Cellular And Molecular Mechanisms Underlying Homeostatic Synaptic Plasticity

It is well established that modification of sensory cortices of animals is integral to many functions of the brain. While input-specific synaptic plasticity mechanisms are thought to underlie developmental refinement of synaptic connectivity with sensory experience, theoretical analyses suggest that slower global homeostatic mechanisms are required to stabilize dynamic neural networks. One of the homeostatic mechanisms that have been proposed is synaptic scaling, where a prolonged increase in neural activity globally scales down excitatory synaptic responses, while a chronic decrease in activity scales them up. This phenomenon has been demonstrated by pharmacological manipulations in cultured neurons, as well as in vivo visual cortex by several days of visual deprivation. However, whether restoring vision could reverse these changes and the molecular mechanisms of visual experience-induced homeostatic synaptic plasticity were not known. Moreover, whether there are more global regulations beyond one sensory modality was unknown. Several human studies demonstrated that loss of vision is usually accompanied by increased functionality of other sensory modalities. We found that visual deprivation produces synaptic changes in primary somatosensory and auditory cortices, opposite to that seen in the visual cortex. The reversible homeostatic synaptic modification in primary sensory cortices by visual experience correlated with changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation and subunit composition, which could underlie changes in AMPA receptor function. Interestingly, the reversible homeostatic modification occurred in juveniles and also in adults well beyond the closure of the "classical" critical period in the superficial layers of the visual cortex. This correlates with the persistence of synapse-specific plasticity in this cortical layer, supporting the need for homeostatic synaptic plasticity in stabilizing dynamic circuits. Our investigation of the molecular mechanisms of synaptic scaling in juvenile visual cortex suggest that multiplicative scaling up of excitatory synapses by dark rearing may occur in two steps, requiring phosphorylation of the GluR1-S845 residue and anchoring of GluR1 to the postsynaptic density. Our data also suggests that GluR2-mediated mechanisms may interact with the GluR1-dependent processes to enable synaptic scaling following visual deprivation. Collectively, this study shows that the AMPA receptor regulation is a common downstream mechanism shared between Hebbian and homeostatic plasticity

Kajian Keprihatinan Ahli Akademik Terhadap Tatacara Berpakaian, Sahsiah dan Rupa Diri Pelajar Universiti Malaysia Pahang

Tamadun adalah perkataan Arab “Maddana” yang bermaksud adab, akhlaq, moral dan mempunyai agama yang baik. Manakala hidup bertamadun bermaksud kehidupan yang penuh dengan adab sopan, moral dan berakhlak. Dalam konteks dunia pendidikan hari ini isu tatacara berpakaian, rupa diri, sahsiah dan akhlak pelajar pernah dibincangkan dan diketengahkan di peringkat institusi pengajian tinggi amnya, namun masih tidak menampakkan hasil positif. Kelihatan seolah-olah tiada keseriusan daripada pelbagai pihak untuk mengendalikan dan menjayakan isu ini sebaik mungkin sehingga ke akar umbinya dan secara tidak langsung untuk berusaha menyelesaikannya. Justeru, satu kajian berfokus telah dijalankan terhadap pelajar di Universiti Malaysia Pahang dari pelbagai fakulti. Kajian ini bertujuan meninjau sejauh mana komitmen pensyarah selaku aset penting yang berintegriti tinggi, bernilai dan berakhlak mulia dalam menjalankan amanah mereka mendidik anak bangsa khususnya dalam membangunkan akhlak dan sahsiah diri terpuji dalam kalangan mahasiswa. Kajian ini dilakukan secara tinjauan melalui aplikasi internet iaitu SurveyMonkey kepada lebih dari 100 orang pelajar. Melalui kajian ini terdapat enam perkara yang diperhatikan dan dikaji secara terperinci. Kajian ini berkisar komitmen pelajar dan pensyarah di kampus antaranya ialah komitmen pelajar terhadap pemakaian kad pelajar universiti (kad matrik), komitmen pensyarah memperuntukkan masa dalam kelas bagi menyatakan kepentingan tatacara berpakaian dan rupa diri di kampus, komitmen mengambil tindakan terhadap pelajar yang gagal mematuhi peraturan tatacara berpakaian dan rupa diri, komitmen mengambil tindakan terhadap pelajar yang lewat atau gagal hadir dalam kelas, dan amanah dalam mengisi ruang di slip kehadiran rakan sekuliah dalam kelas. Hasil kajian mendapati bahawa komitmen di kalangan pelajar dan pensyarah kurang memberangsangkan. Perkara ini harus dipandang serius dan sangat membimbangkan kerana penekanan terhadap isu-isu tersebut sangat penting dalam melahirkan pelajar bertamadun iaitu berpengetahuan luas, berkemahiran tinggi dan bersikap, berakhlak serta bersahsiah terpuji

Improving inorganic composition and ash fusion behavior of spruce bark by leaching with water, acetic acid, and steam pre-treatment condensate

The present study evaluates the effect of water and acetic acid washing on the chemical composition of spruce bark in-depth. Also, washing with steam explosion condensate (SEC) was investigated which is a novel attempt. The leaching kinetics of troubling elements (TE) was studied to understand the leaching behavior of TEs and for upscaling the process. Furthermore, to study the ash transformation behavior of TEs in pre-treated and raw bark at high temperatures (500–1500 °C), thermodynamic equilibrium modeling (TEM) was also performed. The result of washing pre-treatment shows high removal of TEs: 22–97% Na, 46–82% Cl, 14–79% K, 14–65% Mg, 25–50% S, 3–22% Ca, 12–36% P, 3–43% Si, and 6–35% N. Continuous removal of TEs was seen with increasing washing duration where most of TEs followed a second-order leaching kinetics. Acid washing results in a much higher and quicker removal for all TEs than water washing. Due to the acidic nature of the SEC, it shows similar removal of TEs as the 0.1 M acetic acid solution. TEM reveals that the transformation behavior of TEs in bark changes considerably after pre-treatment. Pre-treated bark shows the formation of fewer problematic compounds responsible for fouling, slagging, and corrosion at typical gasification and combustion temperatures, such as KCl, K2SO4, K2CO3, KOH, Na2SO4, NaCl, and K-, Na-, P-, and Ca-slag. Though best washing efficiency was seen for longer washing durations, 10 min washing with 0.1 M acetic acid or SEC may be adequate for practical applications.publishedVersionPeer reviewe

Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knockout mouse model of autism

Sensory hypersensitivity is a common symptom in autism spectrum disorders (ASDs), including Fragile X Syndrome (FXS), and frequently leads to tactile defensiveness. In mouse models of ASDs, there is mounting evidence of neuronal and circuit hyperexcitability in several brain regions, which could contribute to sensory hypersensitivity. However, it is not yet known whether or how sensory stimulation might trigger abnormal sensory processing at the circuit level or abnormal behavioral responses in ASD mouse models, especially during an early developmental time when experience-dependent plasticity shapes such circuits. Using a novel assay, we discovered exaggerated motor responses to whisker stimulation in young Fmr1 knockout (KO) mice (postnatal days (P) 14-16), a model of FXS. Adult Fmr1 KO mice actively avoided a stimulus that was innocuous to wild-type controls, a sign of tactile defensiveness. Using in vivo two-photon calcium imaging of Layer 2/3 barrel cortex neurons expressing GCaMP6s, we found no differences between wild-type and Fmr1 KO mice in overall whisker-evoked activity, though 45% fewer neurons in young Fmr1 KO mice responded in a time-locked manner. Notably, we identified a pronounced deficit in neuronal adaptation to repetitive whisker stimulation in both young and adult Fmr1 KO mice. Thus, impaired adaptation in cortical sensory circuits is a potential cause of tactile defensiveness in autism

EZcalcium: Open-Source Toolbox for Analysis of Calcium Imaging Data

Fluorescence calcium imaging using a range of microscopy approaches, such as two-photon excitation or head-mounted “miniscopes,” is one of the preferred methods to record neuronal activity and glial signals in various experimental settings, including acute brain slices, brain organoids, and behaving animals. Because changes in the fluorescence intensity of genetically encoded or chemical calcium indicators correlate with action potential firing in neurons, data analysis is based on inferring such spiking from changes in pixel intensity values across time within different regions of interest. However, the algorithms necessary to extract biologically relevant information from these fluorescent signals are complex and require significant expertise in programming to develop robust analysis pipelines. For decades, the only way to perform these analyses was for individual laboratories to write their custom code. These routines were typically not well annotated and lacked intuitive graphical user interfaces (GUIs), which made it difficult for scientists in other laboratories to adopt them. Although the panorama is changing with recent tools like CaImAn, Suite2P, and others, there is still a barrier for many laboratories to adopt these packages, especially for potential users without sophisticated programming skills. As two-photon microscopes are becoming increasingly affordable, the bottleneck is no longer the hardware, but the software used to analyze the calcium data optimally and consistently across different groups. We addressed this unmet need by incorporating recent software solutions, namely NoRMCorre and CaImAn, for motion correction, segmentation, signal extraction, and deconvolution of calcium imaging data into an open-source, easy to use, GUI-based, intuitive and automated data analysis software package, which we named EZcalcium

Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible.

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we adopted a symptom-to-circuit approach in the Fmr1-knockout (Fmr1-/-) mouse model of Fragile X syndrome. Using a go/no-go task and in vivo two-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons and with a decrease in the activity of parvalbumin interneurons in primary visual cortex. Restoring visually evoked activity in parvalbumin cells in Fmr1-/- mice with a chemogenetic strategy using designer receptors exclusively activated by designer drugs was sufficient to rescue their behavioral performance. Strikingly, human subjects with Fragile X syndrome exhibit impairments in visual discrimination similar to those in Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in Fragile X syndrome

A Versatile Method for Viral Transfection of Calcium Indicators in the Neonatal Mouse Brain

The first three postnatal weeks in rodents are a time when sensory experience drives the maturation of brain circuits, an important process that is not yet well understood. Alterations in this critical period of experience-dependent circuit assembly and plasticity contribute to several neurodevelopmental disorders, such as autism, epilepsy, and schizophrenia. Therefore, techniques for recording network activity and tracing neuronal connectivity over this time period are necessary for delineating circuit refinement in typical development and how it deviates in disease. Calcium imaging with GCaMP6 and other genetically encoded indicators is rapidly becoming the preferred method for recording network activity at the single-synapse and single-cell level in vivo, especially in genetically identified neuronal populations. We describe a protocol for intracortical injection of recombinant adeno-associated viruses in P1 neonatal mice and demonstrate its use for longitudinal imaging of GCaMP6s in the same neurons over several weeks to characterize the developmental desynchronization of cortical network activity. Our approach is ideally suited for chronic in vivo two-photon calcium imaging of neuronal activity from synapses to entire networks during the early postnatal period

Phosphorylation of AMPA Receptors Is Required for Sensory Deprivation-Induced Homeostatic Synaptic Plasticity

Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca2+-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity