Mtor and cerebral cortex

The primary cilium is a central signaling component during embryonic development. Here we focus on CROCCP2, a hominid-specific gene duplicate from ciliary rootlet coiled coil (CROCC), also known as rootletin, that encodes the major component of the ciliary rootlet. We find that CROCCP2 is highly expressed in the human fetal brain and not in other primate species. CROCCP2 gain of function in the mouse embryonic cortex and human cortical cells and organoids results in decreased ciliogenesis and increased cortical progenitor amplification, particularly basal progenitors...

Autism is often comorbid with other psychiatric disorders. We have previously shown that Dip2a knockout (KO) induces autism-like behaviors in mice. However, the role of Dip2a in other psychiatric disorders remains unclear. In this paper, we revealed that Dip2a KO mice had comorbid anxiety. Dip2a KO led to a reduction in the dendritic length of cortical and hippocampal excitatory neurons. Molecular mechanism studies suggested that AMPK was overactivated and suppressed the mTOR cascade, contributing to defects in dendritic morphology...

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates fundamental cellular processes including growth control, autophagy and metabolism. mTOR has key functions in nervous system development and mis-regulation of mTOR signaling causes aberrant neurodevelopment and neurological diseases, collectively called mTORopathies. In this mini review we discuss recent studies that have deepened our understanding of the key roles of the mTOR pathway in human nervous system development and disease...

In this study we aimed to reduce tau pathology, a hallmark of Alzheimer's Disease (AD), by activating mTOR-dependent autophagy in a transgenic mouse model of tauopathy by long-term dosing of animals with mTOR-inhibitors. Rapamycin treatment reduced the burden of hyperphosphorylated and aggregated pathological tau in the cerebral cortex only when applied to young mice, prior to the emergence of pathology. Conversely, PQR530 which exhibits better brain exposure and superior pharmacokinetic properties, reduced tau pathology even when the treatment started after the onset of pathology...

BACKGROUND: Alzheimer's disease (AD) was the main cause of dementia in an aging society; unfortunately, there is no effective treatment for AD now. Meditation has been reported to thicken the cerebral cortex, and gamma wave at a frequency of 40 hertz (Hz) was recorded during the meditation process from the brain. Previous study showed that non-invasive scintillation gamma frequency oscillation increased the space in recognition and memory of auditory cortex hippocampal gyrus in AD mice model...

OBJECTIVE: To observe the effect of electroacupuncture (EA) on miRNA-126-3p and mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway in rats with cerebral ischemia (CI), so as to explore the underlying mechanism of EA on angiogenesis. METHODS: Male SD rats were randomly divided into control group, model group, EA group and EA+inhibitor group (inhibitor group), which were further divided into 3, 7 and 14 d subgroups, with 12 rats in each sub-group...

Hemimegalencephaly, or unilateral megalencephaly, is a sporadic congenital brain malformation characterized by enlargement of a cerebral hemisphere due to an abnormal proliferation of neurons or glial cells. Hemimegalencephaly is part of a spectrum of disorders, increasingly referred to as mTORopathies, which arise as a result of dysregulation or hyperactivation of the mammalian target of rapamycin (mTOR)-signaling cascade resulting in less restricted cell growth and survival. The resultant cortical disorganization and enhanced neuronal excitability often manifest clinically in the form of seizures...

Myocardia-Related Transcription Factors-A (MRTF-A), which is enriched in the hippocampus and cerebral cortex, has been shown to have a protective function against ischemia hypoxia-induced neuronal apoptosis. However, the function of MRTF-A on β-amyloid peptide (Aβ)-induced neurotoxicity and autophagy dysfunction in Alzheimer's disease is still unclear. This study shows that the expression of MRTF-A in the hippocampus of Tg2576 transgenic mice is reduced, and the overexpression of MRTF-A mediated by lentiviral vectors carrying MRTF-A significantly reduces the accumulation of hippocampal β-amyloid peptide and reduces cognition defect...

ETHNOPHARMACOLOGICAL RELEVANCE: Piperine (PIP), a main active component isolated from Piper nigrum L., exerts neuroprotective effects in a rat model of ischemic stroke (IS). However, studies on the effects of PIP on neuroprotection and autophagy after IS are limited. AIM OF THE STUDY: This study aimed to prove the protective effects of PIP against brain IS and elucidate its underlying mechanisms. MATERIALS AND METHODS: Specific pathogen-free male Sprague-Dawley rats were selected to establish a permanent middle cerebral artery occlusion model...

The tuberous sclerosis complex (TSC) 1 and 2 proteins associate with TBC1D7 to form the TSC complex, which is an essential suppressor of mTOR complex 1 (mTORC1), a ubiquitous driver of cell and tissue growth. Loss-of-function mutations in TSC1 or TSC2, but not TBC1D7, give rise to TSC, a pleiotropic disorder with aberrant activation of mTORC1 in various tissues. Here, we characterize mice with genetic deletion of Tbc1d7, which are viable with normal growth and development. Consistent with partial loss of function of the TSC complex, Tbc1d7 knockout (KO) mice display variable increases in tissue mTORC1 signaling with increased muscle fiber size but with strength and motor defects...

Urolithin A (UA) is a natural metabolite produced from polyphenolics in foods such as pomegranates, berries, and nuts. UA is neuroprotective against Parkinson's disease, Alzheimer's disease, and cerebral hemorrhage. However, its effect against traumatic brain injury remains unknown. In this study, we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA. We found that UA greatly reduced brain edema; increased the expression of tight junction proteins in injured cortex; increased the immunopositivity of two neuronal autophagy markers, microtubule-associated protein 1A/B light chain 3A/B (LC3) and p62; downregulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), two regulators of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway; decreased the phosphorylation levels of inhibitor of NFκB (IκB) kinase alpha (IKKα) and nuclear factor kappa B (NFκB), two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway; reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex; and improved mouse neurological function...

Mutations in nitrogen permease regulator-like 3 (NPRL3), a component of the GATOR1 complex within the mTOR pathway, are associated with epilepsy and malformations of cortical development. Little is known about the effects of NPRL3 loss on neuronal mTOR signalling and morphology, or cerebral cortical development and seizure susceptibility. We report the clinical phenotypic spectrum of a founder NPRL3 pedigree (c.349delG, p.Glu117LysFS; n = 133) among Old Order Mennonites dating to 1727. Next, as a strategy to define the role of NPRL3 in cortical development, CRISPR/Cas9 Nprl3 knockout in Neuro2a cells in vitro and in foetal mouse brain in vivo was used to assess the effects of Nprl3 knockout on mTOR activation, subcellular mTOR localization, nutrient signalling, cell morphology and aggregation, cerebral cortical cytoarchitecture and network integrity...

Cadmium is a toxic metal that can damage the brain and other organs. This study aimed to explore the protective effects of Potentilla anserine L. polysaccharide (PAP) against CdCl2 -induced neurotoxicity in N2a and SH-SY5Y cells and in the cerebral cortex of BALB/c mice. In addition, we aimed to identify the potential mechanisms underlying these protective effects. Relative to CdCl2 treatment alone, pretreatment with PAP prevented the reduction in cell viability evoked by CdCl2 , decreased rates of apoptosis, promoted calcium homeostasis, decreased ROS accumulation, increased mitochondrial membrane potential, inhibited cytochrome C and AIF release, and prevented the cleavage of caspase-3 and PARP...

Spontaneous recovery of ischemic stroke is very limited and often results in the loss of motor and sensory function. Till now, rehabilitative training is the most widely accepted therapy to improve long-term outcome. However, its effectiveness is often suboptimal, largely due to a sharp decline of neuroplasticity in adults. In this study, we hypothesized that a combination of proprioceptive stimulation and rehabilitative training will promote neuroplasticity and functional recovery post injury. To test this hypothesis, we first established a photothrombotic stroke model that lesions the hindlimb sensorimotor cortex...

Objective: Ischemic stroke is an important cause of death and disability worldwide. Early reperfusion by thrombolysis or thrombectomy has improved the outcome of acute ischemic stroke. However, the therapeutic window for reperfusion therapy is narrow, and adjuvant therapy for neuroprotection is demanded. Electrical stimulation (ES) has been reported to be neuroprotective in many neurological diseases. In this study, the neuroprotective effect of early somatosensory cortical ES in the acute stage of ischemia/reperfusion injury was evaluated...

Septic encephalopathy results from the intense reaction of the immune system to infection. The role of growth hormone (GH) signaling in maintaining brain function is well established; however, the involvement of the vascular endothelial growth factor receptor-2 (VEGFR2) in the potential modulatory effect of GH on septic encephalopathy-associated endoplasmic reticulum stress (ERS) and blood-brain barrier (BBB) permeability is not well-understood. Therefore, after the induction of mid-grade sepsis by cecal ligation/perforation, rats were subcutaneously injected with recombinant human GH (rhGH)/somatropin alone or preceded by the VEGFR2 antagonist WAG-4S for 7 days...

Axon regeneration after spinal cord injury (SCI) is limited by both a decreased intrinsic ability of neurons to grow axons and the growth-hindering effects of extrinsic inhibitory molecules expressed around the lesion. Deletion of phosphatase and tensin homolog ( Pten ) augments mechanistic target of rapamycin (mTOR) signaling and enhances the intrinsic regenerative response of injured corticospinal neurons after SCI. Because of the variety of growth-restrictive extrinsic molecules, it remains unclear how inhibition of conserved inhibitory signaling elements would affect axon regeneration and rewiring after SCI...

Apoptosis is an intrinsic biochemical, cellular process that regulates cell death and is crucial for cell survival, cellular homeostasis, and maintaining the optimum functional status. Apoptosis in a predetermined and programmed manner regulates several molecular events, including cell turnover, embryonic development, and immune system functions but may be the exclusive contributor to several disorders, including neurodegenerative manifestations, when it functions in an aberrant and disorganized manner. Alzheimer's disease (AD) is a fatal, chronic neurodegenerative disorder where apoptosis has a compelling and divergent role...

It has been reported that the mechanistic target of rapamycin (mTOR) pathway is involved in cerebral ischemia-reperfusion injury. One of the important pathological changes during reperfusion after cerebral ischemia is disruption of blood-brain barrier (BBB). Rapamycin, a first-generation mTOR inhibitor, produces divergent effects on neuronal survival and alteration in BBB disruption. In this study, we investigated how Rapalink-1, a third-generation mTOR inhibitor, would affect neuronal survival and BBB disruption in the very early stage of cerebral ischemia-reperfusion that is within the time window of thrombolysis therapy...

Methylmercury (MeHg) is a environmental contaminant, which can induce neurotoxic effects. So far, the exact molecular mechanisms of autophagy and its effect on apoptosis in MeHg-induced neurotoxicity have not been elucidated. Here, rats were exposed to MeHg (4, 8, or 12 μmol/kg) for 4 weeks to evaluate the dose-effect relationship between MeHg and apoptosis, or autophagy in cerebral cortex. On this basis, rapamycin (Rapa) or 3-methyladenine (3-MA) was administrated to further explore the regulatory mechanisms of autophagy on MeHg-induced neuronal apoptosis...