Young Brain Research Articles

KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.

Cognitive deficits are a major biomedical challenge—and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.

Identification of microRNA/target gene in the dentate gyrus of 7‑day‑old mice following isoflurane exposure.

Studies on rodents and nonhuman primates suggest that exposure to anesthetics, particularly in the young brain, is associated with neuronal apoptosis as well as hippocampal‑dependent cognitive dysfunction. Disruption of the development of dentate gyrus may play an important role in anesthetics‑induced neurotoxicity. However, the anesthetics triggered molecular events in the dentate gyrus of the developing brain are poorly understood. By integrating two independent data sets obtained from miRNA‑seq and mRNA‑seq respectively, this study aims to profile the network of miRNA and potential target genes, as well as relevant events occurring in the dentate gyrus of isoflurane exposed 7‑day‑old mice. We found that a single four hours exposure to isoflurane yielded 1059 pairs of differently expressed miRNAs/target genes in the dentate gyrus. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis further indicates that dysregulated miRNAs/target genes have far‑reaching effects on the cellular pathophysiological events, such as cell apoptosis, axon development, and synaptic transmission. Our results would greatly broaden our functional understanding of the role of miRNA/target gene in the context of anesthetics‑induced neurotoxicity.

Photobiomodulation of Cytochrome c Oxidase by Chronic Transcranial Laser in Young and Aged Brains

In cellular bioenergetics, cytochrome c oxidase (CCO) is the enzyme responsible for oxygen consumption in the mitochondrial electron transport chain, which drives oxidative phosphorylation for adenosine triphosphate (ATP) production. CCO is also the major intracellular acceptor of photons in the light wavelengths used for photobiomodulation (PBM). Brain function is critically dependent on oxygen consumption by CCO for ATP production. Therefore, our objectives were (1) to conduct the first detailed brain mapping study of the effects of PBM on regional CCO activity, and (2) to compare the chronic effects of PBM on young and aged brains. Specifically, we used quantitative CCO histochemistry to map the differences in CCO activity of brain regions in healthy young (4 months old) and aged (20 months old) rats from control groups with sham stimulation and from treated groups with 58 consecutive days of transcranial laser PBM (810 nm wavelength and 100 mW power). We found that aging predominantly decreased regional brain CCO activity and systems-level functional connectivity, while the chronic laser stimulation predominantly reversed these age-related effects. We concluded that chronic PBM modified the effects of aging by causing the CCO activity on brain regions in laser-treated aged rats to reach levels similar to those found in young rats. Given the crucial role of CCO in bioenergetics, PBM may be used to augment brain and behavioral functions of older individuals by improving oxidative energy metabolism.

Aging-Related Alterations of Glymphatic Transport in Rat: In vivo Magnetic Resonance Imaging and Kinetic Study.

ObjectiveImpaired glymphatic waste clearance function during brain aging leads to the accumulation of metabolic waste and neurotoxic proteins (e.g., amyloid-β, tau) which contribute to neurological disorders. However, how the age-related glymphatic dysfunction exerts its effects on different cerebral regions and affects brain waste clearance remain unclear.MethodsWe investigated alterations of glymphatic transport in the aged rat brain using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and advanced kinetic modeling. Healthy young (3–4 months) and aged (18–20 months) male rats (n = 12/group) underwent the identical MRI protocol, including T2-weighted imaging and 3D T1-weighted imaging with intracisternal administration of contrast agent (Gd-DTPA). Model-derived parameters of infusion rate and clearance rate, characterizing the kinetics of cerebrospinal fluid (CSF) tracer transport via the glymphatic system, were evaluated in multiple representative brain regions. Changes in the CSF-filled cerebral ventricles were measured using contrast-induced time signal curves (TSCs) in conjunction with structural imaging.ResultsCompared to the young brain, an overall impairment of glymphatic transport function was detected in the aged brain, evidenced by the decrease in both infusion and clearance rates throughout the brain. Enlarged ventricles in parallel with reduced efficiency in CSF transport through the ventricular regions were present in the aged brain. While the age-related glymphatic dysfunction was widespread, our kinetic quantification demonstrated that its impact differed considerably among cerebral regions with the most severe effect found in olfactory bulb, indicating the heterogeneous and regional preferential alterations of glymphatic function.ConclusionThe robust suppression of glymphatic activity in the olfactory bulb, which serves as one of major efflux routes for brain waste clearance, may underlie, in part, age-related neurodegenerative diseases associated with neurotoxic substance accumulation. Our data provide new insight into the cerebral regional vulnerability to brain functional change with aging.

TAPPing into the potential of inducible tau/APP transgenic mice.

Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy. We crossed an inducible tauopathy model with two β-amyloid models utilising the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis and then assessed tauopathy, amyloidosis and gliosis. We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aβ and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7months before inducing expression for a subsequent 6months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1month before inducing expression for 5months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy. These data suggest that tau misfolding is exacerbated by both newly forming Aβ deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of ageing, amyloid and tauopathy and to test interventions to disrupt the amyloid cascade.

Characterization of Cysteine Cathepsin Expression in the Central Nervous System of Aged Wild-Type and Cathepsin-Deficient Mice

The association of cathepsin proteases in neurobiology is increasingly recognized. Our previous studies indicated that cathepsin-K-deficient (Ctsk−/−) mice have learning and memory impairments. Alterations in cathepsin expression are known to result in compensatory changes in levels of related cathepsins. To gain insight into the therapeutic usefulness of cathepsin inhibitors in aging individuals with osteoporosis or neurodegenerative diseases, we studied for variations in cathepsin expression and activity in aged (18–20 months) versus young (5–7 months) wild-type (WT) and cathepsin-deficient mice brains. There were age-dependent increases in cathepsin B, D, and L and cystatin C protein levels in various brain regions, mainly of WT and Ctsk−/− mice. This corresponded with changes in activity levels of cathepsins B and L, but not cathepsin D. In contrast, very little age-dependent variation was observed in cathepsin-B- and cathepsin-L-deficient mouse brain, especially at the protein level. The observed alterations in cathepsin protein amounts and activity are likely contributing to changes in important aging-related processes such as autophagy. In addition, the results provide insight into the potential impact of cathepsin inhibitor therapy in aged individuals, as well as in long-term use of cathepsin inhibitor therapy.

Inter-alpha Inhibitor Proteins Ameliorate Brain Injury and Improve Behavioral Outcomes in a Sex-Dependent Manner After Exposure to Neonatal Hypoxia Ischemia in Newborn and Young Adult Rats.

Hypoxic-ischemic (HI) brain injury is a major contributor to neurodevelopmental morbidities. Inter-alpha inhibitor proteins (IAIPs) have neuroprotective effects on HI-related brain injury in neonatal rats. However, the effects of treatment with IAIPs on sequential behavioral, MRI, and histopathological abnormalities in the young adult brain after treatment with IAIPs in neonates remain to be determined. The objective of this study was to examine the neuroprotective effects of IAIPs at different neurodevelopmental stages from newborn to young adults after exposure of neonates to HI injury. IAIPs were given as 11-sequential 30-mg/kg doses to postnatal (P) day 7-21 rats after right common carotid artery ligation and exposure to 90min of 8% oxygen. The resulting brain edema and injury were examined by T2-weighted magnetic resonance imaging (MRI) and cresyl violet staining, respectively. The mean T2 values of the ipsilateral hemisphere from MRI slices 6 to 10 were reduced in IAIP-treated HI males + females on P8, P9, and P10 and females on P8, P9, P10, and P14. IAIP treatment reduced hemispheric volume atrophy by 44.5 ± 29.7% in adult male + female P42 rats and improved general locomotor abilities measured by the righting reflex over time at P7.5, P8, and P9 in males + females and males and muscle strength/endurance measured by wire hang on P16 in males + females and females. IAIPs provided beneficial effects during the learning phase of the Morris water maze with females exhibiting beneficial effects. IAIPs confer neuroprotection from HI-related brain injury in neonates and even in adult rats and beneficial MRI and behavioral benefits in a sex-dependent manner.

Pharmacological Depletion of Microglia Leads to a Dose-Dependent Reduction in Inflammation and Senescence in the Aged Murine Brain

Chronic macrophage activation was implicated as one of the main culprits for chronical, low-grade inflammation which significantly contributes to development of age-related diseases. Microglia as the brain macrophages have been recently implicated as key players in neuroinflammation and neurodegeneration in the aged brain. Microglial cell functions are indispensable in early development, however, activation or senescence of microglia in aging cells may be detrimental. Depletion of microglia using genetical or pharmacological approaches leads to opposite results regarding effects on brain cognition. In this study we pharmacologically depleted microglia using orally delivered low and high doses of the CSF1R inhibitor PLX5622 and assessed the expression levels of known inflammation markers (TNF-α, IL1-β, IL-6, IL-10), glia markers (Iba-1 and Gfap) and specific senescence marker p16Ink4a in the aged murine brain. Our results indicate that treatment with low and high doses of PLX5622 leads to a dose-dependent depletion of microglial cells with similar levels in young and aged mice. We also show that treatment with low and high PLX5622 differentially affected cytokine levels in young and old brains. By using low doses we could achieve reduction in inflammation circumventing the astrocyte activation. Removal of microglia cells led to decreased expression of the senescence marker p16Ink4a in the aged brain, indicating a relevant contribution of these cells to the expression of this marker and their senescent status in the healthy aging brain. Our results indicate that increased and detrimental brain inflammation in aged murine brain can be impaired by selectively reducing the microglial cell population.

Outcome of human amniotic membrane wrap around neurorrhaphy in high radial nerve injury - a case report following monkey bite

IntroductionPeripheral nerve injury due to animal bite is a rare phenomenon. Most animal bites are from dogs. Monkey bites constitute a common risk, second only to dog bites, among travelers. Peripheral nerve injuries may occur due to a combination of monkey's strong jaws and sharp long teeth penetrating deep into the soft tissues. Such injuries are associated with increased perineural fibrosis. Human amniotic membrane (HAM) wrap around the nerve repair site reduces fibrotic response, prevents adhesions and scar formation thereby improving outcome. We report a case of “High Radial nerve palsy due to monkey bite, treated by neurorrhaphy with HAM wrap”. MethodA 3-year old boy presented with wrist drop, and inability to extend the fingers and thumb of his right dominant hand, following a monkey bite over the distal arm. The diagnosis of high radial nerve injury was corroborated by high frequency ultrasound and electrodiagnostic studies. On exploration the radial nerve was found to be transected. An end to end repair was performed, with HAM wrap around the neurorrhaphy. ResultsWrist dorsiflexion recovered at 2.5 months followed by active finger and thumb extension at 4 months with no infection or immune rejection. ConclusionNerve regeneration in our patient occurred at a faster rate as compared to the conventional 1 mm/day. This could be attributed to decreased perineural fibrosis, improved neurotropism due to the HAM wrap and neuronal plasticity in young brain in addition, the patient being a small child having better regenerative ability in comparison to an adult.

Next-generation sequencing of cerebrospinal fluid for clinical molecular diagnostics in pediatric, adolescent and young adult brain tumor patients.

Safe sampling of central nervous system tumor tissue for diagnostic purposes may be difficult if not impossible, especially in pediatric patients, and an unmet need exists to develop less invasive diagnostic tests. We report our clinical experience with minimally invasive molecular diagnostics using a clinically validated assay for sequencing of cerebrospinal fluid (CSF) cell-free DNA (cfDNA). All CSF samples were collected as part of clinical care, and results reported to both clinicians and patients/families. We analyzed 64 CSF samples from 45 pediatric, adolescent and young adult (AYA) patients (pediatric = 25; AYA = 20) with primary and recurrent brain tumors across 12 histopathological subtypes including high-grade glioma (n = 10), medulloblastoma (n = 10), pineoblastoma (n = 5), low-grade glioma (n = 4), diffuse leptomeningeal glioneuronal tumor (DLGNT) (n = 4), retinoblastoma (n = 4), ependymoma (n = 3), and other (n = 5). Somatic alterations were detected in 30/64 samples (46.9%) and in at least one sample per unique patient in 21/45 patients (46.6%). CSF cfDNA positivity was strongly associated with the presence of disseminated disease at the time of collection (81.5% of samples from patients with disseminated disease were positive). No association was seen between CSF cfDNA positivity and the timing of CSF collection during the patient's disease course. We identified three general categories where CSF cfDNA testing provided additional relevant diagnostic, prognostic, and/or therapeutic information, impacting clinical assessment and decision making: (1) diagnosis and/or identification of actionable alterations; (2) monitor response to therapy; and (3) tracking tumor evolution. Our findings support broader implementation of clinical CSF cfDNA testing in this population to improve care.

Lactate-Dependent Cross-Talk Between Astrocyte and GnRH-I Neurons in Hypothalamus of Aged Brain: Decreased GnRH-I Transcription.

GnRH-I produced by hypothalamic neurosecretory cells is considered a master regulator of mammalian reproduction. Although GnRH-I transcription is well studied, the effect of ageing on transcriptional regulation of GnRH-I has not yet been explored. Here, we elucidate the effects of ageing on the metabolic environment like lactate level and TNF-α and how these affect GnRH-I transcription. Using pathway analysis of transcriptomic data, we found that lactate is upregulated in ageing astrocytes due to the downregulation of cellular respiration pathways possibly resulting in greater pyruvate concentration for lactate production. This lactate could then be shuttled into neurons where it would affect GnRH-I transcription. We showed that supra-physiological level of lactate in young mouse brain can mimic metabolic disturbances in the old brain and cause downregulation in GnRH-I transcription at a young age. In particular, we found upregulation of GnRH-I repressors in the young brain treated with high levels of lactate similar to old brain. Hence, this confirmed that aged metabolic environment can affect GnRH-I transcription even in the young brain. Further downstream analysis using the TRUST database showed NF-Kb signalling which lies downstream of both lactate and TNF-α as being capable of upregulating GnRH-I repressors. Since NF-Kb signalling has been shown in our study as well as others to be induced by TNF-α during ageing, it is likely that GnRH-I transcriptional regulation is mediated through these pathways. Thus, we formed a model for explaining the downregulation of GnRH-I transcription during ageing through differential expression of its TFs in an aged metabolic environment.

General Anesthesia and the Young Brain: The Importance of Novel Strategies with Alternate Mechanisms of Action.

Over the past three decades, we have been grappling with rapidly accumulating evidence that general anesthetics (GAs) may not be as innocuous for the young brain as we previously believed. The growing realization comes from hundreds of animal studies in numerous species, from nematodes to higher mammals. These studies argue that early exposure to commonly used GAs causes widespread apoptotic neurodegeneration in brain regions critical to cognition and socio-emotional development, kills a substantial number of neurons in the young brain, and, importantly, results in lasting disturbances in neuronal synaptic communication within the remaining neuronal networks. Notably, these outcomes are often associated with long-term impairments in multiple cognitive-affective domains. Not only do preclinical studies clearly demonstrate GA-induced neurotoxicity when the exposures occur in early life, but there is a growing body of clinical literature reporting similar cognitive-affective abnormalities in young children who require GAs. The need to consider alternative GAs led us to focus on synthetic neuroactive steroid analogues that have emerged as effective hypnotics, and analgesics that are apparently devoid of neurotoxic effects and long-term cognitive impairments. This would suggest that certain steroid analogues with different cellular targets and mechanisms of action may be safe alternatives to currently used GAs. Herein we summarize our current knowledge of neuroactive steroids as promising novel GAs.

An ode to fetal, infant, and toddler neuroimaging: Chronicling early clinical to research applications with MRI, and an introduction to an academic society connecting the field

Fetal, infant, and toddler neuroimaging is commonly thought of as a development of modern times (last two decades). Yet, this field mobilized shortly after the discovery and implementation of MRI technology. Here, we provide a review of the parallel advancements in the fields of fetal, infant, and toddler neuroimaging, noting the shifts from clinical to research use, and the ongoing challenges in this fast-growing field. We chronicle the pioneering science of fetal, infant, and toddler neuroimaging, highlighting the early studies that set the stage for modern advances in imaging during this developmental period, and the large-scale multi-site efforts which ultimately led to the explosion of interest in the field today. Lastly, we consider the growing pains of the community and the need for an academic society that bridges expertise in developmental neuroscience, clinical science, as well as computational and biomedical engineering, to ensure special consideration of the vulnerable mother-offspring dyad (especially during pregnancy), data quality, and image processing tools that are created, rather than adapted, for the young brain.

Abstract 160: Age-associated CD11b High B Cells Are Recruited To The Brain After Stroke And Regulate Microglial Function

CD11b expression is essential for immunity due to its role in cell motility and phagocytosis. Leukocytes, including monocytes, neutrophils and macrophages, express CD11b. B lymphocytes, which are both adaptive immune cells and antigen presenting cells (APCs), also express CD11b at varying levels. The role of B lymphocytes after stroke is multifaceted, and recent studies have highlighted their deleterious contributions to post-stroke recovery and cognitive decline. CD11b high B cells have not been studied in the context of aging and stroke. We hypothesized that CD11b high B cells increase in the brain after stroke and regulate microglia function. We used a middle cerebral artery occlusion (MCAO) model of stroke in young (2mo) and aged (18mo) WT male mice to investigate the role of CD11b high B cells in post-ischemic immune responses. In the acute phase following stroke, resident immune cells, primarily microglia (MG), are rapidly activated. Thus, we studied the ability of CD11b high B cells to influence MG phenotype in young and aged brain. We found that CD11b high B cells are a heterogeneous subpopulation of B lymphocytes and predominantly found in aged mice (n=4/gp, p=0.0089 ) and after stroke (n=5/gp, p=0.0078 ). This subset is characterized by their higher expression of CD80 and CD73 (n=8/gp, p<0.0001, for both ). The frequency of CD11b high B cells increases in the brain after stroke in both young and aged mice. These cells are capable of changing MG phenotype sorted from either young or aged brain, as assessed by decreased expression of CD45, CD11b, and MHC-II by MG (n=4/gp, p=0.0013, p=0.0033, p=0.0310 , respectively). When co-incubated with ex vivo sorted MG, CD11b high B cells increased phagocytic function MG more than their CD11b low B cell counterparts (n=4/gp, p=0.0486 ). Lastly, the regulatory influence of CD11b high B cells is likely through production of inflammatory cytokines including TNF-α (n=5/gp, p<0.0001 ). As both APCs and adaptive immune cells with memory function, B lymphocytes are uniquely positioned to regulate both acute and chronic phases of the post-stroke immune response, and their influence is subset-specific. Future studies are warranted to better understand the function of these age-associated CD11b high B cells in neuroinflammation.

Abstract WMP19: Cumulative Vascular Risk Factors Exposure During Young Adulthood And Brain Structure In Midlife

Objective: Vascular risk factors (VRF) are known contributors to brain health in old age, with minority populations disproportionately impacted. The role of duration and severity of exposure to VRF remains unclear. We examined the association between cumulative exposures to VRF (cVRF) from young adulthood to midlife and midlife brain health, while addressing racial differences. Methods: 142 participants (39% black, 42% women) from the Coronary Artery Risk Development in Young Adults study with longitudinal VRF data over 30 years and a brain MRI at Y30 were included. Cumulative blood pressure (cBP), cholesterol, BMI, smoking, and glucose was calculated as the mean of two measures across two consecutive visits, multiplied by the number of years between visits from Y0 to Y30. Multivariate linear regression models including all VRF, demographics, and medications were used to assess the independent association of cVRF with brain MRI outcomes across races. Results: Higher cSBP was associated with lower total brain, gray matter, and hippocampal volumes in blacks, but not in whites (interaction p<0.05, Table1), independent of other cVRF. Similarly, higher cDBP was associated with lower total brain and hippocampal volumes only in blacks, but not in whites (interaction p<0.05, Table1). However, when examining these relationships across comparable cBP exposure levels, race differences were no longer significant. There was no interaction between race and other cVRF in relation to white matter hyperintensities, gray matter thickness or cerebral perfusion (interaction p>0.05). Conclusions: Exposure to higher BP across young adulthood is associated with midlife brain structure, possibly irrespective of race. Given higher level of cBP exposure in minorities, our observations should encourage clinicians to be aggressive in addressing hypertension in young adults, especially in young minority populations as a potential target to narrow disparities in brain health.

Abstract WMP116: Age-related Dysfunction In Leptomeningeal Collateral Remodeling After Ischemic Stroke

Introduction: The leptomeningeal collaterals (LMCs) are specialized brain surface arterioles that interconnect the major cerebral artery territories. Good outcome following ischemic stroke is highly correlated with high collateral number and function. Unfortunately, with aging and disease, the LMCs demonstrate impaired dilatory capacity, reduced vessel diameter, and even complete vessel loss (rarefaction). The present study examined the chronic remodeling capacity of LMCs following permanent stroke in young and aged mice. Methods: Young and aged C57BL6 mice (5 and 20 months) were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). At 2 weeks or 3 months, LMCs were evaluated for inner diameter and VWF expression (% LMC coverage). We compared the LMCs feeding the occluded MCA territory (LMC ipsi) to the contralateral equivalent vessels (LMC contra). Diameter change is reported as fold change relative to the distal-most arteriole (DMA) associated with each LMC. Results: Young male mice demonstrated increased diameter of LMC ipsi relative to DMA at both 2 weeks (1.36 ± 0.075; n=24 vessels/4 mice, P<0.01) and 3 months after stroke (1.27 ± 0.073, n=19 vessels/2 mice, P<0.01). LMC contra were 0.901 ± 0.064 and 1.01 ± 0.053 for the same time points (n=19 and 10 vessels, P=NS). VWF expression was significantly increased in LMC ipsi at 2 weeks (ipsi 10.9 ± 2.87 vs. contra 2.91 ± 0.82, P<0.05) and neared significance at 3 months (ipsi 6.45 ± 1.54 vs. contra 2.06 ± 0.264, P=0.051). Aged mice demonstrated increased diameter of LMC ipsi relative to DMA at 2 weeks (1.24 ± 0.052, n=25 vessels from 3 mice, P<0.01), but not at 3 months (1.08 ± 0.044, n=14 from 2 mice, P=NS). Notably, the 3 month LMC ipsi vessels demonstrated irregular diameter and characteristics of rarefaction. LMC contra were 0.897 ± 0.032 and 0.967 ± 0.092 for the same time points (n=17 and 8 vessels, P=NS). VWF expression was significantly elevated in LMC ipsi vs. LMC contra at 2 weeks (6.74 ± 1.33 vs. 1.87 ± 0.361, P<0.01), but not at 3 months (2.27 ± 0.387 vs. 1.81 ± 0.398, P=NS). Conclusions: Our data show lasting LMC remodeling in young stroke brain, consisting of increased LMC diameter and expression of VWF. With aging, LMC remodeling is transient and evidence of LMC rarefaction is apparent by 3 months.

Adolescent and young adult brain tumors: current topics and review.

The management of brain tumors developed in adolescents and young adults (AYAs) is challenging because of their histological heterogeneity and low incidence. The brain tumor and its treatment interventions can negatively affect neurological, neurocognitive, and endocrinological function, and dramatically affect the circumstances of AYA patients progressing to further education, employment, and marriage. Specific support is thus necessary to maintain the quality of life (QOL) of AYA brain tumor patients. AYA patients and survivors require active intervention and support for returning to school or work, progressing to further education, finding employment, and preserving fertility. Recent cancer genome profiling revealed that AYA gliomas include pediatric- and adult-type genetic alteration. Insights into the biology underlying the distribution of tumors in AYAs may influence the development of prospective trials. A more individualized view of brain tumors may influence stratification of patients’ in future clinical studies as well as selection for molecular targeted therapy. Here I review strategies for achieving a better outcome to decrease late effects and improve QOL.

Individualized spatial network predictions using Siamese convolutional neural networks: A resting-state fMRI study of over 11,000 unaffected individuals.

Individuals can be characterized in a population according to their brain measurements and activity, given the inter-subject variability in brain anatomy, structure-function relationships, or life experience. Many neuroimaging studies have demonstrated the potential of functional network connectivity patterns estimated from resting functional magnetic resonance imaging (fMRI) to discriminate groups and predict information about individual subjects. However, the predictive signal present in the spatial heterogeneity of brain connectivity networks is yet to be extensively studied. In this study, we investigate, for the first time, the use of pairwise-relationships between resting-state independent spatial maps to characterize individuals. To do this, we develop a deep Siamese framework comprising three-dimensional convolution neural networks for contrastive learning based on individual-level spatial maps estimated via a fully automated fMRI independent component analysis approach. The proposed framework evaluates whether pairs of spatial networks (e.g., visual network and auditory network) are capable of subject identification and assesses the spatial variability in different network pairs’ predictive power in an extensive whole-brain analysis. Our analysis on nearly 12,000 unaffected individuals from the UK Biobank study demonstrates that the proposed approach can discriminate subjects with an accuracy of up to 88% for a single network pair on the test set (best model, after several runs), and 82% average accuracy at the subcortical domain level, notably the highest average domain level accuracy attained. Further investigation of our network’s learned features revealed a higher spatial variability in predictive accuracy among younger brains and significantly higher discriminative power among males. In sum, the relationship among spatial networks appears to be both informative and discriminative of individuals and should be studied further as putative brain-based biomarkers.

Mitochondrial transplantation improves anxiety- and depression-like behaviors in aged stress-exposed rats

Impaired mitochondrial function and abnormalities in the tryptophan (Trp)-kynurenine (Kyn) pathway are linked to age-related mood disorders. This study investigated the effect of intracerebroventricular (ICV) injection of the mitochondria isolated from young rat brain on depression-like behaviors of aged rats subjected to chronic mild stress (CMS). Aged (22 months old) male rats were randomly assigned into four groups: Aged, Aged + Mit, Aged + CMS, and Aged + CMS + Mit. Anxiety- and depression-like behaviors were assessed using elevated plus maze (EPM), open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT). Mitochondrial membrane potential (MMP), ATP levels, indoleamine 2, 3-dioxygenase (IDO) levels, and Kyn metabolites were measured in the prefrontal cortex (PFC). Golgi Cox staining was used to investigate the neuronal morphology. Mitotherapy decreased immobility time and anhedonia in the FST; increased open arm time and entries in the EPM; decreased grooming and increased rearing, center time, and the entrance in the OFT. Mitotherapy also reduced IDO and Kyn metabolites, restored MMP and ATP production, and enhanced dendritic length and spine density in the PFC. Overall, mitotherapy improved anxiety-and depression-like behaviors in aged rats and it could be considered as a new therapeutic strategy for age-related depressive disorders.

Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes.

Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212−/−) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3–CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212−/− mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3–CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212−/− mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212−/− mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.