Repurposing ibrutinib:therapeutic effects and implications for translational approaches in Alzheimer’s disease

Alzheimer’s disease(AD)is the most prevalent neurodegenerative disease,and the number of patients with AD is estimated to double by 2060(Alzheimer’s Association,2022).The AD mortality rate has increased by 145%over the last decade,the largest increase among the ten leading causes of death in the US(Alzheimer’s Association,2022).

Translocator protein 18 kDa(TSPO): old dogma, new mice, new structure, and new questions for neuroprotection

The normal development and optimal functioning of the brain requires a vigilant immune surveillance system to detect and remove potential risk factors and prevent infection and tissue damage. Microglia are the resident immune cells and the frontline defenders responsible for the immune response of the brain. Resting microglia possess a ramified morphology with numerous thin processes that continuously sample the environment. In response to inflammatory signals, microglia become activated and transform their morphology into a thick, amoeboid-like shape. Activated microglia proliferate, tolerate to sites of iniurv,

Use of multi-electrode array recordings in studies of network synaptic plasticity in both time and space

Simultaneous multisite recording using multi-electrode arrays（MEAs） in cultured and acutely-dissociated brain slices and other tissues is an emerging technique in the field of network electrophysiology.Over the past 40 years,great efforts have been made by both scientists and commercial concerns,to advance this technique.The MEA technique has been widely applied to many regions of the brain,retina,heart and smooth muscle in various studies at the network level.The present review starts from the development of MEA techniques and their uses in brain preparations,and then specifically concentrates on the use of MEA recordings in studies of synaptic plasticity at the network level in both the temporal and spatial domains.Because the MEA technique helps bridge the gap between single-cell recordings and behavioral assays,its wide application will undoubtedly shed light on the mechanisms underlying brain functions and dysfunctions at the network level that remained largely unknown due to the technical difficulties before it matured.

Neural circuits underlying motor and non-motor defects of Parkinson’s disease

AN OVERVIEW OF PARKINSON’S DISEASE Parkinson’s disease(PD)is a neurodegenerative disorder that causes unintended and uncontrollable movements,such as tremors,rigidity,and difficulty with balance and coordination.Neuronal degeneration in the basal ganglia network has been suggested as a likely cause for some PD symptoms.More specifically,such degeneration would lead to an imbalance between the direct pathway(from striatum to substantia nigra)and the indirect pathway(from striatum to pallidum),which subsequently drives movement deficits.1 Current treatments for the motor dysfunction of PD include dopamine agonists,deep brain stimulation(DBS),and physical therapy.

Targeted down-regulation of Hipp1 ameliorates tau-induced deficits in Drosophila melanogaster

Tauopathies,such as Alzheimer's disease(AD),are neurodegenerative diseases characterized by the deposition of neurofibrillary tangles comprising hyperphosphorylated tau protein in the human brain.1 Given that abnormal epigenetic alterations in heterochromatin configuration have been documented in AD patients and transgenic animal models of AD,2 we investigated the roles of novel heterochromatin-associated interactors3 in tauopathies.Using transgenic flies via UAS-Gal4 binary system,we found that knockdown of Hipp1(HP1a and insulator partner protein-1)3 ameliorates.tauR4ow(referred to as"tau"hereafter for simplicity)2-induced locomotion defects,reduced lifespan,and degeneration of brain tissues.Intriguingly,Hipp1 knockdown restored tau-driven aberrant expression of putative insulator targets and aberrant insulator-mediated epigenetic alterations.HIPP1 may have a role as an insulator-binding partner regarding being implicated in tauinduced neurodegeneration.

The Antidepressant Effect of Light Therapy from Retinal Projections

Observations from clinical trials have frequently demonstrated that light therapy can be an effective therapy for seasonal and non-seasonal major depression. Despite the fact that light therapy is known to have several advantages over antidepressant drugs like a low cost,minimal side-effects, and fast onset of therapeutic effect,the mechanism underlying light therapy remains unclear.So far, it is known that light therapy modulates mood states and cognitive functions, involving circadian and noncircadian pathways from retinas into brain. In this review,we discuss the therapeutic effect of light on major depression and its relationship to direct retinal projections in the brain. We finally emphasize the function of the retino-raphe projection in modulating serotonin activity,which probably underlies the antidepressant effect of light therapy for depression.

Mitochondrial Reactive Oxygen Species Elicit Acute and Chronic Itch via Transient Receptor Potential Canonical 3 Activation in Mice

Mitochondrial reactive oxygen species(mROS)that are overproduced by mitochondrial dysfunction are linked to pathological conditions including sensory abnormalities.Here,we explored whether mROS overproduction induces itch through transient receptor potential canonical 3(TRPC3),which is sensitive to ROS.Intradermal injection of antimycin A(AA),a selective inhibitor of mitochondrial electron transport chain complex III for mROS overproduction,produced robust scratching behavior in naïve mice,which was suppressed by MitoTEMPO,a mitochondria-selective ROS scavenger,and Pyr10,a TRPC3-specific blocker,but not by blockers of TRPA1 or TRPV1.AA activated subsets of trigeminal ganglion neurons and also induced inward currents,which were blocked by MitoTEMPO and Pyr10.Besides,dry skin-induced chronic scratching was relieved by MitoTEMPO and Pyr10,and also by resveratrol,an antioxidant.Taken together,our results suggest that mROS elicit itch through TRPC3,which may underlie chronic itch,representing a potential therapeutic target for chronic itch.

Recent advances in parametric neuroreceptor mapping with dynamic PET:basic concepts and graphical analyses

Tracer kinetic modeling in dynamic positron emission tomography （PET） has been widely used to investigate the characteristic distribution patterns or dysfunctions of neuroreceptors in brain diseases. Its practical goal has progressed from regional data quantification to parametric mapping that produces images of kinetic-model parameters by fully exploiting the spatiotemporal information in dynamic PET data. Graphical analysis （GA） is a major parametric mapping technique that is independent on any compartmental model configuration, robust to noise, and computationally efficient. In this paper, we provide an overview of recent advances in the parametric mapping of neuroreceptor binding based on GA methods. The associated basic concepts in tracer kinetic modeling are presented, including commonly-used compartment models and major parameters of interest. Technical details of GA approaches for reversible and irreversible radioligands are described, considering both plasma input and reference tissue input models. Their statistical properties are discussed in view of parametric imaging.

Formation of the Looming-evoked Innate Defensive Response during Postnatal Development in Mice

Environmental threats often trigger innate defensive responses in mammals.However,the gradual development of functional properties of these responses during the postnatal development stage remains unclear.Here,we report that looming stimulation in mice evoked fight behavior commencing at P14-16 and had fully developed by P20-24.The visual-evoked innate defensive response was not significantly altered by sensory deprivation at an early postnatal stage.Furthermore,the percentages of wide-field and horizontal cells in the superior colliculus were notably elevated at P20-24.Our findings define a developmental time window for the formation of the visual innate defense response during the early postnatal period and_provide important insight into the underlying mechanism.

Wide-field three-photon excitation in biological samples

Three-photon wide-field depth-resolved excitation is used to overcome some of the limitations in conventional point-scanning two-and three-photon microscopy.Excitation of chromophores as diverse as channelrhodopsins and quantum dots is shown,and a penetration depth of more than 700μm into fixed scattering brain tissue is achieved,approximately twice as deep as that achieved using two-photon wide-field excitation.Compatibility with live animal experiments is confirmed by imaging the cerebral vasculature of an anesthetized mouse;a complete focal stack was obtained without any evidence of photodamage.As an additional validation of the utility of wide-field three-photon excitation,functional excitation is demonstrated by performing threephoton optogenetic stimulation of cultured mouse hippocampal neurons expressing a channelrhodopsin;action potentials could reliably be excited without causing photodamage.