparatively large size, this synapse is accessible to direct presynaptic recording, allowing a rigorous investigation of the biophysical mechanisms of synaptic transmission and plasticity. Furthermore, because of its placement in the very center of the hippocampal memory circuit, this synapse seems to be critically involved in several higher network functions, such as learning, memory, pattern separation, and pattern completion. Recent work based on new technologies in both nanoanatomy and nanophysiology, including presynaptic patch-clamp recording, paired recording, super-resolution light microscopy, and freeze-fracture and "flash-and-freeze" electron microscopy, has provided new insights into the structure, biophysics, and network function of this intriguing synapse. This brings us one step closer to answering a fundamental question in neuroscience: how basic synaptic properties shape higher network computations.
Topics: Mossy Fibers, Hippocampal; Presynaptic Terminals; Synaptic Transmission; CA3 Region, Hippocampal; Pyramidal Cells; Humans; Animals
PubMed: 38452088
DOI: 10.1126/science.adg6757 -
The EMBO Journal Nov 2023For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental... (Review)
Review
For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above-mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into "supra-pyramidal" and "infra-pyramidal". Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.
Topics: Animals; Dentate Gyrus; Hippocampus; Neurons; Learning; Memory; Neurogenesis; Mammals
PubMed: 37743770
DOI: 10.15252/embj.2023113524 -
Clinical EEG and Neuroscience Nov 2023Electroconvulsive therapy (ECT) is the most effective antidepressant treatment, although its mechanisms of action remain unclear. Since 2010, several structural magnetic... (Review)
Review
Electroconvulsive therapy (ECT) is the most effective antidepressant treatment, although its mechanisms of action remain unclear. Since 2010, several structural magnetic resonance imaging studies based on a neuroplastic hypothesis have consistently reported increases in the hippocampal volume following ECT. Moreover, volume increases in the human dentate gyrus, where neurogenesis occurs, have also been reported. These results are in line with the preclinical findings of ECT-induced neuroplastic changes, including neurogenesis, gliogenesis, synaptogenesis, and angiogenesis, in rodents and nonhuman primates. Despite this robust evidence of an effect of ECT on hippocampal plasticity, the clinical relevance of these human hippocampal changes continues to be questioned. This narrative review summarizes recent findings regarding ECT-induced hippocampal volume changes. Furthermore, this review also discusses methodological considerations and future directions in this field.
Topics: Animals; Humans; Electroconvulsive Therapy; Electroencephalography; Hippocampus; Magnetic Resonance Imaging; Antidepressive Agents
PubMed: 34547937
DOI: 10.1177/15500594211044066