Null effect of antidepressants on the astrocytes-mediated proliferation of hippocampal progenitor cells in vitro

<p>Abstract</p> <p>Background</p> <p>It is well known that antidepressants increase neurogenesis in the dentate gyrus of the hippocampus. The increase of neurogenesis might contribute to the behavioral effects of antidepressants. However, the mechanism by which antidepressants increase hippocampal neurogenesis is largely unknown. It has been recently reported that astroglia induce the neurogenesis of the hippocampal neural progenitor cells (NPCs). Therefore, we hypothesized that antidepressants may act on astrocytes, and this in turn induces neurogenesis of NPCs.</p> <p>Results</p> <p>To examine this hypothesis, we used two co-culture systems, i.e., a contact-independent Banker culture and a contact-dependent overlay co-culture. In both of these systems, in comparison with naïve astrocytes, antidepressant-treated astrocytes did not further increase the proliferation of NPCs.</p> <p>Conclusion</p> <p>These results suggest that astrocytes increase the proliferation of hippocampal NPCs, however, this may not be directly involved in the antidepressant-induced proliferation of NPCs.</p

Molecular Pathogenesis of Alzheimer’s Disease: Reductionist versus Expansionist Approaches

Alzheimer’s disease (AD) is characterized clinically by dementia and pathologically by two hallmark lesions, senile plaques and neurofibrillary tangles. About a quarter century ago these hallmark lesions were purified and their protein constituents identified, precipitating an avalanche of molecular studies as well as substantial optimism about successful therapeutic intervention. In 2009, we now have copious knowledge on the biochemical cascades that produce these proteins, the different modifications and forms in which these proteins exist, and the ability to selectively target these proteins for therapeutic intervention on an experimental basis. At the same time, there has been no discernible alteration in the natural course of AD in humans. While it may be that the complexity of AD will exceed our capacity to make significant treatment progress for decades or more, a paradigm shift from the reductionism that defines amyloid-β and tau hypotheses, to one that more accurately reflects the meaning of neuropathological changes, may be warranted. We and others have demonstrated that AD pathology is a manifestation of cellular adaptation, specifically as a defense against oxidative injury. As such, AD pathology is therefore a host response rather than a manifestation of cytotoxic protein injury, and is unlikely to be a fruitful target for therapeutic intervention. An “expansionist” view of the disease, we believe, with oxidative stress as a pleiotropic and upstream process, more aptly describes the relationship between various and numerous molecular alterations and clinical disease

Loosely synchronized activation of anterior cingulate cortical neurons for scratching response during histamine-induced itch

Itch is a distinctive sensation that causes a specific affection and scratching reaction. The anterior cingulate cortex (ACC) has been linked to itch sensation in numerous studies; however, its precise function in processing pruritic inputs remains unknown. Distinguishing the precise role of the ACC in itch sensation can be challenging because of its capacity to conduct heterologous neurophysiological activities. Here, we used in vivo calcium imaging to examine how ACC neurons in free-moving mice react to pruritogenic histamine. In particular, we focused on how the activity of the ACC neurons varied before and after the scratching response. We discovered that although the change in neuronal activity was not synchronized with the scratching reaction, the overall activity of itch-responsive neurons promptly decreased after the scratching response. These findings suggest that the ACC does not directly elicit the feeling of itchiness.This work was supported by grants from the National Research Foundation (NRF) of Korea funded by the Korean government (MSIP) (NRF-2012R1A3A1050385 (B-KK), 2021R1A2C1013092 (H-GK), and 2022R1F1A1071248 (J-HL

PKA-activated ApAF–ApC/EBP heterodimer is a key downstream effector of ApCREB and is necessary and sufficient for the consolidation of long-term facilitation

Long-term memory requires transcriptional regulation by a combination of positive and negative transcription factors. Aplysia activating factor (ApAF) is known to be a positive transcription factor that forms heterodimers with ApC/EBP and ApCREB2. How these heterodimers are regulated and how they participate in the consolidation of long-term facilitation (LTF) has not, however, been characterized. We found that the functional activation of ApAF required phosphorylation of ApAF by PKA on Ser-266. In addition, ApAF lowered the threshold of LTF by forming a heterodimer with ApCREB2. Moreover, once activated by PKA, the ApAF–ApC/EBP heterodimer transactivates enhancer response element–containing genes and can induce LTF in the absence of CRE- and CREB-mediated gene expression. Collectively, these results suggest that PKA-activated ApAF–ApC/EBP heterodimer is a core downstream effector of ApCREB in the consolidation of LTF

Tau phosphorylation in Alzheimer's disease: pathogen or protector?

During the past decade, hypotheses concerning the pathogenesis of most neurodegenerative diseases have been dominated by the notion that the aggregation of specific proteins and subsequent formation of cytoplasmic and extracellular lesions represent a harbinger of neuronal dysfunction and death. As such, in Alzheimer's disease, phosphorylated tau protein, the major component of neurofibrillary tangles, is considered a central mediator of disease pathogenesis. We challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress and serves a protective function. This novel concept, which can also be applied to protein aggregates in other neurodegenerative diseases, opens a new window of knowledge with broad implications for both the understanding of mechanisms underlying disease pathophysiology and the design of new therapeutic strategies.http://www.sciencedirect.com/science/article/B6W7J-4FNNC51-2/1/3fd57243f3b01d6654fbf488fd3d00a

Proteomic analysis of synaptic protein turnover in the anterior cingulate cortex after nerve injury

Synaptic proteins play an important role for the regulation of synaptic plasticity. Numerous studies have identified and revealed individual synaptic protein functions using protein overexpression or deletion. In neuropathic pain nociceptive stimuli conveyed from the periphery repetitively stimulate neurons in the central nerve system, brain and spinal cord. Neuronal activities change the turnover (synthesis and degradation) rate of synaptic proteins. Thus, the analysis of synaptic protein turnover rather than just expression level change is critical for studying the role of synaptic proteins in synaptic plasticity. Here, we analyzed synaptosomal proteome in the anterior cingulate cortex (ACC) to identify protein turnover rate changes caused by peripheral nerve injury. Whereas PKCγ levels were not altered, we found that the proteins turnover rate decreased after peripheral nerve injury. Our results suggest that postsynaptic PKCγ synthesized by neuronal activities in the ACC is translocated to the postsynaptic membrane with an extended half-life.This work was supported by two National Research Foundation (NRF) of Korea grants funded by the Korean government (MSIP) [NRF2012R1A3A1050385 to BKK and 2018R1C1B6008530 to HGK] and the Max Planck Society to CWT and DIP

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory

Ferromagnetic quasi-atomic electrons in two-dimensional electride.

An electride, a generalized form of cavity-trapped interstitial anionic electrons (IAEs) in a positively charged lattice framework, shows exotic properties according to the size and geometry of the cavities. Here, we report that the IAEs in layer structured [Gd2C]2+·2e- electride behave as ferromagnetic elements in two-dimensional interlayer space and possess their own magnetic moments of ~0.52 μB per quasi-atomic IAE, which facilitate the exchange interactions between interlayer gadolinium atoms across IAEs, inducing the ferromagnetism in [Gd2C]2+·2e- electride. The substitution of paramagnetic chlorine atoms for IAEs proves the magnetic nature of quasi-atomic IAEs through a transition from ferromagnetic [Gd2C]2+·2e- to antiferromagnetic Gd2CCl caused by attenuating interatomic exchange interactions, consistent with theoretical calculations. These results confirm that quasi-atomic IAEs act as ferromagnetic elements and trigger ferromagnetic spin alignments within the antiferromagnetic [Gd2C]2+ lattice framework. These results present a broad opportunity to tailor intriguing ferromagnetism originating from quasi-atomic interstitial electrons in low-dimensional materials