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Gamma-oryzanol (ORY), found in rice (Oryza sativa L.), is a mixture of ferulic acid esters with triterpene alcohols, well-known for its antioxidant and anti-inflammatory properties. Our past research demonstrated its positive impact on cognitive function in adult mice, influencing synaptic plasticity and neuroprotection. In this study, we explored whether ORY can exert neuro-differentiating effects by using different experimental models. For this purpose, chemical characterization identified four components that are most abundant in ORY. In human neuroblastoma cells, we showed ORY's ability to stimulate neurite outgrowth, upregulating the expression of GAP43, BDNF, and TrkB genes. In addition, ORY was found to guide adult mouse hippocampal neural progenitor cells (NPCs) toward a neuronal commitment. Microinjection of ORY in zebrafish Tg (-3.1 neurog1:GFP) amplified neurog1-GFP signal, islet1, and bdnf mRNA levels. Zebrafish nrf2a and nrf2b morphants (MOs) were utilized to assess ORY effects in the presence or absence of Nrf2. Notably, ORY's ability to activate bdnf was nullified in nrf2a-MO and nrf2b-MO. Furthermore, computational analysis suggested ORY's single components have different affinities for the Keap1-Kelch domain. In conclusion, although more in-depth studies are needed, our findings position ORY as a potential source of bioactive molecules with neuro-differentiating potential involving the Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Adolescence represents a crucial period for maturation of brain structures involved in cognition. Early in life unhealthy dietary patterns are associated with inferior cognitive outcomes at later ages; conversely, healthy diet is associated with better cognitive results. In this study we analyzed the effects of a short period of hypercaloric diet on newborn hippocampal doublecortin+ (DCX) immature neurons in adolescent mice. Male mice received high fat diet (HFD) or control low fat diet (LFD) from the 5th week of age for 1 or 2 weeks, or 1 week HFD followed by 1 week LFD. After diet supply, mice were either perfused for immunohistochemical (IHC) analysis or their hippocampi were dissected for biochemical assays. Detailed morphometric analysis was performed in DCX+ cells that displayed features of immature neurons. We report that 1 week-HFD was sufficient to dramatically reduce dendritic tree complexity of DCX+ cells. This effect occurred specifically in dorsal and not ventral hippocampus and correlated with reduced BDNF expression levels in dorsal hippocampus. Both structural and biochemical changes were reversed by a return to LFD. Altogether these studies increase our current knowledge on potential consequences of hypercaloric diet on brain and in particular on dorsal hippocampal neuroplasticity. [ABSTRACT FROM AUTHOR]

Dysregulated hippocampal neurogenesis has been associated with neurodegenerative disorders, including Alzheimer's disease (AD), in which it may potentially represent an auto-reparatory mechanism that could counteract neuronal loss and cognitive impairment. We evaluated hippocampal neurogenesis in TgCRND8 mice and reported that, at 32 weeks of age, corresponding to an advanced AD-like neuropathology stage, increased numbers of proliferating cells, doublecortin-expressing progenitors/neuroblasts, and early postmitotic calretinin-expressing neurons were present compared with wild-type (WT) littermates. When hippocampal neural progenitor cells (NPCs) were isolated from TgCRND8 mice, we demonstrated that (1) their neurogenic potential was higher compared with WT NPCs; (2) medium conditioned by TgCRND8 NPC promoted neuronal differentiation of WT NPCs; and (3) the proneurogenic effect of TgCRND8-conditioned medium was counteracted by blockade of the receptor for advanced glycation end products (RAGE)/nuclear factor-κB (NF-κB) axis. Furthermore, we showed that β-amyloid 1-42 (Aβ1-42) oligomers, but not monomers and fibrils, and the alarmin high-mobility group box-1 protein (HMGB-1) could promote neuronal differentiation of NPCs via activation of the RAGE/NF-κB axis. Altogether, these data suggest that, in AD brain, an endogenous proneurogenic response could be potentially triggered and involve signals (Aβ1-42 oligomers and HMGB-1) and pathways (RAGE/NFκB activation) that also contribute to neuroinflammation/neurotoxicity. A more detailed analysis confirmed no significant increase of new mature neurons in hippocampi of TgCRND8 compared with WT mice, suggesting reduced survival and/or integration of newborn neurons. Therapeutic strategies in AD should ideally combine the ability of sustaining hippocampal neurogenesis as well as of counteracting an hostile brain microenvironment so to promote survival of vulnerable cell populations, including adult generated neurons. [ABSTRACT FROM AUTHOR]

Neurogenesis proceeds throughout adulthood in the brain of most mammalian species, but the molecular mechanisms underlying the regulation of stem/progenitor cell proliferation, survival, maturation, and differentiation have not been completely unraveled. We have studied hippocampal neurogenesis in NF-κB p50-deficient mice. Here we demonstrate that in absence of p50, the net rate of neural precursor proliferation does not change, but some of the steps leading to the final neuron differentiation status are hampered, resulting in ∼50% reduction in the number of newly born neurons in the adult mutant hippocampus. Additionally, in p50-/- mice, we observed a selective defect in short-term spatial memory performance without impairment of hippocampal-dependent spatial long-term memory and learning. Our results highlight the role of NF-κB p50 in hippocampal neurogenesis and in short-term spatial memory. [ABSTRACT FROM AUTHOR]

Positive modulation of adult hippocampal neurogenesis may contribute to the therapeutic effects of clinically relevant antidepressant drugs, including atypical antipsychotics. Quetiapine, an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants, promotes adult hippocampal neurogenesis in preclinical studies. Norquetiapine, the key active metabolite of quetiapine in humans, has a distinctive receptor profile than the parent compound. The drug is indeed a high affinity norepinephrine transporter inhibitor and such activity has been proposed to contribute to its antidepressant effect. At present, no information is available on the effects of norquetiapine on adult neurogenesis. We extensively investigated the activity of quetiapine and norquetiapine on adult murine neural stem/progenitor cells and their progeny. Additionally, selective antagonists for β 2 /α 2 adrenergic receptors allowed us to evaluate if these receptors could mediate quetiapine and norquetiapine effects. We demonstrated that both drugs elicit in vitro proneurogenic effects but also that norquetiapine had distinctive properties which may depend on its ability to inhibit norepinephrine transporter and involve β 2 /α 2 adrenergic receptors. Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at University of Piemonte Orientale, Italy (approval No. 1033/2015PR) on September 29, 2015., Competing Interests: None

Competing Interests: None

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca 2+ /calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein-expressing astrocytes (astroglial calcineurin KO [ACN-KO]). Here, we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K + homeostasis. Indeed, blockade of Na + /K + -ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca 2+ -sensitive switch., (© 2019 Wiley Periodicals, Inc.)

Within the CNS nuclear factor-kappa B (NF-κB) transcription factors are involved in a wide range of functions both in homeostasis and in pathology. Over the years, our and other groups produced a vast array of information on the complex involvement of NF-κB proteins in different aspects of postnatal neurogenesis. In particular, several extracellular signals and membrane receptors have been identified as being able to affect neural progenitor cells (NPC) and their progeny via NF-κB activation. A crucial role in the regulation of neuronal fate specification in adult hippocampal NPC is played by the NF-κB p50 subunit. NF-κB p50KO mice display a remarkable reduction in adult hippocampal neurogenesis which correlates with a selective defect in hippocampal-dependent short-term memory. Moreover absence of NF-κB p50 can profoundly affect the in vitro proneurogenic response of adult hippocampal NPC (ahNPC) to several endogenous signals and drugs. Herein we briefly review the current knowledge on the pivotal role of NF-κB p50 in the regulation of adult hippocampal neurogenesis. In addition we discuss more recent data that further extend the relevance of NF-κB p50 to novel astroglia-derived signals which can influence neuronal specification of ahNPC and to astrocyte-NPC cross-talk., Competing Interests: Conflicts of interest: None declared.

Background & Objective: Since its initial discovery, current understanding on the functional role of the Receptor for Advanced Glycation End-products (RAGE) in physiology and in pathology has impressively grown, especially in consideration of its large ligand repertoire (AGEs, HMGB-1, β amyloid, S100B/S100A12) and its potential involvement in the pathophysiology of several chronic human disorders. Downstream RAGE engagement by its ligands, NF-κB signaling activation has been demonstrated in several cell phenotypes, including neurons and glia. Based on the observation that in Alzheimer's Disease (AD) brain expression of RAGE and its ligands is upregulated and that RAGE/NF-κB axis activation can trigger an autoregulatory loop which further amplifies neuroinflammation and neurodegeneration, this signaling pathway has been hypothesized to greatly contribute to AD pathophysiology. Herein we review the vast array of information supporting a detrimental role of RAGE/NF-κB axis activation in AD brain and discuss those data in the context of recent findings obtained in our laboratory pointing to an unexpected effect elicited by this signaling pathway which may rather contribute to reparative mechanisms in AD, namely positive modulation of adult neurogenesis. Interestingly, the proneurogenic effect resulting from RAGE/NF-κB axis activation could be induced by molecules which are commonly considered as mediators of toxicity, like Aβ oligomers and HMGB-1., Conclusion: Altogether, despite a large set of data suggesting that RAGE may represent an interesting target for the pharmacological treatment of AD, the complex functional roles of the receptor would require the use of molecules able to counteract RAGE negative effects without altering the positive ones such as the promotion of adult neurogenesis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)