KDS2010, a reversible MAO-B inhibitor, extends the lifetime of neural probes by preventing glial scar formation.

Implantable neural probes have been extensively utilized in the fields of neurocircuitry, systems neuroscience, and brain-computer interface. However, the long-term functionality of these devices is hampered by the formation of glial scar and astrogliosis at the surface of electrodes. In this study, we administered KDS2010, a recently developed reversible MAO-B inhibitor, to mice through ad libitum drinking in order to prevent glial scar formation and astrogliosis. The administration of KDS2010 allowed long-term recordings of neural signals with implantable devices, which remained stable over a period of 6 months and even restored diminished neural signals after probe implantation. KDS2010 effectively prevented the formation of glial scar, which consists of reactive astrocytes and activated microglia around the implant. Furthermore, it restored neural activity by disinhibiting astrocytic MAO-B dependent tonic GABA inhibition induced by astrogliosis. We suggest that the use of KDS2010 is a promising approach to prevent glial scar formation around the implant, thereby enabling long-term functionality of neural devices.

Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model.

Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound injury model (STAB) display aberrant cellular gamma-aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO-B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO-B, a GABA-producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO-B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO-B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by-products of the MAO-B action, H2 O2 , but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar-forming astrogliosis-the recently developed reversible MAO-B inhibitor, KDS2010, and an H2 O2 scavenger, crisdesalazine (AAD-2004). Our results implicate that inhibiting MAO-B activity has dual beneficial effects in preventing astrogliosis and scar-formation under brain injury, and that the MAO-B/H2 O2 pathway can be a useful therapeutic target with a high clinical potential.

Longitudinal intravital imaging of cerebral microinfarction reveals a dynamic astrocyte reaction leading to glial scar formation.

Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage of 3 kDa dextran (but not 2 MDa dextran) indicating microinfarction-related blood-brain barrier (BBB) dysfunction for small molecules. At day 5, the local edema disappeared with the partial restoration of microcirculation and recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes expressing glial fibrillary acidic protein (GFAP) appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct until 30 days, inducing glial scar formation in cerebral cortex. Our longitudinal intravital imaging of serial microscopic neurovascular pathophysiology in cerebral microinfarction newly revealed that astrocytes are critically susceptible to the acute microinfarction and their reactive response leads to the fibrous glial scar formation.

The Brain-Enriched MicroRNA miR-9-3p Regulates Synaptic Plasticity and Memory.

UNLABELLED: MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression in many tissues. Although a number of brain-enriched miRNAs have been identified, only a few specific miRNAs have been revealed as critical regulators of synaptic plasticity, learning, and memory. miR-9-5p/3p are brain-enriched miRNAs known to regulate development and their changes have been implicated in several neurological disorders, yet their role in mature neurons in mice is largely unknown. Here, we report that inhibition of miR-9-3p, but not miR-9-5p, impaired hippocampal long-term potentiation (LTP) without affecting basal synaptic transmission. Moreover, inhibition of miR-9-3p in the hippocampus resulted in learning and memory deficits. Furthermore, miR-9-3p inhibition increased the expression of the LTP-related genes Dmd and SAP97, the expression levels of which are negatively correlated with LTP. These results suggest that miR-9-3p-mediated gene regulation plays important roles in synaptic plasticity and hippocampus-dependent memory. SIGNIFICANCE STATEMENT: Despite the abundant expression of the brain-specific microRNA miR-9-5p/3p in both proliferating and postmitotic neurons, most functional studies have focused on their role in neuronal development. Here, we examined the role of miR-9-5p/3p in adult brain and found that miR-9-3p, but not miR-9-5p, has a critical role in hippocampal synaptic plasticity and memory. Moreover, we identified in vivo binding targets of miR-9-3p that are involved in the regulation of long-term potentiation. Our study provides the very first evidence for the critical role of miR-9-3p in synaptic plasticity and memory in the adult mouse.

Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition.

GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mM by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca(2+)-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain.

The "immigrant paradox" phenomenon: assessing problem behaviors and risk factors among immigrant and native adolescents.

We investigated the "immigrant paradox" phenomenon by examining differences in problem behavior engagement and exposure to risk factors across four adolescent groups: 1,157 first-generation, 1,498 second-generation, and 3,316 White and minority third or higher generations. Latent mean differences in problem behavior engagement (i.e., academic failure, aggression, and substance use) and risk factors (i.e., low socioeconomic status, poor family relationship, and low sense of school belonging) were associated with significant differences across adolescent groups. Results supported the generational status effect by demonstrating sequentially greater adolescent problem behavior engagement. However, the difference in exposure to risk factors across adolescent groups only partially supported the immigrant paradox. Further, the multiple group analysis of the relationships between risk factors and engagement in problem behaviors showed increased susceptibility among second generation immigrants for substance use, White natives for academic failure and substance use, and minority natives for physical aggression. Study findings have implications for understanding how the immigrant paradox leads to different adjustment patterns and problem behavior manifestations among immigrant and native adolescents.

Testing Jessor's problem behavior theory and syndrome: a nationally representative comparative sample of Latino and African American adolescents.

Based on Jessor's problem behavior theory (PBT; R. Jessor, 1987, Problem-behavior theory, psychosocial development, and adolescent problem drinking, British Journal of Addiction, Vol. 82, pp. 331-342), the comparability of a second-order problem behavior model (SPBM) was investigated employing structural equation modeling (SEM) and latent mean differences in problem behavior engagement were examined among racial/ethnic adolescents. Within a span of nearly 25 years, this study represents the first nationally representative sample of Latino and African American adolescents utilized in testing Jessor's PBT and problem behavior syndrome (PBS). Using a sample of 5,831 Latino, African American, and European American adolescents drawn from the National Longitudinal Study of Adolescent Health, a series of invariance tests evidenced support for Jessor's PBT and PBS. Latent mean difference test results evidenced significant differences in problem behaviors (e.g., academic failure [AF], aggression [AG], substance use [SU], and risky sexual activity[RSA]) across racial/ethnic adolescent groups, which could be explained partially by PBS. A discussion of findings, limitations, and recommendations for future research is presented.

Psychoecological model of alcohol use in Mexican American adolescents.

In this study, we proposed and tested a structural model based on Bronfenbrenner's ecological systems theory in order to further understand alcohol use among Hispanic adolescents, who are at greater risk of alcohol use than adolescents of other racial/ethnic groups. Family cohesion, school connectedness, and peer influence were conceptualized as three primary process factors, while psychological distress was used as a mediating factor and Mexican culture orientation as a cultural factor. The sample comprised 444 Mexican American adolescents (aged 16-20) living along the U.S./Mexico border. The proposed model explained 33 % of the variance in alcohol use. Most of the hypothesized relationships in the proposed model were supported: (a) low family cohesion had significant indirect effects mediated through psychological distress, poor school connectedness, and negative peer influence; (b) poor school connectedness had significant indirect effects mediated through psychological distress and negative peer influence; (c) psychological distress had a significant direct effect as well as a significant indirect effect mediated through negative peer influence; and (d) negative peer influence had the strongest direct effect. However, contrary to the hypothesis, Mexican culture orientation was not a protective factor, but rather had a significant positive relationship with negative peer influence. Lastly, it was found that gender, school status, Anglo cultural orientation, and severity of alcohol use did not have any moderating effects. Based on the collective findings, suggestions for primary prevention programs designed to reduce underage drinking among Mexican American youth were given.

Role of spinal astrocytes through the perisynaptic astrocytic process in pathological pain.

Pathological pain is caused by abnormal activity in the neural circuit that transmits nociceptive stimuli. Beyond homeostatic functions, astrocytes actively participate in regulating synaptic transmission as members of tripartite synapses. The perisynaptic astrocytic process (PAP) is the key structure that allows astrocytes to play these roles and not only physically supports synapse formation through cell adhesion molecules (CAMs) but also regulates the efficiency of chemical signaling. Accumulating evidence has revealed that spinal astrocytes are involved in pathological pain by modulating the efficacy of neurotransmitters such as glutamate and GABA through transporters located in the PAP and by directly regulating synaptic transmission through various gliotransmitters. Although various CAMs contribute to pathological pain, insufficient evidence is available as to whether astrocytic CAMs also have this role. Therefore, more in-depth research is needed on how pathological pain is induced and maintained by astrocytes, especially in the PAP surrounding the synapse, and this will subsequently increase our understanding and treatment of pathological pain.

Understanding the Experiences of Mothers with Academic Socialization in South Korea: A Phenomenological Approach.

We explored academic socialization experiences of nine mothers in South Korea. Academic socialization has been defined as parents' practices that transfer their educational expectations, values, and aspirations to their children (Hill, 2001). Adopting Giorgi's phenomenological research method (1997), we interviewed nine mothers who had recently prepared their children to get into college. The interviews were focused on the ways in which they intervened in the academic process when their children were in high school. The data analysis proceeded along the four steps suggested by Giorgi (1997). The analysis resulted in the 12 constituents, which are the themes underlying the essential structure of the academic socialization experiences. The findings showed that during the academic socialization process, all participating mothers set high academic standards for their children. The mothers actively engaged in supporting their children through shadow education (i.e., supplementary private education) to strengthen their academic competitiveness. Further, the mothers found themselves competing with other mothers regarding the academic achievement of their children. The mothers rather than their children took initiatives for decision makings of academic matters. Some of their practices were noticed to have compromised the autonomy of their children. The mothers appeared to fulfill their needs that prove their self-worth by raising their children to be competent. The significance and implications of these results were discussed.

Astrocytes Render Memory Flexible by Releasing D-Serine and Regulating NMDA Receptor Tone in the Hippocampus.

BACKGROUND: NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders with impairment of cognitive flexibility. However, the molecular mechanism of how NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility has been minimally understood. Furthermore, it has been unclear whether hippocampal astrocytes regulate NMDAR tone and cognitive flexibility. METHODS: We employed cell type-specific genetic manipulations, ex vivo electrophysiological recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility. RESULTS: We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and α1 adrenergic receptor-dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning. CONCLUSIONS: These findings indicate that NMDAR tone during initial learning is important for subsequent learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.

A psychoecological model of academic performance among Hispanic adolescents.

Although the number of students who complete high school continues to rise, dramatic differences in school success remain across racial/ethnic groups. The current study addressed Hispanic adolescents' academic performance by investigating the relationships of parental involvement, culturally responsive teaching, sense of school belonging, and academic self-efficacy and academic performance. Participants were 478 (51.5% female) Hispanic 7th graders in the US-Mexico borderlands. Based on Bronfenbrenner's ecological systems theory, a structural model was tested. Results showed that the proposed model was supported by demonstrating significant indirect effects of parental involvement, culturally responsive teaching, and sense of school belonging on academic performance. Furthermore, academic self-efficacy was found to mediate the relationships between parental involvement, culturally responsive teaching, and sense of school belonging and academic performance. The current study provides a useful psychoecological model to inform educators and psychologists who seek to meet the needs of Hispanic students.

Gender and grade-level comparisons in the structure of problem behaviors among adolescents.

Based on Jessor's theory (1987) the comparability of a second-order problem behavior model (SPBM) was investigated across gender and grade-level among adolescents. In addition, gender and grade-level differences in problem behavior engagement were addressed examining latent mean differences. Using a sample of 6504 adolescents drawn from the National Longitudinal Study of Adolescent Health, a series of invariance tests evidenced partial invariance. The non-invariance of SPBM resulted from aggression across gender and grade-level. Latent mean difference test results showed greater differences in academic failure, aggression, substance use, and risky sexual activity among males compared to females. Results also showed greater engagement in academic failure, substance use, and risky sexual activity among upper vs. lower grade students. Overall, analyses revealed that both gender and grade-level differences could be explained by the common cause problem behavior syndrome (PBS), offering further support for Jessor's theory.

Dynamic Changes in the Bridging Collaterals of the Basal Ganglia Circuitry Control Stress-Related Behaviors in Mice.

The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) ('bridging collaterals') was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and controls appropriate coping responses in which the bridging collateral connections in the GPe play a critical regulatory role.

Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer's disease via H2O2- production.

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.

A parental involvement and academic socialization model: A cultural approach.

Utilizing ecological theory and multiple world theory, the current study investigated the effects of cultural factors (i.e., Familismo and school climate), parental involvement, and academic socialization on academic achievement of Latina/o secondary school students. This study had 2 primary foci. First, this study sought to address how the cultural value of Familismo and the interaction between home and school cultures play a role in parental involvement and academic achievement. Second, the effect of academic socialization was tested as a distinct factor from parental involvement. Data were collected from 116 Latina/o students living along the U.S./Mexico border. This study tested a path model that explained 30% of the variance in academic achievement, 25% of the variance in academic socialization, and 21% of the variance in parental involvement. Among 8 proposed relationships, 6 were supported while 2 were not. The mediating effects of parental involvement and academic socialization were supported that connect Familismo, school climate, and academic achievement. Implications for Latina/o secondary students who navigate between the different cultural worlds of home and school are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Activation of Astrocytic µ-Opioid Receptor Causes Conditioned Place Preference.

The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic µ-opioid receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease.

Monoamine oxidase-B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer's disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

Reactive astrocytes in Alzheimer's disease: A double-edged sword.

Alzheimer's disease (AD) is a chronic and fatal disease, in which neuronal damage at its late stage cannot be easily reversed. Because AD progression is caused by multiple factors including diverse cellular processes, studies on AD pathogenesis at the molecular and cellular level are challenging. Based on the lessons from unsuccessful neuron-focused research for an AD cure, non-cell autonomous mechanisms including brain inflammation and reactive astrocytes have recently been in the spotlight as potential therapeutic targets for AD. Studies have shown that reactive astrocytes are not only the result of inflammatory defense reactions, but also an active catabolic decomposer that acts by taking up amyloid beta toxins. Here, we give an overview of the characteristics of reactive astrocytes as pathological features of AD. Reactive astrocytes exert biphasic effects, that is, beneficial or detrimental depending on multiple factors. Many efforts have been put forth for defining and characterizing molecular signatures for the beneficial and detrimental reactive astrocytes. In the foreseeable future, manipulating and targeting each established molecular signature should have profound therapeutic implications for the treatment of AD.

Elucidating the Interactive Roles of Glia in Alzheimer's Disease Using Established and Newly Developed Experimental Models.

Alzheimer's disease (AD) is an irreversible neurodegenerative illness and the exact etiology of the disease remains unknown. It is characterized by long preclinical and prodromal phases with pathological features including an accumulation of amyloid-beta (Aß) peptides into extracellular Aß plaques in the brain parenchyma and the formation of intracellular neurofibrillary tangles (NFTs) within neurons as a result of abnormal phosphorylation of microtubule-associated tau proteins. In addition, prominent activation of innate immune cells is also observed and/or followed by marked neuroinflammation. While such neuroinflammatory responses may function in a neuroprotective manner by clearing neurotoxic factors, they can also be neurotoxic by contributing to neurodegeneration via elevated levels of proinflammatory mediators and oxidative stress, and altered levels of neurotransmitters, that underlie pathological symptoms including synaptic and cognitive impairment, neuronal death, reduced memory, and neocortex and hippocampus malfunctions. Glial cells, particularly activated microglia and reactive astrocytes, appear to play critical and interactive roles in such dichotomous responses. Accumulating evidences clearly point to their critical involvement in the prevention, initiation, and progression, of neurodegenerative diseases, including AD. Here, we review recent findings on the roles of astrocyte-microglial interactions in neurodegeneration in the context of AD and discuss newly developed in vitro and in vivo experimental models that will enable more detailed analysis of glial interplay. An increased understanding of the roles of glia and the development of new exploratory tools are likely to be crucial for the development of new interventions for early stage AD prevention and cures.