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Microglia play a vital role in maintaining brain homeostasis. Their continuous sensing of surrounding micro‐environments is crucial for their activity. Cross talk between specific neurons and microglia might occur through specific neurotransmitter receptors on microglia. Impairment with this interaction might result in pathological activity of microglia against potential insults. The reason for this activity in many neurodegenerative diseases such as Alzheimer's disease (AD) is not known. However, several papers report of the effects of different neurotransmitter agonists on microglial cells function that relate to their activity in AD. This review aims to summarize those works and to raise potential fundamental questions for future research. [ABSTRACT FROM AUTHOR]

Phosphacan, a chondroitin sulfate proteoglycan, is a repulsive cue of cerebellar granule cells. This study aims to explore the molecular mechanism. The glycosylphosphatidylinositol‐anchored neural adhesion molecule TAG‐1 is a binding partner of phosphacan, suggesting that the repulsive effect of phosphacan is possibly because of its interaction with TAG‐1. The repulsive effect was greatly reduced on primary cerebellar granule cells of TAG‐1‐deficient mice. Surface plasmon resonance analysis confirmed the direct interaction of TAG‐1 with chondroitin sulfate C. On postnatal days 1, 4, 7, 11, 15, and 20 and in adulthood, phosphacan was present in the molecular layer and internal granular layer, but not in the external granular layer. In contrast, transient TAG‐1 expression was observed exclusively within the premigratory zone of the external granular layer on postnatal days 1, 4, 7, and 11. Boyden chamber cell migration assay demonstrated that phosphacan exerted its repulsive effect on the spontaneous and brain‐derived neurotrophic factor (BDNF)‐induced migration of cerebellar granule cells. The BDNF‐induced migration was inhibited by MK‐2206, an Akt inhibitor. The pre‐treatment with a raft‐disrupting agent, methyl‐β‐cyclodextrin, also inhibited the BDNF‐induced migration, suggesting that lipid rafts are involved in the migration of cerebellar granule cells. In primary cerebellar granule cells obtained on postnatal day 7 and cultured for 7 days, the ganglioside GD3 and TAG‐1 preferentially localized in the cell body, whereas the ganglioside GD1b and NB‐3 localized in not only the cell body but also neurites. Pre‐treatment with the anti‐GD3 antibody R24, but not the anti‐GD1b antibody GGR12, inhibited the spontaneous and BDNF‐induced migration, and attenuated BDNF‐induced Akt activation. These findings suggest that phosphacan is responsible for the repulsion of TAG‐1‐expressing cerebellar granule cells via GD3 rafts to attenuate BDNF‐induced migration signaling. [ABSTRACT FROM AUTHOR]

BDNF and its expressing neurons in the brain critically control feeding and energy expenditure (EE) in both rodents and humans. However, whether BDNF neurons would function in thermoregulation during temperature challenges is unclear. Here, we show that BDNF neurons in the dorsomedial hypothalamus (DMHBDNF) of mice are activated by afferent cooling signals. These cooling‐activated BDNF neurons are mainly GABAergic. Activation of DMHBDNF neurons or the GABAergic subpopulations is sufficient to increase body temperature, EE, and physical activity. Conversely, blocking DMHBDNF neurons substantially impairs cold defense and reduces energy expenditure, physical activity, and UCP1 expression in BAT, which eventually results in bodyweight gain and glucose/insulin intolerance. Therefore, we identify a subset of DMHBDNF neurons as a novel type of cooling‐activated neurons to promote cold defense. Thus, we reveal a critical role of BDNF circuitry in thermoregulation, which deepens our understanding of BDNF in controlling energy homeostasis and obesity. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD), a progressive neurodegenerative disorder, is mainly caused by the interaction of genetic and environmental factors. The impact of environmental factors on the genetic mutation in the amyloid precursor protein (APP) is not well characterized. We hypothesized that endoplasmic reticulum (ER) stress would promote disease for the patient carrying the APP D678H mutation. Therefore, we analyzed the impact of a familial AD mutation on amyloid precursor protein (APP D678H) under ER stress. Induced pluripotent stem cells (iPSCs) from APP D678H mutant carrier was differentiated into neurons, which were then analyzed for AD‐like changes. Immunocytochemistry and whole‐cell patch‐clamp recording revealed that the derived neurons on day 28 after differentiation showed neuronal markers and electrophysiological properties similar to those of mature neurons. However, the APP D678H mutant neurons did not have significant alterations in the levels of amyloid‐β (Aβ) and phosphorylated tau (pTau) compared to its isogenic wild‐type neurons. Only under ER stress, the neurons with the APP D678H mutation had more Aβ and pTau via immune detection assays. The higher level of Aβ in the APP D678H mutant neurons was probably due to the increased level of β‐site APP cleaving enzyme (BACE1) and decreased level of Aβ‐degrading enzymes under ER stress. Increased Aβ and pTau under ER stress reduced the N‐methyl‐D‐aspartate receptor (NMDAR) in Western blot analysis and altered electrophysiological properties in the mutant neurons. Our study provides evidence that the interaction between genetic mutation and ER stress would induce AD‐like changes. Cover Image for this issue: https://doi.org/10.1111/jnc.15420 [ABSTRACT FROM AUTHOR]

A confluence of factors has renewed interest in the scientific understanding and translational potential of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin: the desire for additional approaches to mental health care, incremental progress in basic and clinical research, and the reconsideration and relaxation of existing drug policies. With the United States Food and Drug Administration's designation of psilocybin as a "Breakthrough Therapy" for treatment‐resistant depression, a new path has been forged for the conveyance of psychedelics to the clinic. Essential to the further development of such applications, however, is a clearer understanding of how these drugs exert their effects at the molecular level. Here we review the current knowledge regarding the molecular details of psychedelic drug actions and suggest that these discoveries can facilitate new insights into their hallucinogenic and therapeutic mechanisms. [ABSTRACT FROM AUTHOR]

Neocortex development comprises of a complex series of time‐ and space‐specific processes to generate the typical interconnected six‐layered architecture of adult mammals. Axon growth is required for the proper establishment of cortical circuits. Malformations in axonal growth and pathfinding might lead to severe neuropathologies, such as corpus callosum dysgenesis. Cenpj, a microcephaly gene, encodes a scaffold protein that regulates centrosome biogenesis and microtubule stabilization. During corticogenesis, Cenpj regulates progenitor division and neuronal migration. Since microtubule stabilization is crucial for axon extension, we investigated the role of Cenpj in axon growth during cortical development in a mouse model. Through loss‐ and gain‐of‐function assays ex vivo and in utero, we quantified callosal axonal length, branching, and growth cone size compared to controls. We observed that silencing Cenpj results in an increased axonal length. Ex vivo, we assessed the number of branches, the area of growth cones and the stability of microtubules. In silenced Cenpj axons, there were more branches, larger growth cone area, and more stable microtubules. Rescue experiments confirmed that neurons present axonal length comparable to controls. Here we propose that Cenpj regulates axon growth by destabilizing microtubules during cortical development. Finally, our findings suggest that Cenpj might be a novel target for axonal regeneration. [ABSTRACT FROM AUTHOR]

Pigment epithelium‐derived factor (PEDF) is a cytoprotective protein for the retina. We hypothesize that this protein acts on neuronal survival and differentiation of photoreceptor cells in culture. The purpose of the present study was to evaluate the neurotrophic effects of PEDF and its fragments in an in vitro model of cultured primary retinal neurons that die spontaneously in the absence of trophic factors. We used Wistar albino rats. Cell death was assayed by immunofluorescence and flow cytometry through TUNEL assay, propidium iodide, mitotracker, and annexin V. Immunofluorescence of cells for visualizing rhodopsin, CRX, and antisyntaxin under confocal microscopy was performed. Neurite outgrowth was also quantified. Results show that PEDF protected photoreceptor precursors from apoptosis, preserved mitochondrial function and promoted polarization of opsin enhancing their developmental process, as well as induced neurite outgrowth in amacrine neurons. These effects were abolished by an inhibitor of the PEDF receptor or receptor‐derived peptides that block ligand/receptor interactions. While all the activities were specifically conferred by short peptide fragments (17 amino acid residues) derived from the PEDF neurotrophic domain, no effects were triggered by peptides from the PEDF antiangiogenic region. The observed effects on retinal neurons imply a specific activation of the PEDF receptor by a small neurotrophic region of PEDF. Our findings support the neurotrophic PEDF peptides as neuronal guardians for the retina, highlighting their potential as promoters of retinal differentiation, and inhibitors of retinal cell death and its blinding consequences. Cover Image for this issue:https://doi.org/10.1111/jnc.15089 [ABSTRACT FROM AUTHOR]

Two common conjugated linoleic acids (LAs), cis‐9, trans‐11 CLA (c9,t11 CLA) and trans‐10, cis‐12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid‐β (Aβ) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aβ in mouse neurons. CLA treatment did not affect the level of β‐site APP‐cleaving enzyme 1 (BACE1), a component of active γ‐secretase complex presenilin 1 amino‐terminal fragment, or Aβ protein precursor (APP) in cultured neurons. BACE1 and γ‐secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA‐containing phosphatidylcholine (CLA‐PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane‐associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aβ generation. Our findings suggest that the accumulation of c9,t11 CLA‐PC/LPC in neuronal membranes suppresses the production of neurotoxic Aβ in neurons. [ABSTRACT FROM AUTHOR]