Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain growth and cognitive function. Consistent with its importance in the brain, DHA is highly enriched in brain ...phospholipids. Despite being an abundant fatty acid in brain phospholipids, DHA cannot be de novo synthesized in brain and must be imported across the blood-brain barrier, but mechanisms for DHA uptake in brain have remained enigmatic. Here we identify a member of the major facilitator superfamily--Mfsd2a (previously an orphan transporter)--as the major transporter for DHA uptake into brain. Mfsd2a is found to be expressed exclusively in endothelium of the blood-brain barrier of micro-vessels. Lipidomic analysis indicates that Mfsd2a-deficient (Mfsd2a-knockout) mice show markedly reduced levels of DHA in brain accompanied by neuronal cell loss in hippocampus and cerebellum, as well as cognitive deficits and severe anxiety, and microcephaly. Unexpectedly, cell-based studies indicate that Mfsd2a transports DHA in the form of lysophosphatidylcholine (LPC), but not unesterified fatty acid, in a sodium-dependent manner. Notably, Mfsd2a transports common plasma LPCs carrying long-chain fatty acids such LPC oleate and LPC palmitate, but not LPCs with less than a 14-carbon acyl chain. Moreover, we determine that the phosphor-zwitterionic headgroup of LPC is critical for transport. Importantly, Mfsd2a-knockout mice have markedly reduced uptake of labelled LPC DHA, and other LPCs, from plasma into brain, demonstrating that Mfsd2a is required for brain uptake of DHA. Our findings reveal an unexpected essential physiological role of plasma-derived LPCs in brain growth and function.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term ...cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response-particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.
Cellular scaling rules for primate brains Herculano-Houzel, Suzana; Collins, Christine E; Wong, Peiyan ...
Proceedings of the National Academy of Sciences,
02/2007, Letnik:
104, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Primates are usually found to have richer behavioral repertoires and better cognitive abilities than rodents of similar brain size. This finding raises the possibility that primate brains differ from ...rodent brains in their cellular composition. Here we examine the cellular scaling rules for primate brains and show that brain size increases approximately isometrically as a function of cell numbers, such that an 11x larger brain is built with 10x more neurons and almost equal to12x more nonneuronal cells of relatively constant average size. This isometric function is in contrast to rodent brains, which increase faster in size than in numbers of neurons. As a consequence of the linear cellular scaling rules, primate brains have a larger number of neurons than rodent brains of similar size, presumably endowing them with greater computational power and cognitive abilities.
Larger brains have an increasingly folded cerebral cortex whose white matter scales up faster than the gray matter. Here we analyze the cellular composition of the subcortical white matter in 11 ...primate species, including humans, and one Scandentia, and show that the mass of the white matter scales linearly across species with its number of nonneuronal cells, which is expected to be proportional to the total length of myelinated axons in the white matter. This result implies that the average axonal cross-section area in the white matter, a, does not scale significantly with the number of neurons in the gray matter, N. The surface area of the white matter increases with N 0.87 , not N 1.0 . Because this surface can be defined as the product of N, a, and the fraction n of cortical neurons connected through the white matter, we deduce that connectivity decreases in larger cerebral cortices as a slowly diminishing fraction of neurons, which varies with N -0.16 , sends myelinated axons into the white matter. Decreased connectivity is compatible with previous suggestions that neurons in the cerebral cortex are connected as a small-world network and should slow down the increase in global conduction delay in cortices with larger numbers of neurons. Further, a simple model shows that connectivity and cortical folding are directly related across species. We offer a white matter-based mechanism to account for increased cortical folding across species, which we propose to be driven by connectivity-related tension in the white matter, pulling down on the gray matter.
Patients with amyotrophic lateral sclerosis (ALS) can have abnormal TDP-43 aggregates in the nucleus and cytosol of their surviving neurons and glia. Although accumulating evidence indicates that ...astroglial dysfunction contributes to motor neuron degeneration in ALS, the normal function of TDP-43 in astrocytes are largely unknown, and the role of astroglial TDP-43 loss to ALS pathobiology remains to be clarified. Herein, we show that TDP- 43–deleted astrocytes exhibit a cell-autonomous increase in GFAP immunoreactivity without affecting astrocyte or microglia proliferation. At the transcriptomic level, TDP-43–deleted astrocytes resemble A1-reactive astrocytes and induce microglia to increase C1q expression. These astrocytic changes do not cause loss of motor neurons in the spinal cord or denervation at the neuromuscular junction. In contrast, there is a selective reduction of mature oligodendrocytes, but not oligodendrocyte precursor cells, suggesting triglial dysfunction mediated by TDP-43 loss in astrocytes. Moreover, mice with astroglial TDP-43 deletion develop motor, but not sensory, deficits. Taken together, our results demonstrate that TDP-43 is required to maintain the protective functions of astrocytes relevant to the development of motor deficits in mice.
basic nonuniformity of the cerebral cortex Herculano-Houzel, Suzana; Collins, Christine E; Wong, Peiyan ...
Proceedings of the National Academy of Sciences - PNAS,
08/2008, Letnik:
105, Številka:
34
Journal Article
Recenzirano
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Evolutionary changes in the size of the cerebral cortex, a columnar structure, often occur through the addition or subtraction of columnar modules with the same number of neurons underneath a unit ...area of cortical surface. This view is based on the work of Rockel et al. Rockel AJ, Hiorns RW, Powell TP (1980) The basic uniformity in structure of the neocortex. Brain 103:221-244, who found a steady number of approximately 110 neurons underneath a surface area of 750 μm² (147,000 underneath 1 mm²) of the cerebral cortex of five species from different mammalian orders. These results have since been either corroborated or disputed by different groups. Here, we show that the number of neurons underneath 1 mm² of the cerebral cortical surface of nine primate species and the closely related Tupaia sp. is not constant and varies by three times across species. We found that cortical thickness is not inversely proportional to neuronal density across species and that total cortical surface area increases more slowly than, rather than linearly with, the number of neurons underneath it. The number of neurons beneath a unit area of cortical surface varies linearly with neuronal density, a parameter that is neither related to cortical size nor total number of neurons. Our finding of a variable number of neurons underneath a unit area of the cerebral cortex across primate species indicates that models of cortical organization cannot assume that cortical columns in different primates consist of invariant numbers of neurons.
Accumulating evidence suggests that disruptions in brain energy metabolism may be a key player in the pathogenesis of Alzheimer's disease (AD). Pioglitazone (PIO) has been found to exert beneficial ...effects on metabolic dysfunction in many AD preclinical studies. However, limited success in clinical trials remains an obstacle to its development for the treatment of AD. PIO's poor brain penetration was often cited as a contributing factor to the lack of clinical benefit. In this study, we prepared PIO-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and administered them as suspended nanoparticles via nebulization. Preliminary investigation of drug distribution to the brain revealed comparatively reduced systemic exposure after administering PIO nanoparticles via the intranasal route. In vitro, extracellular flux analysis showed significantly raised spare respiratory capacity when cells were treated with low-dose PIO nanoparticles. Tg2576 transgenic mice treated with low-dose PIO nanoparticles over four months exhibited an overall trend of reduced hyperactivity in open field tests but did not show any visible effect on alternation rates in the Y-maze task. Subsequent
H NMR-based metabolic profiling of their plasma and different brain regions revealed differences in metabolic profiles in the cerebellum, cortex, and hippocampus of Tg2576 mice after long-term PIO treatment, but not in their midbrain and plasma. In particular, the specificity of PIO's treatment effects on perturbed amino acid metabolism was observed in the cortex of transgenic mice with increases in alanine and N-acetylaspartate levels, supporting the notion that PIO treatment exerts beneficial effects on impaired energy metabolism associated with AD. In conclusion, inhalation exposure to PIO nanoparticles presents an exciting opportunity that this drug could be administered intranasally at a much lower dose while achieving a sufficient level in the brain to elicit metabolic benefits at an early stage of AD but with reduced systemic exposure.
Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy ...is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1–5. In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2. We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.
Forceps, clamps, and haemostats are essential surgical tools required for all surgical interventions. While they are widely used to grasp, hold, and manipulate soft tissue, their metallic rigid ...structure may cause tissue damage due to the potential risk of applying excessive gripping forces. Soft pneumatic surgical grippers fabricated by silicone elastomeric materials with low Young’s modulus may offer a promising solution to minimize this unintentional damage due to their inherent excellent compliance and compressibility. The goal of this work is to evaluate and compare the grip-induced nerve damage caused by the soft pneumatic elastomeric gripper and conventional haemostats during surgical manipulation. Twenty-four Wistar rats (male, seven weeks) are subjected to sciatic nerve compression (right hind limb) using the soft pneumatic elastomer gripper and haemostats. A histopathological analysis is conducted at different time-points (Day 0, Day 3, Day 7 and Day 13) after the nerve compression to examine the morphological tissue changes between the rats in the ‘soft gripper’ group and the ‘haemostats’ group. A free walking analysis is also performed to examine the walking function of the rats after recovery from different time points. Comparing the rigid haemostats and soft gripper groups, there is a visible difference in the degree of axonal vacuolar degeneration between the groups, which could suggest the presence of substantial nerve damage in the ‘haemostats’ group. The rats in the haemostats group exhibited reduced right hind paw pressure and paw size after the nerve compression. It shows that the rats tend not to exert more force on the affected right hind limb in the haemostats group compared to the soft gripper group. In addition, the stance duration was reduced in the injured right hind limb compared to the normal left hind limb in the haemostats group. These observations show that the soft pneumatic surgical gripper made of silicone elastomeric materials might reduce the severity of grip-induced damage by providing a safe compliant grip compared to the conventional haemostats. The soft pneumatic elastomer gripper could complement the current surgical gripping tool in delicate tissue manipulation.
Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS), which has been suggested to enhance cognitive functions through GABA(A) receptor signaling by its ...metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO). DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI) deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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