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Similar to insulin, central administration of insulin-like Growth Factor-1 (IGF-1) can suppress hepatic glucose production (HGP), but it is unclear if this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we utilized pharmacologic and genetic approaches in combination with hyperinsulinemic-euglycemic clamps to decipher the role of these receptors in mediating central effects of IGF-1 and insulin on HGP. In rats, we observed that intracerebroventricular (ICV) administration of IGF-1 or insulin markedly increased the glucose infusion rate (GIR) by >50% and suppressed HGP (P Likewise, ICV infusion of the InsR antagonist, S961, which also can bind HybridRs, interfered with the ability of central insulin, but not IGF-1 to increase the GIR. Furthermore, hyperinsulinemic clamps in mice lacking IGF-1Rs in AgRP neurons revealed ~30% reduction in the GIR in KO animals, which was explained by an impaired ability of peripheral insulin to completely suppress HGP (P

Alzheimer’s disease (AD) is the most common type of dementia worldwide, characterized by the deposition of neurofibrillary tangles and amyloid-β (Aβ) peptides in the brain. Additionally, increasing evidence demonstrates that a neuroinflammatory state and oxidative stress, iron-dependent, play a crucial role in the onset and disease progression. Besides conventional therapies, the use of natural-based products represents a future medical option for AD treatment and/or prevention. We, therefore, evaluated the effects of a ribonucleotides-based ingredient (Ribodiet®) in a non-genetic mouse model of AD. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aβ1–42 peptide (3 µg/3 μl) and after with Ribodiet® (0.1–10 mg/mouse) orally (p.o.) 3 times weekly for 21 days following the induction of experimental AD. The mnemonic and cognitive decline was then evaluated, and, successively, we have assessed ex vivo the modulation of different cyto-chemokines on mice brain homogenates. Finally, the level of GFAP, S100β, and iron-related metabolic proteins were monitored as markers of reactive gliosis, neuro-inflammation, and oxidative stress. Results indicate that Ribodiet® lessens oxidative stress, brain inflammation, and amyloid pathology via modulation of iron-related metabolic proteins paving the way for its rationale use for the treatment of AD and other age-related diseases.

The aim of our study is to investigate the change of peroxisomal proteins in the neurodegenerative and oxidative process caused by the neurotoxicity of Aβ 1-42 in aged rats supplemented with taurine and to show the possible positive effects of taurine in this process.30 Wistar albino rats were randomly divided into 5 groups as control, sham, Aβ 1-42, taurine, and Aβ 1-42+taurine. Taurine administration continued for 6 weeks (1000 mg/kg/day with drinking water). Stereotaxic surgery was applied to all groups (intracerebroventricular per lateral ventricle needle only or 5 μl, PBS, or Aβ 1-42). Spatial learning and memory performances of the animals were evaluated with Morris water maze and elevated plus maze. The levels of MDA and GSH were measured as oxidative stress parameters in the cerebral cortex and hippocampus. Expressions of CAT, PEX14, PMP70 of peroxisomal membrane proteins were indicated by Western blot analysis.Our results showed that injection of Aβ 1-42 decreased the spatial learning and memory performance, cortex CAT and hippocampus PEX14, PMP70 and GSH levels, and increased cortex and hippocampus MDA levels (p0.05). Although the administration of taurine partially ameliorated the adverse effects of Aβ 1-42 injection, a significant difference was found only at the hippocampus GSH levels (p0.05). Also, taurine caused anxiety at this dose (p0.05).In conclusion, decreased peroxisomal proteins and antioxidant capacity in neurodegenerative and oxidative processes induced by intracerebroventricular Aβ 1-42 injection showed that peroxisomes may play a role in this process and taurine supplementation may have positive effects especially in increasing antioxidant capacity.

Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction, however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH.

Background Thrombin has been implicated in playing a role in hydrocephalus development following intraventricular hemorrhage (IVH). However, the mechanisms underlying the sex differences to the detrimental effects of thrombin post-IVH remain elusive. Method Three-month old male and female Sprague-Dawley rats underwent unilateral intracerebroventricular (ICV) injections of 3U or 5U thrombin, or saline, to examine differences in thrombin-induced hydrocephalus and white matter injury. Mortality, and lateral ventricle volume and white matter injury were measured on magnetic resonance imaging evaluation at 24 h post-injection. In addition, male rats were pretreated with 17-β estradiol (E2, 5 mg/kg) or vehicle at 24 and 2 h prior to ICV injection of 3U thrombin. All rats were euthanized at 24 h post-injection for histology and immunohistochemistry. Results ICV injection of 5U thrombin caused 100 and 0% mortality in female and male rats, respectively. 3U of thrombin resulted in significant ventricular dilation and white matter damage at 24 h in both male and female rats, but both were worse in females (p Conclusions ICV thrombin injection induced more severe ventricular dilation and white matter damage in female rats compared to males. Estrogen appears to contribute to this difference which may involve greater neutrophil infiltration in females. Understanding sex differences in thrombin-induced brain injury may shed light on future interventions for hemorrhagic stroke.

Management of moderate to severe pain relies heavily on opioid analgesics such as morphine, oxycodone, and fentanyl in clinics. However, their prolonged use was associated with undesirable side effects. Many new strategies to reduce side effects have been proposed, but not without disadvantages. Using a hot plate model as a phenotypic screening method, our studies identified (3

The importance of glutamate transporters in learning, memory, and emotion remains poorly understood; hence, in the present study, we investigated whether deficiency of pharmacological GLAST in neurodevelopmental processes affects cognitive and/or emotional behaviors in mice. The mice were injected with a glutamate transporter inhibitor, dl -threo-β-benzyloxyaspartate ( dl -TBOA), during the early postnatal period. At 8 weeks of age, they showed impairments in cognitive or emotional behaviors; dysfunction of glutamatergic neurotransmission (increased expressions of GLAST, GLT-1, or GFAP protein, and decreased ability of glutamate release) in the cortex or hippocampus; morphological changes (decreased cell size in the cortex and thickness of the pyramidal neuronal layer of the CA1 area in the hippocampus). Such behavioral and morphological changes were not observed in adult mice injected with dl- TBOA. These results suggest that GLAST plays an important role in the regulation of cognitive and emotional behaviors. Early postnatal glutamatergic facilitation by GLAST dysfunction leads to cognitive and emotional abnormalities due to neurodevelopmental abnormalities such as morphological changes.

Increasing evidence shows that astrocytes, by releasing and uptaking neuroactive molecules, regulate synaptic plasticity, considered the neurophysiological basis of memory. This study investigated the impact of l-α-aminoadipate (l-AA) on astrocytes which sense and respond to stimuli at the synaptic level and modulate hippocampal long-term potentiation (LTP) and memory. l-AA selectivity toward astrocytes was proposed in the early 70's and further tested in different systems. Although it has been used for impairing the astrocytic function, its effects appear to be variable in different brain regions. To test the effects of l-AA in the hippocampus of male C57Bl/6 mice we performed two different treatments (ex vivo and in vivo) and took advantage of other compounds that were reported to affect astrocytes. l-AA superfusion did not affect the basal synaptic transmission but decreased LTP magnitude. Likewise, trifluoroacetate and dihydrokainate decreased LTP magnitude and occluded the effect of l-AA on synaptic plasticity, confirming l-AA selectivity. l-AA superfusion altered astrocyte morphology, increasing the length and complexity of their processes. In vivo, l-AA intracerebroventricular injection not only reduced the astrocytic markers but also LTP magnitude and impaired hippocampal-dependent memory in mice. Interestingly, d-serine administration recovered hippocampal LTP reduction triggered by l-AA (2 h exposure in hippocampal slices), whereas in mice injected with l-AA, the superfusion of d-serine did not fully rescue LTP magnitude. Overall, these data show that both l-AA treatments affect astrocytes differently, astrocytic activation or loss, with similar negative outcomes on hippocampal LTP, implying that opposite astrocytic adaptive alterations are equally detrimental for synaptic plasticity.

Neuroinflammation is initiated by activation of the brain’s innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer’s disease. Nicotinamide adenine dinucleotide (NAD(+)) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD(+), suppressed cuprizone-induced demyelination, neuroinflammation and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD(+) level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD(+) on lipopolysaccharide (LPS)-induced neuroinflammation in mice. First, intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS-induced inflammatory responses and glial activation. Pre-administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD(+) precursor, increased NAD(+) level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS-induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD(+), NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF-κB signaling pathway in microglia. These results suggest that CD38-mediated neuroinflammation is linked to NAD(+) consumption and that boosting NAD(+) by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain.

The incidence of abnormal cerebrospinal fluid (CSF) flow dynamics in children with central nervous system (CNS) tumors before intraventricular therapy has not been described. Methods: We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003 and 2018 (15 y). Patients underwent (111)In-diethylenetriaminepentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 min, 4 h, 24 h, and 48 h (if required). CSF flow was classified as normal, delayed, asymmetric, or obstructed. Results: In total, 278 CSF flow studies were performed on 224 patients, 202 of whom (90%) were less than 18 y old. Of these, 116 patients (52%) had metastatic CNS neuroblastoma, 57 (25%) had medulloblastoma, and 51 (23%) had other histologic types of CNS tumors. Of the 278 studies, 237 (85%) were normal, 9 (3%) required neurosurgical intervention, 25 (9%) were delayed, and 7 (3%) were asymmetric. Conclusion: Abnormal CSF flow and the necessity for neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.

Cerebral edema and the subsequent increased intracranial pressure are associated with mortality and poor outcome following traumatic brain injury. Previous in vitro studies have shown that the Gibbs-Donnan effect, which describes the tendency of a porous, negatively charged matrix to attract positive ions and water, applies to brain tissue and that enzymatic reduction of the fixed charge density can prevent tissue swelling. We tested whether hyaluronidase, an enzyme that degrades the large, negatively charged glycosaminoglycan hyaluronan, could reduce brain edema after traumatic brain injury. In vivo, intracerebroventricular injection of hyaluronidase after controlled cortical impact in mice reduced edema in the ipsilateral hippocampus at 24 h by both the wet-weight/dry-weight method (78.15 ± 0.65% vs. 80.4 ± 0.46%; p 2-weighted magnetic resonance imaging (13.88 ± 3.09% vs. 29.23 ± 6.14%; p

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3±8.9 s), when compared to controls (546.2±130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction.

Aim: Food intake regulated by a complex of physiologic mechanisms in the nervous system. Muscarinergic system has an important role in the central regulation of appetite in mammals, but the...

Neurons of the cerebellar cortex contain a circadian oscillator, with circadian expression of clock genes being controlled by the master clock of the suprachiasmatic nucleus (SCN). However, the signaling pathway connecting the SCN to the cerebellum is unknown. Glucocorticoids exhibit a prominent SCN-dependent circadian rhythm, and high levels of the glucocorticoid receptor have been reported in the cerebellar cortex; we therefore hypothesized that glucocorticoids may control the rhythmic expression of clock genes in the cerebellar cortex. We here applied a novel methodology by combining the electrolytic lesion of the SCN with implantation of a micropump programmed to release corticosterone in a circadian manner mimicking the endogenous hormone profile. By use of this approach, we were able to restore the corticosterone rhythm in SCN-lesioned male rats. Clock gene expression in the cerebellum was abolished in rats with a lesioned SCN, but exogenous corticosterone restored the daily rhythm in clock gene expression in the cerebellar cortex, as revealed by quantitative real-time PCR and radiochemical in situ hybridization for the detection of the core clock genes Per1, Per2, and Arntl. On the contrary, exogenous hormone did not restore circadian rhythms in body temperature and running activity. RNAscope in situ hybridization further revealed that the glucocorticoid receptor colocalizes with clock gene products in cells of the cerebellar cortex, suggesting that corticosterone exerts its actions by binding directly to receptors in neurons of the cerebellum. However, rhythmic clock gene expression in the cerebellum was also detectable in adrenalectomized rats, indicating that additional control mechanisms exist. These data show that the cerebellar circadian oscillator is influenced by SCN-dependent rhythmic release of corticosterone.

Although the pathogenesis of Alzheimer’s disease (AD) remains unclear, some molecular aspects that precede or accompany the deposit of β-amyloid in senile plaques attract attention, such as calcium dysregulation and neuroinflammation. It has been suggested that the Ca2+/calmodulin-dependent protein phosphatase, calcineurin (CaN), plays an important role in AD pathogenesis. We hypothesized that CaN activation is involved in the inflammatory changes observed in the streptozotocin (STZ)-induced model of AD. We investigated hippocampal inflammatory and CaN changes in Wistar rats in two moments after intracerebroventricular STZ administration: in the first week (early) and fourth week (later on). We found an early (at 1 week) and persistent (at fourth week) increment in the subunit A of CaN, as well as an increase in the major 48 kDa fragment of this subunit. Glial and inflammatory activation were confirmed by changes of IBA-1, TLR-4, glial fibrillary acidic protein (GFAP), and S100B in the hippocampus. Augmented CaN activity was accompanied by reduced phosphorylation of the pro-apoptotic protein BAD, at Ser 136. Importantly, we found an increase in the nuclear translocation of NFAT4 (more associated to astroglial reactivity) in the hippocampus at 1 and 4 weeks in this model. NFAT3 (more associated with neuronal activation) exhibited an early increase, but decreased later on. Taken together, these data contribute to the understanding of neurochemical changes in the STZ model of sporadic AD, and may explain the persistent inflammatory response in AD, which might occur via the proteolytic activation of CaN, and signaling of NFAT mediated by isoform 4, in activated astrocytes.

Intraventricular hemorrhage (IVH) is an independent poor prognostic factor in subarachnoid and intra-parenchymal hemorrhage. The use of intraventricular fibrinolytics (IVF) has long been debated, and its exact effects on outcomes are unknown. A systematic review and meta-analysis were performed in accordance with the PRISMA guidelines to assess the impact of IVF after non-traumatic IVH on mortality, functional outcome, intracranial bleeding, ventriculitis, time until clearance of third and fourth ventricles, obstruction of external ventricular drains (EVD), and shunt dependency. Nineteen studies were included in the meta-analysis, totaling 1020 patients. IVF was associated with lower mortality (relative risk [RR] 0.58; 95% confidence interval [CI] 0.47–0.72), fewer EVD obstructions (RR 0.41; 95% CI 0.22–0.74), and a shorter time until clearance of the ventricles (median difference [MD] − 4.05 days; 95% CI − 5.52 to − 2.57). There was no difference in good functional outcome, RR 1.41 (95% CI 0.98–2.03), or shunt dependency, RR 0.93 (95% CI 0.70–1.22). Correction for publication bias predicted an increased risk of intracranial bleeding, RR 1.67 (95% CI 1.01–2.74) and a lower risk of ventriculitis, RR 0.68 (95% CI 0.45–1.03) in IVH patients treated with IVF. IVF was associated with improved survival, faster clearance of blood from the ventricles and fewer drain obstructions, but further research is warranted to elucidate the effects on ventriculitis, long-term functional outcomes, and re-hemorrhage. Electronic supplementary material The online version of this article (10.1007/s12028-019-00786-5) contains supplementary material, which is available to authorized users.

Background Under stress stimulation, p25 is generated by cleavage of p35 and acts as an activator of cyclin-dependent kinase 5 (Cdk5) like p35. Unlike Cdk5/p35, which is important for brain development, aberrant activity of Cdk5/p25 plays a pathological role in neurodegenerative diseases, such as Alzheimer's disease, by inducing hyperphosphorylation of downstream substrates related to pathological progression. A truncated fragment of the c-terminus of p35, the Cdk5 inhibitory peptide (CIP), selectively inhibits Cdk5/ p25 activity in cultured neurons and in CIP/p25 tetra-transgenic mice. Objective First, we aimed to establish a p25 overexpression adult mouse model, then to evaluate whether CIP delivered by adeno-associated virus serotype 9 (AAV9) can ameliorate neuronal toxicity induced by p25. Methods The p25 overexpression mouse model was established by intracerebroventricular (i.c.v.) injection of AAV8-GFP-p25 in 8-week-old mice. One month later, these mice were i.c.v. injected with AAV9-CIP-T2A-mCherry or AAV9 vector as control. Pathological and behavioral changes were assessed 3-months post-injection in all mice. Results The p25 overexpression mice displayed hyperphosphorylation of tau at multiple sites, activation of astrocytes, and elevated inflammatory factors, including IL-1 and TNF-α, which were significantly decreased by the administration of CIP. However, Aβ deposition and microgliosis were not obvious in p25 overexpression mice. In addition, a significant learning decline and anxiety-like behavior were induced by p25 toxicity, and CIP treatment improved learning ability in p25 mice. Conclusion AAV-mediated p25 overexpression mouse model is easy to construct to study p25-induced neuronal toxicity. Application of CIP after p25 insult reverses the pathological changes and behavioral abnormalities.

Large cerebral infarctions are major predictors of death and severe disability from stroke. Conversely, data concerning these types of infarctions and the affected adjacent brain circuits are scarce. It remains to be determined if the co-morbid concurrence of large infarct and β-amyloid (Aβ) toxicity can precipitate the early development of dementia. Here, we described a dose-dependent effect of a unilateral striatal injection of vasoconstrictive endothelin-1 (ET-1) along with Aβ toxicity on CNS pathogenesis; driven by the anatomical and functional networks within a brain circuit. After 21 days of treatment, a high dose (60 pmol) of ET-1 (E60) alone caused the greatest increase in neuroinflammation, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion such as white matter (subcortical white matter, corpus callosum, internal capsule, anterior commissure), gray matter (globus pallidus, thalamus), and cortices (cingulate, motor, somatosensory, entorhinal). The combined E60 + Aβ treatment also extended perturbation in the contralateral hemisphere of these rats, such as increased deposition of amyloid precursor protein fragments associated with the appearance of degenerating cells and the leakage of laminin from the basement membrane across a compromised blood-brain barrier. However, the cerebral damage induced by the 6 pmol ET-1 (E6), Aβ and E6 + Aβ rats was not detrimental enough to injure the complete network. The appreciation of the causal interactions among distinct anatomical units in the brain after ischemia and Aβ toxicity will help in the design of effective and alternative therapeutics that may disassociate the synergistic or additive association between the infarcts and Aβ toxicity.

Hyperacusis may be defined as diminishing tolerance to moderate and high intensity sounds in people with normal hearing sensitivity. Serotonin plays a critical role in some of auditory tasks including startle reflex and prepulse inhibition. Serotonin deficiency can cause some diseases which can coincide with hyperacusis. The aim of the present study was to investigate the probable influence of serotonergic depletion in nucleus accumbens (NAcc) on the startle reflex. The startle reflexes were examined in Wistar rats (n: 48) in different intensities with and without the background noise. The amplitude of startle reflex significantly increased in NAcc-injected rats without background noise, while this difference disappeared in the presence of background noise in all intensities. These data proposed that the injection of 5, 7-Dihydroxytryptamine (5, 7-DHT) into nucleus accumbens will cause hyperacusis-like behavior, and strengthens the possibility of the role of serotonin and nucleus accumbens in hyperacusis.

Nociceptin/Orphanin FQ (N/OFQ) plays an important role in the regulation of spatial, fear and recognition memories. N/OFQ receptors are highly distributed in the perirhinal cortex, which is a key brain area involved in modulating novel object recognition (NOR) memory. However, the role of N/OFQ in NOR memory in the perirhinal cortex was still unknown. Moreover, the effects of N/OFQ on different stages of NOR memory were still unclear. In NOR task, we found that pre-training intracerebroventricular (icv) injection of N/OFQ (0.3 and 1 nmol) impaired long-term memory in a dose-dependent manner. However, icv infusion of N/OFQ immediately after training did not affect NOR memory consolidation even at a high dose of 3 nmol. Pre-test icv injection of N/OFQ (1 nmol) also did not influence NOR memory retrieval. These data indicate that N/OFQ negatively modulates long-term NOR memory during the acquisition phase. Furthermore, the amnesia effect of N/OFQ (1 nmol, icv) could be antagonist by pre-treatment with the selective N/OFQ receptor antagonist [Nphe1]N/OFQ(1-13)NH2 (10 nmol, icv), indicating pharmacological specificity. Then, we found that pre-training infusion of N/OFQ (0.1 and 0.3 nmol/side) into the bilateral perirhinal cortex impaired long-term NOR memory, suggesting the perirhinal cortex is a critical brain structure in mediating the amnesic effect of N/OFQ in NOR task. In conclusion, our data, for the first time, indicate that N/OFQ in the perirhinal cortex impairs NOR memory acquisition through the NOP receptors.

Metabolic conditions during brain development may have long-term consequences on brain metabolism, thereby influencing the risk of neurodegenerative disease in later life. To ascertain the long-term consequences of omega-3 (ω3) fatty acid deficiency during brain development on oxidative fatty acid degradation in the brain and the development of Alzheimer-like pathology, wild-type (WT) female mice were fed diets that were either replete or deficient in ω3 fatty acids for 5 weeks. These females were then mated with hemizygous 5xFAD male transgenic (TG) mouse models of Alzheimer's disease, and the progeny were continued on diets that were either ω3-replete or ω3-deficient. When the progeny were 6 months of age, they received radiolabeled arachidonic acid (ARA) by intracerebroventricular injection. Five days after these injections, the brains were harvested and oxidative degradation of the radiolabeled ARA was characterized. Among the progeny of female mice on an ω3-replete diet, TG progeny had lower PSD-95 expression and higher oxidative ARA degradation than WT progeny. Progeny on an ω3-deficient diet, however, had no significant differences in PSD-95 expression between TG and WT mice, or in the extent of ARA degradation. In TG mice, an ω3-deficient diet reduced oxidative ARA degradation to a greater extent than in WT mice. The reductions in oxidative ARA degradation occurred even if the progeny of female mice on an ω3-deficient diet resumed an ω3-replete diet immediately on weaning. These results demonstrate that dietary ω3 fatty acid deficiency during development can cause long-term changes in the expression of a synaptic marker and long-term reductions in the rate of ARA degradation in the WT brain, which are not completely alleviated by an ω3-replete diet after weaning. The elimination of differences between TG and WT mice by an ω3-deficient diet suggests that mechanisms regulating PSD-95 expression and the oxidative degradation of ARA are related and that the timing of dietary ω3 intake during development may influence Alzheimer's disease-related pathological changes later in life.

Objective To evaluate the effect of thrombin (TM) injection via the cerebellomedullary cistern on cerebral vessels in rats with subarachnoid hemorrhage (SAH). Methods Eighteen rats were randomly divided into three groups. In the A1 group, physiological saline was injected via the cerebellomedullary cistern; in the A2 group, 3 U of TM was injected into the subarachnoid space; and in the A3 group, SAH models were established and 3 U of TM was injected with the first injection of whole blood. Three days later, basilar artery specimens were collected for pathological examination. Results The basilar arterial lumen cross-sectional area was significantly smaller in the A2 versus the A1 group, and proteinase-activated receptor (PAR)-1 and tumor necrosis factor (TNF)-α average optical densities were significantly higher (all P Conclusions There was no significant difference in the extent of cerebral vasospasm between SAH and non-SAH model groups following TM injection into the subarachnoid space, so TM was considered to be an independent factor affecting cerebral vasospasm.

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.

MicroRNAs (miRNAs) have been widely reported to induce posttranscriptional gene silencing and led to an explosion of new strategies for the treatment of human disease. It has been reported that the expression of MicroRNA-132 (miR-132) are altered both in the blood and brain after stroke. However, the effect of miR-132 on blood-brain barrier (BBB) disruption in ischemia stroke has not been studied. Here we will investigate the effects of miR-132 on the permeability of BBB after ischemic stroke and explore the potential mechanism underlying observed protection. Eight week-old mice were injected intracerebroventricularly with miR-132, antagomir-132 or agomir negative control (agomir-NC) 2 h before middle cerebral artery occlusion (MCAO), followed by animal behavior tests and infraction volume measurement at 24 h after MCAO. BBB permeability and integrity were measured by Evan's blue extravasation and brain water content. The expression of tight junction proteins was detected by immnostaining and Western blots. The level of MiR-132 and its targeted gene Mmp9 were assayed. Treatment with exogenous MiR-132 (agomir-132) decreased the infraction volume, reduced brain edema, and improved neurological functions compared to control mice. Agomir-132 increased the level of MiR-132 in brain tissue, suppressed the expression of MMP-9 mRNA and decreased the degradation of tight junction proteins VE-cadherin and β-Catenin in ischemic stroke mice. Inhibition of MMP-9 has a similar protective effect to agomir-132 on infraction volume, brain edema, and tight-junction protein expression after MCAO. Our results indicated that miR-132/MMP-9 axis might be a novel therapeutic target for BBB protection in ischemic stroke.

The brain tissue has only a limited capacity for generating new neurons. Therefore, to treat neurological diseases, there is a need of other cell sources for brain repair. Different sources of cells have been subject of intense research over the years, including cells from primary tissue, stem cell-derived cells and reprogrammed cells. As an alternative, direct reprogramming of resident brain cells into neurons is a recent approach that could provide an attractive method for treating brain injuries or diseases as it uses the patient’s own cells for generating novel neurons inside the brain. In vivo reprogramming is still in its early stages but holds great promise as an option for cell therapy. To date, both inhibitory and excitatory neurons have been obtained via in vivo reprogramming, but the precise phenotype or functionality of these cells has not been analysed in detail in most of the studies. Recent data shows that in vivo reprogrammed neurons are able to functionally mature and integrate into the existing brain circuitry, and compose interneuron phenotypes that seem to correlate to their endogenous counterparts. Interneurons are of particular importance as they are essential in physiological brain function and when disturbed lead to several neurological disorders. In this review, we describe a comprehensive overview of the existing studies involving brain repair, including in vivo reprogramming, with a focus on interneurons, along with an overview on current efforts to generate interneurons for cell therapy for a number of neurological diseases.

Hepatic steatosis develops when lipid influx and production exceed the liver’s ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin’s anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis., Obesity is associated with leptin resistance and rising blood leptin levels while central leptin exposure may be limited. Here, the authors show that brain leptin infusion reduces hepatic lipid content in rats by increasing hepatic VLDL secretion and lowering liver de novo lipogenesis via a vagal mechanism.

Mate choice decisions of animals show significant variability-both among and within individuals. Clearly, such variability can profoundly impact individual fitness, as well as subtly alter sexual selection processes, but we know little about the neural mechanisms underlying such variability. We examined the influence of the neuropeptide arginine vasotocin (AVT) on the strength of attraction of female gray treefrogs (Hyla versicolor) showing positive phonotaxis to the call of a conspecific male. Female treefrogs received intracerebroventricular injections with either saline, AVT (five doses), or the AVT receptor antagonist Manning compound (two doses). By 30 min after injection, AVT significantly increased the speed with which females approached the speaker, at doses of 1, 10 and 50 ng per frog. At the highest dose, the average speed was doubled. The AVT antagonist significantly inhibited phonotaxis at both doses (50 and 100 ng). The effects of AVT on treefrog phonotaxis were shorter lived (disappearing within 60-90 min), compared to Manning compound (effects persisted at least 90 min). These findings support the hypothesis that endogenous AVT is critical to the display of female phonotaxis behavior. AVT may thus contribute to variability in female mate choices by modulating proceptive behaviors.

Background Our previous research confirmed that electroacupuncture (EA) stimulus elicits neuroprotective effects against cerebral ischemic injury through α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of high-mobility group box 1 release mechanism. This study investigated whether the signal transducer of α7nAChR and inhibition of NLRP3 inflammasome are involved in the neuroprotective effects of EA stimulus. Methods In adult male Sprague-Dawley rats, the focal cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO) models for 1.5 h. The expression of NLRP3 inflammasome in the penumbral tissue following reperfusion was assessed by western blotting and immunoflourescent staining. The infarct size, neurological deficit score, TUNEL staining and the expression of proinflammatory factors or anti-inflammatory cytokines were evaluated at 72 h after reperfusion in the presence or absence of either α7nAChR antagonist (α-BGT) or agonist (PHA-543,613). Results The contents of inflammasome proteins were gradually increased after cerebral ischemia/reperfusion (I/R). EA stimulus attenuated NLRP3 inflammasome mediated inflammatory reaction and regulated the balance between proinflammatory factors and anti-inflammatory cytokines. The agonist of α7nAChR induced similar neuroprotective effects as EA stimulus. In contrast, α7nAChR antagonist reversed not only the neuroprotective effects, but also the inhibitory effects of NLRP3 inflammasome and the regulatory effects on the balance between proinflammatory factors and anti-inflammatory cytokines. Conclusions These results provided compelling evidence that α7nAChR played a pivotal role in regulating the activation and expression of NLRP3 inflammasome in neurons after cerebral I/R. These findings highlighted a novel anti-inflammatory mechanism of EA stimulus by α7nAChR modulating the inhibition of NLRP3 inflammasome, suggesting that α7nAChR-dependent cholinergic anti-inflammatory system and NLRP3 inflammasome in neurons might act as potential therapeutic targets in EA induced neuroprotection against cerebral ischemic injury.

Central administration of corticotropin-releasing factor (CRF), a 41-amino acid peptide, is associated with anorexigenic effects across various species, with particularly potent reductions in food intake in rodents and chickens (Gallus gallus domesticus), a species for which the most is known. The purpose of the current study was to determine the hypothalamic mechanism of CRF-induced anorexigenic effects in 7 day-old Japanese quail (Coturnix japonica), a less-intensely-selected gallinaceous relative to the chicken that can provide more evolutionary perspective. After intracerebroventricular (ICV) injection of 2, 22, or 222 pmol of CRF, a dose-dependent decrease in food intake was observed that lasted for 3 and 24 h for the 22 and 222 pmol doses, respectively. The 2 pmol dose had no effect on food or water intake. The numbers of c-Fos immunoreactive cells were increased in the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) at 1 h post-injection in quail injected with 22 pmol of CRF. The hypothalamic mRNA abundance of proopiomelanocortin, melanocortin receptor subtype 4, CRF, and CRF receptor sub-type 2 was increased at 1 h in quail treated with 22 pmol of CRF. Behavior analyses demonstrated that CRF injection reduced feeding pecks and jumps and increased the time spent standing. In conclusion, results demonstrate that the anorexigenic effects of CRF in Japanese quail are likely influenced by the interaction between CRF and melanocortin systems and that injection of CRF results in species-specific behavioral changes.

The early postnatal stage is a critical period of hippocampal neurodevelopment and also a period of high vulnerability to adverse life experiences. Recent evidence suggests that nectin‐3, a cell adhesion molecule, mediates memory dysfunction and dendritic alterations in the adult hippocampus induced by postnatal stress. But it is unknown whether postnatal nectin‐3 reduction alone is sufficient to alter hippocampal structure and function in adulthood. Here, we down regulated hippocampal expression of nectin‐3 and its heterophilic adhesion partner nectin‐1, respectively, from early postnatal stage by injecting adeno‐associated virus (AAV) into the cerebral lateral ventricles of neonatal mice (postnatal day 2). We found that suppression of nectin‐3, but not nectin‐1, expression from the early postnatal stage impaired hippocampus‐dependent novel object recognition and spatial object recognition in adult mice. Moreover, AAV‐mediated nectin‐3 knockdown significantly reduced dendritic complexity and spine density of pyramidal neurons throughout the hippocampus, whereas nectin‐1 knockdown only induced the loss of stubby spines in CA3. Our data provide direct evidence that nectins, especially nectin‐3, are necessary for postnatal hippocampal development of memory functions and structural integrity.

1. The aim of the current study was to determine the effects of the central dopaminergic system on N/OFQ-induced feed intake in 3-h feed-deprived neonatal broilers. 2. In experiment 1, chicken received intracerebroventricular (ICV) injections of a control solution, SCH 23 390 (D

Tumor-associated macrophages (TAMs) are recruited from circulatory monocytes by tumor-derived factors, which differentiate into macrophages residing in the tumor microenvironment. TAMs play critical roles in promoting angiogenesis, invasion, metastasis and immune escape, and the direct depletion of TAMs is a promising strategy for tumor immunotherapy. In this study, we developed lipid-coated calcium zoledronate nanoparticles (CaZol@pMNPs) containing conjugated mannose, which were sterically shielded with an extracellular pH-sensitive material. The NPs specifically targeted TAMs and induced their apoptosis in vitro and in vivo. In a S180 tumor-bearing mouse model, CaZol@pMNPs effectively depleted TAMs, markedly decreased angiogenesis, reduced immune suppression, and eventually restrained tumor growth without eliciting systemic effects. The collective data indicate the potential of the direct depletion of TAMs using CaZol@pMNPs for cancer immunotherapy.

Oxytocin (OT) is a well-characterized neurotransmitter that participates in a wide range of physiological processes including the inhibition of food intake. The avian ortholog, mesotocin (MT), differs from OT by a single amino acid. Little is known regarding the function of OT in regulating energy balance in birds; thus, this study was designed to determine the effects of central OT injection on food intake and adipose tissue physiology in chicks. At 4-d post-hatch, broiler chicks were fasted for 3 h and injected intracerebroventricularly with 0 (vehicle), 0.63, 2.5, 5.0, or 10 nmol OT. Oxytocin decreased food and water intake during the entire 180-min observation period. The reduction in water intake was likely not prandial because chicks that were food restricted after OT injection also drank less. There was increased c-Fos immunoreactivity in several appetite-associated hypothalamic nuclei in OT-injected chicks at 1 h, including the arcuate (ARC), dorsomedial nucleus (DMN), lateral hypothalamus (LH), paraventricular nucleus (PVN), and ventromedial hypothalamus (VMH). OT treatment was associated with reduced hypothalamic corticotropin-releasing factor (CRF) mRNA and increased cloacal temperature at 1 h post-injection. We then investigated appetite- and adipose tissue–associated effects of OT in chicks from lines that have undergone long-term selection for either low (LWS) or high (HWS) juvenile body weight. Central injection of OT decreased food intake in both lines with the magnitude of response greater in the HWS than LWS chicks. Adipose tissue abundance of fatty acid–binding protein 4, monoglyceride lipase (MGLL), MT, and perilipin-1 mRNA was greater in LWS than HWS chicks. Lipoprotein lipase, MGLL, and MT mRNAs increased in response to OT injection in LWS but not HWS chicks. In conclusion, central injection of OT induced anorexia, reduced water intake, increased body temperature, and was associated with activation of the ARC, DMN, LH, PVN, and VMH in the hypothalamus. The effects on appetite and body temperature may involve CRF signaling in the hypothalamus and lipolysis in the adipose tissue, respectively. There were differences in the appetite, and adipose tissue response to OT in body weight–selected lines of chicks supports that MT plays a role in energy balance regulation in chickens.

Aim Intracerebroventricular (ICV) administration of ultrasound-responsive bubbles and cranial ultrasound irradiation is reported as a transfection system for the cerebroventricular region. This study aimed to characterize the transfection system with respect to transfection efficiency, spatial distribution of transgene expression, and safety. Methods Plasmid DNA was transfected to mouse brain by ICV injection of ultrasound-responsive nanobubbles, followed by ultrasound irradiation to brain. Spatial distribution of transgene expression in the cerebroventricular region was investigated using multicolor deep imaging. Result This transfection system efficiently transferred the transgene to the choroid plexus with no morphological change or cerebral hemorrhage. Moreover, sustained secretion of transgenic protein was achieved by transferring the transgene encoding the secretable protein. Conclusion We successfully developed an ultrasound-responsive nanobubbles-mediated method for gene transfection into the cerebroventricular region via ICV administration in mice.

Purpose Umbelliferone (Umb), a member of coumarin family, is found in many plants and is a promising molecule with potential anti-inflammatory, anti-oxidative, and anti-tumor activities. However, the effect of Umb on arthritis remains unclear. Methods A rat model with Freund’s complete adjuvant (FCA)-induced arthritis was developed and used to test the efficacy of Umb on arthritis rats. Rats were given an intragastric injection of Umb (20 and 40 mg/kg) once daily from days 21 to 28 after the administration of FCA. Hind paw volume was assessed using a volume meter. The pro-inflammatory cytokine levels and prostaglandin E2 (PEG2) level in serum and synovial fluid were detected by ELISA. HE staining was used to determine representative histological changes in joint tissues, and Western blot analysis was employed to study the effects of Umb on MAPK/NF-κB signaling pathway. Results Our results showed that Umb suppressed the release of IL-6, IL-1β, tumor necrosis factor-alpha, and PEG2. In addition, Umb could also dramatically ameliorate the pathological changes observed in rat joints. Based on the results of Western blot, we also observed that Umb could strikingly suppress the expression of MAPK/NF-κB pathway molecules. Conclusion These results proved that treatment with Umb is very effective for arthritis and inhibiting the MAPK/NF-κB signaling pathway may be a potential therapeutic target for treatment of arthritis.

Prenatal alcohol exposure (PAE) could lead to developmental disorders of the central nervous system (CNS) and mental retardation. Toll-like receptor (TLR) 4 plays an important role in PAE-induced neurodevelopmental defects. However, how PAE affects TLR4 response in the brain remains controversial. Using a moderate PAE model by feeding pregnant rats with liquid ethanol diet, we investigated the TLR4-mediated response to intraventricular injection of lipopolysaccharide (LPS) in the hippocampus of PEA rats at postnatal day (PND) 30. The results showed that PAE significantly up-regulated the expression of Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor protein inducing interferon (IFN)-β (TRIF), TNF-α, and IL-1β in the rat hippocampus in the absence of LPS, indicated by western blot assay. LPS treatment dramatically up-regulated the expressions of TLR4 and its downstream molecules in the hippocampus of paired-food and control groups. But no such significant changes of those molecules were found in the hippocampus of PAE animals. Moreover, the LPS stimulation even down-regulated the levels of TLR4 and TRIF in the PAE group. These data suggest that the relatively moderate level of PAE may lead to a mild neuroinflammation and a suppression of TLR4-mediated response to LPS in the hippocampus of young rats. As innate immunity plays crucial roles in CNS development, moderate PAE-induced suppression of TLR4-mediated response may serve as a new candidate mechanism of CNS developmental defects.

RATIONALE: Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine neurotoxicity. Blocking dopamine receptors prior to MA exposure in adult rats attenuates monoamine reductions and reactive gliosis. OBJECTIVES: We tested whether blocking dopamine receptors protects against cognitive deficits. METHODS: First, we determined the effects of MA alone versus MA in combination with the dopamine receptor D1 antagonist SCH-23390 or the dopamine receptor D2 antagonist sulpiride on cFos expression and monoamines at the age when rats in the cognitive experiment were to begin testing and monoamines in rats after cognitive testing. RESULTS: SCH-23390 infused into the neostriatum prior to systemic administration of MA attenuated MA-induced cFos activation while sulpiride induced cFos activation. Two weeks after MA, rats had dopamine and serotonin reductions that were attenuated by each antagonist. Other rats treated the same way, were tested for egocentric learning and memory in the Cincinnati water maze, for navigational strategy in a star water maze, and spatial learning and memory in a Morris water maze. Pretreatment with SCH-23390 or sulpiride attenuated the effects of MA on egocentric and spatial learning and memory. MA-treated rats showed a shift from an egocentric to a disorganized strategy in the Star maze that was less disorganized in groups receiving MA and an antagonist. Post-behavior monoamine reductions remained but were attenuated by the antagonists but not identically to what was seen in rats not behaviorally tested. CONCLUSIONS: The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.

PURPOSE: We explored the use of intraventricular (131)I-8H9 targeting B7-H3 in patients with ETMR. METHODS: Patients were enrolled in an IRB approved, phase 1, 3+3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3, were eligible. We report on a cohort of 3 patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi (131)I-Omburtamab as a tracer followed by 1 or 2 therapeutic (131)I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after (131)I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted. RESULTS: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received (131)I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to (131)I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then (131)I-Omburtamab (36 mCi). (131)I-Omburtamab was well-tolerated. Mean dose delivered by (131)I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 month after therapy (2 years after diagnosis). CONCLUSIONS: (131)I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, (131)I-Omburtamab may have therapeutic benefit for patients with ETMR.

Aims Aegle marmelos (L.) Correa (A. marmelos) has been used in Ayurvedic medicine as a brain tonic however its neuroprotective effect against streptozotocin (STZ) induced cognitive impairment and oxidative stress has not been reported yet in vivo. Therefore, the present study was attempted to investigate the neuroprotective potential of ethanolic extract of A. marmelos leaves (AME) on STZ induced memory impairment in male rats. Main methods Albino Wistar rats were pre-treated orally with AME at the doses 200 and 400 mg/kg for two weeks, followed by intracerebroventricular (i.c.v.) injection of STZ (3 mg/kg) on day 1 and 3. Two weeks after STZ administration, behavioural parameters were monitored using Morris water maze task. Biochemical and histopathological studies were carried out after three weeks of STZ administration. The levels of oxidative stress markers (malondialdehyde (MDA), glutathione, nitrite, catalase) neuroinflammatory mediators; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and acetylcholinesterase (AChE) activity were estimated in hippocampus of rat brain. Donepezil (5 mg/kg) was taken as a standard drug. Key findings The levels of MDA, nitrite, TNF-α and IL-6 were significantly increased while glutathione levels were significantly decreased in hippocampus of STZ-treated rats. Further, a significant decrease in the activity of catalase and increase in AChE activity was observed indicating cholinergic hypofunction and neuronal damage in STZ-treated animals. All these alterations were significantly ameliorated by AME in a dose dependent manner. Significance The neuroprotective potential of A. marmelos against STZ induced oxidative stress and cognitive deficit in rats indicates its therapeutic value in Alzheimer's disease (AD).

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy., TREM2 is a genetic risk factor for Alzheimer’s disease, and soluble TREM2 (sTREM2) in the CSF correlates with AD progression. Here the authors study the role of sTREM2 in a mouse model of Alzheimer’s disease, and find it reduces amyloid accumulation and increases the numbers of plaque-associated microglia which correlates with improved behavioural function in the mice.

It is well established that newly acquired information is stabilized over time by processes underlying memory consolidation, these events can be impaired by many drug treatments administered shortly after learning. The consolidation hypothesis has been challenged by a memory integration hypothesis, which suggests that the processes underlying new memories are vulnerable to incorporation of the neurobiological alterations induced by amnesic drugs generating a state-dependent memory. The present experiments investigated the effects of amnesic drugs infused into the insular cortex of male Wistar rats on memory for object recognition training. The findings provide evidence that infusions of several amnesic agents including a protein synthesis inhibitor, an RNA synthesis inhibitor, or an NMDA receptor antagonist administered both after a specific period of time and before retrieval induce state-dependent recognition memory. Additionally, when amnesic drugs were infused outside the early consolidation window, there was amnesia, but the amnesia was not state-dependent. Data suggest that amnesic agents can induce state-dependent memory when administered during the early consolidation window and only if the duration of the drug effect is long enough to become integrated to the memory trace. In consequence, there are boundary conditions in order to induce state-dependent memory.

With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer’s disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-β (1–42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Aβ (1–42) peptides infused Wistar rats. ASX also significantly attenuated soluble Aβ (1–42) level, IRS-S307 activity, GSK-3β activity, TNF-α level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer’s disease complications, supporting potential role of hippocampal insulin resistance targeting against AD.

Disruption of the blood-brain barrier results in the formation of edema and contributes to the loss of neurological function following intracerebral hemorrhage (ICH). This study examined insulin-like growth factor-1 (IGF-1) as a treatment and its mechanism of action for protecting the blood-brain barrier after ICH in mice. 171 Male CD-1 mice were subjected to ICH via collagenase or autologous blood. A dose study for recombinant human IGF-1 (rhIGF-1) was performed. Brain water content and behavioral deficits were evaluated at 24 and 72 h after the surgery, and Evans blue extravasation and hemoglobin assay were conducted at 24 h. Western blotting was performed for the mechanism study and interventions were used targeting the IGF-1R/GSK3β/MEKK1 pathway. rhIGF-1 reduced edema and blood-brain barrier permeability, and improved neurobehavior outcomes. Western blots showed that rhIGF-1 reduced p-GSK3β and MEKK1 expression, thereby increasing occludin and claudin-5 expression. Inhibition and knockdown of IGF-1R reversed the therapeutic benefits of rhIGF-1. The findings within suggest that stimulation of the IGF-1R is a therapeutic target for ICH which may lead to improved neurofunctional and blood-brain barrier protection.

Local translation in neurites is considered as an important mechanism to modulate synaptic plasticity of neurons. However, it is hard to specifically express a protein-coding gene in neurites. Recently, the 5′-UTR of Tick-borne encephalitis virus (TBEV) is reported to be able to drive its RNA to the dendrites of infected neurons, as a cis-acting RNA element. To construct a neurite specific gene expression system, present study tested the ability of 5′-UTR of TBEV to bring a mRNA (mCherry CDS) to the neurites for targeted expression. We showed that both the 5′-UTR of TBEV and the 3′-UTR of Actb gene could bring the protein coding mRNA to neurites, and the TBEV 5′-UTR bearing mRNA was more robust targeted into neurites. About the safety of the TBEV 5′-UTR, there was no obvious cytotoxicity to the neurons when adding either cis-acting RNA element to the protein-expressing plasmid vectors. Given the short length and high efficiency of the TBEV 5′-UTR, the 5′-UTR of TBEV were assemble into an AAV plasmid to produce virus particles for expressing protein-coding gene in vivo. After two weeks infection, the TBEV 5′-UTR infected neurons expressed more mCherry protein in their neurites. In conclusion, as a short while high efficient cis-acting RNA element, TBEV 5′-UTR could be useful in neural system research and locally express synaptic proteins more precisely.

Background Previous studies had showed that Apelin 13 could protect against apoptosis induced by ischemic/reperfusion (I/R). However, the mechanisms whereby Apelin 13 protected brain I/R remained to be elucidated. The present study was designed to determine whether Apelin 13 provided protection through AMPK/GSK-3β/Nrf2 pathway. Methods In vivo, the I/R model was induced and Apelin 13 was given intracerebroventricularly 15 min before reperfusion. The neurobehavioral scores, infarction volumes, and some cytokines in the brain were measured. For in vitro study, PC12 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Protein levels were investigated by western blotting. Results The results showed that Apelin 13 treatment significantly reduced infarct size, improved neurological outcomes, decreased brain edema, and inhibited cell apoptosis, oxidative stress, and neuroinflammation after I/R. Apelin 13 significantly increased the expression of Nrf2 and the phosphorylation levels of AMPK and GSK-3β. Furthermore, in cultured PC12 cells, the same protective effects were also observed. Silencing Nrf2 gene with its siRNA abolished the Apelin 13’s prevention of I/R-induced PC12 cell injury, oxidative stress, and inflammation. Inhibition of AMPK by its siRNA decreased the level of Apelin 13-induced Nrf2 expression and diminished the protective effects of Apelin 13. The interplay relationship between GSK-3β and Nrf2 was also verified with relative overexpression. Using selective inhibitors, we further identified the upstream of AMPK/GSK-3β/Nrf2 is AR/Gα/PLC/IP3/CaMKK. Conclusions In conclusion, the previous results showed that Apelin 13 protected against I/R-induced ROS-mediated inflammation and oxidative stress through activating the AMPK/GSK-3β pathway by AR/Gα/PLC/IP3/CaMKK signaling, and further upregulated the expression of Nrf2-regulated antioxidant enzymes.

The endocannabinoid system plays an important role in the organization of panic-like defensive behavior. Threatening situations stimulate brain areas, such as the dorsomedial hypothalamus (DMH). However, there is a lack of studies addressing the role of the DMH endocannabinoid system in panic-like responses. We aimed to verify which mechanisms underlie anandamide-mediated responses in the DMH. To test the hypothesis that the anandamide produces panicolytic-like effects, we treated mice with intra-DMH microinjections of vehicle or increasing doses of anandamide (0.5, 5, or 50 pmol) and then performed confrontation with the South American snake Epicrates cenchria assisi. Intra-DMH anandamide treatment yielded a U-shaped dose-response curve with no effect of the lowest (0.5 pmol) or the highest (50 pmol) dose and significant inhibition of panic-like responses at the intermediate (5 pmol) dose. In addition, this panicolytic-like effect was prevented by pretreatment of the DMH with the CB1 receptor antagonist AM251 (100 pmol). However, pretreatment of the DMH with the TRPV1 receptor antagonist 6-iodo-nordihydrocapsaicin (3 nmol) restored the panicolytic-like effect of the highest dose of anandamide. Immunohistochemistry revealed that CB1 receptors were present primarily on axonal fibers, while TRPV1 receptors were found almost exclusively surrounding the perikarya in DMH. The present results suggest that anandamide exerts a panicolytic-like effect in the DMH by activation of CB1 receptors and that TRPV1 receptors are related to the lack of effect of the highest dose of anandamide.

Neurofibromatosis type II (NF2) is a disease that lacks effective therapies. NF2 is characterized by bilateral vestibular schwannomas (VSs) that cause progressive and debilitating hearing loss, leading to social isolation and increased rates of depression. A major limitation in NF2 basic and translational research is the lack of animal models that allow the full spectrum of research into the biology and molecular mechanisms of NF2 tumor progression, as well as the effects on neurological function. In this protocol, we describe how to inject schwannoma cells into the mouse brain cerebellopontine angle (CPA) region. We also describe how to apply state-of-the-art intravital imaging and hearing assessment techniques to study tumor growth and hearing loss. In addition, ataxia, angiogenesis, and tumor–stroma interaction assays can be applied, and the model can be used to test the efficacy of novel therapeutic approaches. By studying the disease from every angle, this model offers the potential to unravel the basic biological underpinnings of NF2 and to develop novel therapeutics to control this devastating disease. Our protocol can be adapted to study other diseases within the CPA, including meningiomas, lipomas, vascular malformations, hemangiomas, epidermoid cysts, cerebellar astrocytomas, and metastatic lesions. The entire surgical procedure takes ~45 min per mouse and allows for subsequent longitudinal imaging, as well as neurological and hearing assessment, for up to 2 months. Schwannoma cells are injected into the CPA region of the mouse brain to establish a model of vestibular schwannoma. Procedures for intravital imaging and neurological tests for hearing are also described.

Intrathecal nicardipine has been shown to have some efficacy for the treatment of symptomatic cerebral vasospasm in aneurysmal subarachnoid hemorrhage (aSAH). We performed a PRISMA-based systematic review of intrathecal nicardipine for the treatment of cerebral vasospasm in aneurysmal subarachnoid hemorrhage. A total of 825 articles were reviewed. After duplicates were removed and the search criteria was applied, 9 articles remained that were eligible for inclusion and analysis. 377 patients received a total of 6,596 injections of intrathecal nicardipine for aSAH-related cerebral vasospasm. The cumulative ventriculostomy-associated infection risk was 6%. Intrathecal nicardipine injections for aSAH-related cerebral vasospasm appears efficacious and safe. Administration of 4 mg of nicardipine every 12 hours was the most commonly reported dosing regimen. Intrathecal nicardipine decreases mean flow velocities on transcranial Doppler and reduces angiographic and clinical vasospasm. The infection risk appears to be in-line with studies in which rates of EVD-related infections have been reported.

Background Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potential mechanism mediated by Notch1 signaling pathway inhibition. Methods The Sprague-Dawley rats SAH model was induced by endovascular perforation method. BMSCs (3 × 106 cells) were transplanted intravenously into rats, and N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a Notch1 activation inhibitor, and Notch1 small interfering RNA (siRNA) were injected intracerebroventricularly. The effects of BMSCs on EBI were assayed by neurological score, brain water content (BWC), blood-brain barrier (BBB) permeability, magnetic resonance imaging, hematoxylin and eosin staining, and Fluoro-Jade C staining. Immunofluorescence and immunohistochemistry staining, Western blotting, and quantitative real-time polymerase chain reaction were used to analyze various proteins and transcript levels. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Results BMSCs treatment mitigated the neurobehavioral dysfunction, BWC and BBB disruption associated with EBI after SAH, reduced ionized calcium binding adapter molecule 1 and cluster of differentiation 68 staining and interleukin (IL)-1 beta, IL-6 and tumor necrosis factor alpha expression in the left hemisphere but concurrently increased IL-10 expression. DAPT or Notch1 siRNA administration reduced Notch1 signaling pathway activation following SAH, ameliorated neurobehavioral impairments, and BBB disruption; increased BWC and neuronal degeneration; and inhibited activation of microglia and production of pro-inflammatory factors. The augmentation of Notch1 signal pathway agents and phosphorylation of nuclear factor-κB after SAH were suppressed by BMSCs but the levels of Botch were upregulated in the ipsilateral hemisphere. Botch knockdown in BMSCs abrogated the protective effects of BMSCs treatment on EBI and the suppressive effects of BMSCs on Notch1 expression. Conclusions BMSCs treatment alleviated neurobehavioral impairments and the inflammatory response in EBI after SAH; these effects may be attributed to Botch upregulation in brain tissue, which subsequently inhibited the Notch1 signaling pathway. Electronic supplementary material The online version of this article (10.1186/s12974-019-1396-5) contains supplementary material, which is available to authorized users.