Selective role of autophagy in neuronal function and neurodegenerative diseases

Proteostasis is critical for neuronal maintenance and survival, and its imbalance leads to neurodegeneration with the hallmark of protein misfolding and aggregation. Macroautophagy becomes a major route for the clearance of protein aggregates that are normally poor substrates for the proteasome, the other protein quality-control machinery. As a flux process, macroautophagy （hereafter referred to as autophagy） involves the formation of the autophagosome, a double-membrane vesicle for engulfing unwanted cellular components such as protein aggregates, and the fusion of autophagosomes with lysosomes that contain many potent proteases for final degradation.

Engrafted newborn neurons could functionally integrate into the host neuronal network

The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the potential to differentiate into all kinds of neural cells in vitro.

Gravitational and Quantum Effects in Neuron Function

The relation between microtubules architecture in the cytoskeletal structure inside the dendrites and soma and the emergence of neuron function and firing action potential crosses the tiny line between physics and biology. As decoherence is a fundamental mechanism in some biological process such as photosynthesis and others examples, the gravitational quantum approach may contribute to elucidate if neuron function really emerges from quantum coherence in neuronal microtubules. The Einstein equation correlates the stress-energy tensor Tμv to a specific divergence-free combination Ricci tensor Rμv and the metric. In the semiclassical formulation, we have Gμv = Rμv -1/2gμvR=8πG/C^4〈ψ｜μvψ〉 which describes the quantum field in curved space-time geometry. But for a more precise equation in relation to the stress-energy tensor, we know that in a non-zero temperature, the wave-function is not enough to describe the physical reality. A more precise equation demands a formulation in the density-matrix form but for now there is no Diosi-Penrose model with density-matrix formulation. Such a density-matrix description can be viewed as a probability mixture of different wave-functions. Using some algebra and rules related to the mathematical manipulation of the density-matrix applied to operators, such the stress energy tensor, we found the von Neumann-Einstein equation for the general relativity equation in the density matrix operator form, Gμv = 8πG/C^4Tr[pTμv]. Thus density-matrix operator--instead of just a wave function of pure states--applied to the stress-energy tensor gives the curvature of space time, given by Einstein tensor, Gμv. The quantum fluctuation in the gravitational space-time field might feed back to decohere the quantum density-matrix. As long as decoherence can be viewed as the loss of information from a system to the environment, the density-matrix p is also related to that process and considering the measurement problem, density-matrix /garter is a more complete description of the possible outcome of the measurement. It is possible that some characteristics of the special microtubulin-associated proteins （MAP） that capes the dendritic-somatic microtubulins which could induces longer-lived nuclear spin states prevented from de-polymerization and suitable for long term information encode and memory. Understand the mechanism by which the hyper-phosphorylation in type tau-MAP displacements from microtubulins results in neurofibrillary tangles and cognitive dysfunctions in Alzheimer＇s disease.

Do new neurons contribute to functional reorganization after brain damage?

The finding that adult neurogenesis occurs constitutively in the brain was a breakthrough in neuroscience and soon gained attention as a possible mechanism for neurorepair after brain damage. In a recent study we show that the dentate gyrus （DG） reorganizes anatomically over neurons undergo maturation time after damage, while new and activate in response to a contextual fear memory recall （Aguilar-Arredondo and Zepeda, 2018）. These findings provide new evidence on the possible role of neurogenesis in cognitive recovery after brain injury.

Function of pioneer neurons specified by the basic helix-loop-helix transcription factor atonal in neural development

Basic helix-loop-helix （bHLH） transcription factors regulate the differentiation of various tissues in a vast diversity of species. The bHLH protein Atonal was first identified as a proneural gene involved in the formation of mechanosensory cells and photoreceptor cells in Drosophila （larman et al., 1993, 1994）. Atonal is expressed in sensory organ precursors and is required and sufficient for the development of chordotonal organs （Jar- man et al., 1993）. Moreover, Atonal expression is observed in the developing eye and is essential for the differentiation of R8 photoreceptors, which are the first photoreceptors that appear during development. Atonal is not involved in the formation of other photoreceptors （R1-R7） directly. However, R8 photore- ceptors recruit other photoreceptors from the surrounding cells （Jarman et al., 1994）.

Changes in hippocampal neurons and memory function during the developmental stage of newborn rats with hypoxic-ischemic encephalopathy

BACKGROUND: Under the normal circumstance, there exist some synapses with inactive functions in central nervous system (CNS), but these functions are activated following nerve injury. At the early stage of brain injury, the abnormal functions of brain are varied, and they have very strong plasticity and are corrected easily. OBJECTIVE: To observe the changes of neuronal morphology in hippocampal CA1 region and memory function in newborn rats with hypoxic-ischemic encephalopathy(HIE) from ischemia 6 hours to adult. DESIGN: Completely randomized grouping, controlled experiment. SETTING: Taian Health Center for Women and Children; Taishan Medical College. MATERIALS: Altogether 120 seven-day-old Wistar rats, of clean grade, were provided by the Experimental Animal Center, Shandong University of Traditional Chinese Medicine. Synaptophysin (SYN) polyclonal antibody was provided by Maixin Biological Company, Fuzhou. METHODS: This experiment was carried out in the Laboratory of Morphology, Taishan Medical College between October 2000 and December 2003. ① The newborn rats were randomly divided into 2 groups: model group and control group, 60 rats in each group. Five rats were chosen from each group at postoperative 6 hours, 24 hours, 72 hours, 7 days, 2 weeks and 3 weeks separately for immunohistochemical staining. Fifteen newborn rats were chosen from each group at postoperative 4 weeks and 2 months separately for testing memory ability (After test, 5 rats from each group were sacrificed and used for immunohistochemical staining)② The right common carotid artery of newborn rats of model group was ligated under the anesthetized status. After two hours of incubation, the rats were placed for 2 hours in a container filled with nitrogen oxygen atmosphere containing 0.08 volume fraction of oxygen, thus, HIE models were created; As for the newborn rats in the control group, only blood vessels were isolated, and they were not ligated and hypoxia-treated. ③ Thalamencephal tissue sections of newborn rats of two groups were performed DAB developing and haematoxylin slight staining. Cells with normal nucleous in 250 μm-long granular layer which started from hippocampal CA1 region were counted with image analysis system under high-fold optical microscope (×600), and the thickness of granular layer was measured. The absorbance (A) of positive reactant of SYN in immunohistochemically-stained CA1 region was measured. Learning and memory ability were measured with step through test 3 times successively. ④ t test and paired t test were used for comparing intergroup and intragroup difference of measurement data respectively, and Chi-square for comparing the difference of enumeration data. MAIN OUTCOME MEASURES: Comparison of cytological changes in hippocampal CA1 region and memory ability at different postoperative time points between two groups. RESULTS: Totally 120 newborn rats were involved in the result analysis. ① Cell morphological changes in hippocampal CA1 region: In the control group, with aging, perikaryon, nucleus and nucleolus in cortex of parietal lobe were significantly increased, Nissl body was compacted, the amount of neurons was declined, but the A of SYN positive reactant was relatively increased. In the model group, at postoperative each time point, neurons were seriously shrunk and dark-stained, nucleus was contracted, chromatin was condensed, nucleolus was unclear, even cells disappeared, especially the cells in 6 hours and 24 hours groups. The amount of neurons with normal morphology in hippocampal CA1 region and granular layer thickness in the model group at postoperative each time point were significantly less or smaller than those in the control group at postoperative 6 hours respectively (t =3.002-1.254, P < 0.01). The A value of SYN positive reactant at postoperative 2, 3 and 4 weeks was significantly higher than that at previous time point (t =2.011-2.716,P < 0.05-0.01). ② Test results of learning and memory ability: In the first test, there was no significant difference in the ratio of rats which kept memory ability between two groups (P > 0.05); In the third test, the ratio of rats which kept memory ability in the model group was significantly lower than that in the control group at postoperative 4 weeks and 2 months[53%(8/15),100%(15/15);60%(9/15),93%(14/15),χ 2=2.863,2.901,P < 0.01]. CONCLUSION: The destroyed hippocampal structure induces the decrease of learning and memory ability of developmental rats. Early interference can increase the quality of neurons and also promote functional development of the nervous system.

AB052.A standardized quantification of the visual contrast response function

Background:All neurons of the visual system exhibit response to differences in luminance.This neural response to visual contrast,also known as the contrast response function(CRF),follows a characteristic sigmoid shape that can be fitted with the Naka-Rushton equation.Four parameters define the CRF,and they are often used in different visual research disciplines,since they describe selective variations of neural responses.As novel technologies have grown,the capacity to record thousands of neurons simultaneously brings new challenges:processing and robustly analyzing larger amounts of data to maximize the outcomes of our experimental measurements.Nevertheless,current guidelines to fit neural activity based on the Naka-Rushton equation have been poorly discussed in depth.In this study,we explore several methods of boundary-setting and least-square curve-fitting for the CRF in order to avoid the pitfalls of blind curve-fitting.Furthermore,we intend to provide recommendations for experimenters to better prepare a solid quantification of CRF parameters that also minimize the time of the data acquisition.For this purpose,we have created a simplified theoretical model of spike-response dynamics,in which the firing rate of neurons is generated by a Poisson process.The spike trains generated by the theoretical model depending on visual contrast intensities were then fitted with the Naka-Rushton equation.This allowed us to identify combinations of parameters that were more important to adjust before performing experiments,to optimize the precision and efficiency of curve fitting(e.g.,boundaries of CRF parameters,number of trials,number of contrast tested,metric of contrast used and the effect of including multi-unit spikes into a single CRF,among others).Several goodness-of-fit methods were also examined in order to achieve ideal fits.With this approach,it is possible to anticipate the minimal requirements to gather and analyze data in a more efficient way in order to build stronger functional models.Methods:Spike-trains were randomly generated following a Poisson distribution in order to draw both an underlying theoretical curve and an empirical one.Random noise was added to the fit to simulate empirical conditions.The correlation function was recreated on the simulated data and re-fit using the Naka-Rushton equation.The two curves were compared:the idea being to determine the most advantageous boundaries and conditions for the curve-fit to be optimal.Statistical analysis was performed on the data to determine those conditions for experiments.Experiments were then conducted to acquire data from mice and cats to verify the model.Results:Results were obtained successfully and a model was proposed to assess the goodness of the fit of the contrast response function.Various parametres and their influence of the model were tested.Other similar models were proposed and their performance was assessed and compared to the previous ones.The fit was optimized to give semi-strict guidelines for scientists to follow in order to maximize their efficiency while obtaining the contrast tuning of a neuron.Conclusions:The aim of the study was to assess the optimal testing parametres of the neuronal response to visual gratings with various luminance,also called the CRF.As technology gets more powerful and potent,one must make choices when experimenting.With a strong model,robust boundaries,and strong experimental conditioning,the best fit to a function can lead to more efficient analysis and stronger cognitive models.

The cortical activation pattern during bilateral arm raising movements

Bilateral arm raising movements have been used in brain rehabilitation for a long time. However, no study has been reported on the effect of these movements on the cerebral cortex. In this study, using functional near infrared spectroscopy（f NIRS）, we attempted to investigate cortical activation generated during bilateral arm raising movements. Ten normal subjects were recruited for this study. f NIRS was performed using an f NIRS system with 49 channels. Bilateral arm raising movements were performed in sitting position at the rate of 0.5 Hz. We measured values of oxyhemoglobin and total hemoglobin in five regions of interest： the primary sensorimotor cortex, premotor cortex, supplementary motor area, prefrontal cortex, and posterior parietal cortex. During performance of bilateral arm raising movements, oxyhemoglobin and total hemoglobin values in the primary sensorimotor cortex, premotor cortex, supplementary motor area, and prefrontal cortex were similar, but higher in these regions than those in the prefrontal cortex. We observed activation of the arm somatotopic areas of the primary sensorimotor cortex and premotor cortex in both hemispheres during bilateral arm raising movements. According to this result, bilateral arm raising movements appeared to induce large-scale neuronal activation and therefore arm raising movements would be good exercise for recovery of brain functions.

Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders:EEG approach expectations

An imbalance between activities of different structures and neurotransmitter systems in the brain is suggested to be the main cause of its abnormal functioning in neurodegenerative pathologies.Electroencephalogram（EEG）registered from areas specifically linked with a disease in combination with pharmacological testing of involved mediatory systems allows discovery of its progression and mechanism（s）. This, in turn, potentiates development of perspective approaches for early diagnostic and effective treatment of neurodegenerative disorders.

Biophysical neurons,energy,and synapse controllability:a review

Diffusive intracellular and extracellular ions induce a gradient electromagnetic field that regulates membrane potential,and energy injection from external stimuli breaks the energy balance between the magnetic and electric fields in a cell.Indeed,any activation of biophysical function and self-adaption of biological neurons may be dependent on energy flow,and synapse connection is controlled to reach energy balance between neurons.When more neurons are clustered and gathered closely,field energy is exchanged and shape formation is induced to achieve local energy balance.As a result,the coexistence of multiple firing modes in neural activities is fostered to prevent the occurrence of bursting synchronization and seizure.In this review,a variety of biophysical neuron models are presented and explained in terms of their physical aspects,and the controllability of functional synapses,formation of heterogeneity,and defects are clarified for knowing the synchronization stability and cooperation between functional regions.These models and findings are summarized to provide new insights into nonlinear physics and computational neuroscience.

The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders

The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity.PAKs show wide expression in the brain,but they differ in specific cell types,brain regions,and developmental stages.PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines.PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders.Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment,comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases,which may also represent potential therapeutic targets of these diseases.