No abstract available.
Neurobiology

Medium-chain fatty acids (MCFAs) are mostly generated from dietary triglycerides and can penetrate the blood-brain barrier. Astrocytes in the brain use MCFAs as an alternative energy source. In addition, MCFAs have various regulatory and signaling functions in astrocytes. However, it is unclear how astrocytes sense and take up MCFAs. This study demonstrates that decanoic acid (DA; C10), a saturated MCFA and a ligand of G(αs) protein-coupled receptors (G(αs)-GPCRs), is a signaling molecule in energy metabolism in primary astrocytes. cAMP synthesis and lactate release were increased via a putative G(αs)-GPCR and transmembrane adenylyl cyclase upon short-term treatment with DA. By contrast, monoamine oxidase B-dependent gamma-aminobutyric acid (GABA) synthesis was increased in primary cortical and hypothalamic astrocytes upon long-term treatment with DA. Thus, astrocytes respond to DA by synthesizing cAMP and releasing lactate upon short-term treatment, and by synthesizing and releasing GABA upon long-term treatment, similar to reactive astrocytes. Our data suggest that astrocytes in the brain play crucial roles in lipid-sensing via GPCRs and modulate neuronal metabolism or activity by releasing lactate via astrocyte-neuron lactate shuttle or GABA to influence neighboring neurons.
Adenylyl Cyclases ; Animals ; Astrocytes* ; Blood-Brain Barrier ; Brain ; Energy Metabolism ; Fatty Acids ; gamma-Aminobutyric Acid* ; Lactic Acid* ; Metabolism ; Mice* ; Monoamine Oxidase ; Neurons ; Triglycerides

Bestrophin-1 (Best1) is a calcium-activated anion channel identified from retinal pigment epithelium where human mutations are associated with Best's macular degeneration. Best1 is known to be expressed in a variety of tissues including the brain, and is thought to be involved in many physiological processes. This review focuses on the current state of knowledge on aspects of expression and function of Best1 in the brain. Best1 protein is observed in cortical and hippocampal astrocytes, in cerebellar Bergmann glia and lamellar astrocytes, in thalamic reticular neurons, in meninges and in the epithelial cells of the choroid plexus. The most prominent feature of Best1 is its significant permeability to glutamate and GABA in addition to chloride ions because glutamate and GABA are important transmitters in the brain. Under physiological conditions, both Best1-mediated glutamate release and tonic GABA release from astrocytes modulate neuronal excitability, synaptic transmission and synaptic plasticity. Under pathological conditions such as neuroinflammation and neurodegeneration, reactive astrocytes phenotypically switch from GABA-negative to GABA-producing and redistribute Best1 from the perisynaptic microdomains to the soma and processes to tonically release GABA via Best1. This implicates that tonic GABA release from reactive astrocyte via redistributed Best1 is a common phenomenon that occur in various pathological conditions with astrogliosis such as traumatic brain injury, neuroinflammation, neurodegeneration, and hypoxic and ischemic insults. These properties of Best1, including the permeation and release of glutamate and GABA and its redistribution in reactive astrocytes, promise us exciting discoveries of novel brain functions to be uncovered in the future.
Astrocytes ; Brain Injuries ; Brain* ; Carisoprodol ; Choroid Plexus ; Epithelial Cells ; gamma-Aminobutyric Acid ; Glutamic Acid ; Humans ; Ions ; Macular Degeneration ; Meninges ; Neuroglia ; Neuronal Plasticity ; Neurons ; Permeability ; Physiological Processes ; Retinal Pigment Epithelium ; Synaptic Transmission

Sleep is indispensable for living animals to live and maintain a normal life. Due to the growing number of people suffering from sleep disorders such as insomnia, there have been increasing interests in environmentally friendly therapeutic approaches for sleep disorders to avoid any side effects of pharmacological treatment using synthetic hypnotics. It has been widely accepted that the various beneficial effects of forest, such as relieving stress and anxiety and enhancing immune system function, are caused by plant-derived products, also known as phytoncide. Recently, it has been reported that the sleep-enhancing effects of phytoncide are derived from pine trees such as (-)-α-pinene and 3-carene. These are the major constituents of pine tree that potentiate the inhibitory synaptic responses by acting as a positive modulator for GABAA-BZD receptor. In this review, we discuss the effects of phytoncide on sleep and review the latest approaches of sleep-related behavioral assay, electrophysiological recording, and molecular modeling technique.

Developing social strategies to share limited resources equally and maximize the long-term benefits of conflict resolution is critical for appropriate social interactions. During social interactions, social decision-making depends not only on the external environment, but also on internal factors, such as hunger, thirst, or fatigue. In particular, hunger, which is related to food as a physical need, plays a dominant role in social decision-making. However, the consequences of food deprivation on social decision-making are not well understood. We have previously shown that mice with rule-observance behavior are capable of resolving conflict during social decision-making by observing a well-established social strategy based on reward zone allocation. Here, we developed a rule-observance behavior paradigm wherein the hunger state is achieved by applying food restrictions on mice prior to social behavior experiments. We found that the hunger state in mice deteriorated the established social strategy by decreasing reaction time, implying an increase in impulsivity. In contrast, the hunger state did not affect reward zone allocation, indicating no effect on spatial memory. This decrease in reaction time led to a significant increase in the percentage of violations during rule observance and a significant decrease in the amount of reward (payoff equity). Our study proposes that the hunger state exerts a detrimental effect on appropriate social decisionmaking by decreasing reaction time, increasing violation, and decreasing payoff equity in rule-observance behavior.

The μ-opioid receptor (MOR) is a class of opioid receptors characterized by a high affinity for β-endorphin and morphine. MOR is a G proteincoupled receptor (GPCR) that plays a role in reward and analgesic effects. While expression of MOR has been well established in neurons and microglia, astrocytic MOR expression has been less clear. Recently, we have reported that MOR is expressed in hippocampal astrocytes, and its activation has a critical role in the establishment of conditioned place preference. Despite this critical role, the expression and function of astrocytic MOR from other brain regions are still unknown. Here, we report that MOR is significantly expressed in astrocytes and GABAergic neurons from various brain regions including the hippocampus, nucleus accumbens, periaqueductal gray, amygdala, and arcuate nucleus. Using the MORmCherry reporter mice and Imaris analysis, we demonstrate that astrocytic MOR expression exceeded 60% in all tested regions. Also, we observed similar MOR expression of GABAergic neurons as shown in the previous distribution studies and it is noteworthy that MOR expression is particularly in parvalbumin (PV)-positive neurons. Furthermore, consistent with the normal MOR function observed in the MOR-mCherry mouse, our study also demonstrates intact MOR functionality in astrocytes through iGluSnFr-mediated glutamate imaging. Finally, we show the sex-difference in the expression pattern of MOR in PV-positive neurons, but not in the GABAergic neurons and astrocytes. Taken together, our findings highlight a substantial astrocytic MOR presence across various brain regions.

Astrocytes primarily maintain physiological brain homeostasis. However, under various pathological conditions, they can undergo morphological, transcriptomic, and functional transformations, collectively referred to as reactive astrogliosis.Recent studies have accumulated lines of evidence that reactive astrogliosis plays a crucial role in the pathology of Alzheimer’s disease (AD). In particular, monoamine oxidase B, a mitochondrial enzyme mainly expressed in astrocytes, significantly contributes to neuronal dysfunction and neurodegeneration in AD brains. Moreover, it has been reported that reactive astrogliosis precedes other pathological hallmarks such as amyloid-beta plaque deposition and tau tangle formation in AD.Due to the early onset and profound impact of reactive astrocytes on pathology, there have been extensive efforts in the past decade to visualize these cells in the brains of AD patients using positron emission tomography (PET) imaging. In this review, we summarize the recent studies regarding the essential pathological importance of reactive astrocytes in AD and their application as a target for PET imaging.

α-Synuclein (α-Syn) is a small presynaptic protein and its mutant forms (e.g. A53T) are known to be directly associated with Parkinson's disease (PD). Pathophysiological mechanisms underlying α-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant α-Syn causes reduced release of dopamine (DA) in the brain, and contributes to motor deficits in PD. Using a favorable genetic model Drosophila larva, we examined whether reduced DA release is enough to induce key PD symptoms (i.e. locomotion deficiency and DA neurodegeneration), mimicking a PD gene α-Syn. In order to reduce DA release, we expressed electrical knockout (EKO) gene in DA neurons, which is known to make neurons hypo-excitable. EKO led to a decrease in a DA neuronal marker signal (i.e., TH – tyrosine hydroxylase) and locomotion deficits in Drosophila larva. In contrast, acute and prolonged exposure to blue light (BL, 470 nm) was sufficient to activate channelrhodopsin 2 (ChR2) and rescue PD symptoms caused by both α-Syn and EKO. We believe this is for the first time to confirm that locomotion defects by a genetic PD factor such as α-Syn can be rescued by increasing DA neuronal excitability with an optogenetic approach. Our findings strongly support that PD is a failure of DA synaptic transmission, which can be rescued by optogenetic activation of ChR2.
alpha-Synuclein* ; Brain ; Dopamine ; Dopaminergic Neurons ; Drosophila ; Drosophila melanogaster ; Larva ; Locomotion ; Models, Genetic ; Neurons ; Optogenetics* ; Parkinson Disease ; Synaptic Transmission ; Tyrosine

Radial glial cells (RGCs) which function as neural stem cells are known to be non-excitable and their proliferation depends on the intracellular calcium (Ca²⁺) level. It has been well established that Inositol 1,4,5-trisphosphate (IP3)-mediated Ca²⁺ release and Ca²⁺ entry through various Ca²⁺ channels are involved in the proliferation of RGCs. Furthermore, RGCs line the ventricular wall and are exposed to a shear stress due to a physical contact with the cerebrospinal fluid (CSF). However, little is known about how the Ca²⁺ entry through mechanosensitive ion channels affects the proliferation of RGCs. Hence, we hypothesized that shear stress due to a flow of CSF boosts the proliferative potential of RGCs possibly via an activation of mechanosensitive Ca²⁺ channel during the embryonic brain development. Here, we developed a new microfluidic two-dimensional culture system to establish a link between the flow shear stress and the proliferative activity of cultured RGCs. Using this microfluidic device, we successfully visualized the artificial CSF and RGCs in direct contact and found a significant enhancement of proliferative capacity of RGCs in response to increased shear stress. To determine if there are any mechanosensitive ion channels involved, a mechanical stimulation by poking was given to individual RGCs. We found that a poking on radial glial cell induced an increase in intracellular Ca²⁺ level, which disappeared under the extracellular Ca²⁺-free condition. Our results suggest that the shear stress by CSF flow possibly activates mechanosensitive Ca²⁺ channels, which gives rise to a Ca²⁺ entry which enhances the proliferative capacity of RGCs.
Brain ; Calcium Channels* ; Calcium* ; Cerebrospinal Fluid ; Ependymoglial Cells* ; Inositol 1,4,5-Trisphosphate ; Ion Channels ; Lab-On-A-Chip Devices ; Microfluidics ; Neural Stem Cells

Like neurons, astrocytes produce and release GABA to influence neuronal signaling. At the perforant path to dentate gyrus granule neuron synapse, GABA from astrocyte was found to be a strong inhibitory factor, which impairs synaptic transmission, synaptic plasticity and memory in Alzheimer's disease. Although astrocytic GABA is observed in many brain regions, its physiological role has not been clearly demonstrated yet. Here, we show that astrocytic GABA exerts disinhibitory action to dentate granule neurons by targeting GABA(B) receptors of GABAergic interneurons in wild-type mice. This disinhibitory effect is specific to a low intensity of electrical stimulation at perforant path fibers. Inversely in Alzheimer's disease model mice, astrocytic GABA targets GABA(A) receptors and exerts inhibitory action by reducing release probability of glutamatergic perforant path terminals. These results suggest that astrocytic GABA differentially modulates the signaling from cortical input to dentate gyrus under physiological and pathological conditions.
Alzheimer Disease* ; Animals ; Astrocytes ; Brain ; Dentate Gyrus* ; Electric Stimulation ; gamma-Aminobutyric Acid* ; Interneurons ; Memory ; Mice ; Neurons* ; Perforant Pathway* ; Plastics ; Receptors, GABA-A ; Synapses* ; Synaptic Transmission