Electroencephalographic field influence on calcium momentum waves

Macroscopic EEG fields can be an explicit top-down neocortical mechanism that directly drives bottom-up processes that describe memory, attention, and other neuronal processes. The top-down mechanism considered are macrocolumnar EEG firings in neocortex, as described by a statistical mechanics of neocortical interactions (SMNI), developed as a magnetic vector potential $\mathbf{A}$. The bottom-up process considered are $\mathrm{Ca}^{2+}$ waves prominent in synaptic and extracellular processes that are considered to greatly influence neuronal firings. Here, the complimentary effects are considered, i.e., the influence of $\mathbf{A}$ on $\mathrm{Ca}^{2+}$ momentum, $\mathbf{p}$. The canonical momentum of a charged particle in an electromagnetic field, $\mathbf{\Pi} = \mathbf{p} + q \mathbf{A}$ (SI units), is calculated, where the charge of $\mathrm{Ca}^{2+}$ is $q = - 2 e$, $e$ is the magnitude of the charge of an electron. Calculations demonstrate that macroscopic EEG $\mathbf{A}$ can be quite influential on the momentum $\mathbf{p}$ of $\mathrm{Ca}^{2+}$ ions, in both classical and quantum mechanics. Molecular scales of $\mathrm{Ca}^{2+}$ wave dynamics are coupled with $\mathbf{A}$ fields developed at macroscopic regional scales measured by coherent neuronal firing activity measured by scalp EEG. The project has three main aspects: fitting $\mathbf{A}$ models to EEG data as reported here, building tripartite models to develop $\mathbf{A}$ models, and studying long coherence times of $\mathrm{Ca}^{2+}$ waves in the presence of $\mathbf{A}$ due to coherent neuronal firings measured by scalp EEG. The SMNI model supports a mechanism wherein the $\mathbf{p} + q \mathbf{A}$ interaction at tripartite synapses, via a dynamic centering mechanism (DCM) to control background synaptic activity, acts to maintain short-term memory (STM) during states of selective attention.Comment: Final draft. http://ingber.com/smni14_eeg_ca.pdf may be updated more frequentl

Structure-function study of ubiquitin c-terminal hydrolase L1 (UCH-L1) by NMR spectroscopy - insights into UCH-L1 mutation's association with the risk of Parkinson's disease

Poster Presentation: P72Protein ubiquitination and deubiquitination, play important roles in many aspects of cellular mechanisms. Its defective regulation results in diseases that range from developmental abnormalities to neurodegenerative diseases and cancer. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a protein of 223 amino acids, which is highly abundant in brain, constituting up to 2% of total brain proteins. Although it was originally characterized as a deubiquitinating enzyme, recent studies indicate that it also functions as a ubiquitin ligase and a mono-Ub stabilizer. Down-regulation and extensive oxidative modifications of UCH-L1 have been observed in the brains of Alzheimer’s disease and Parkinson’s disease (PD) patients. Of importance, I93M and S18Y point mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from PD respectively. Hence, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable interest. Our circular dichroism studies suggest that the S18Y point mutation only slightly perturbs the structure while a significant decrease in the α-helical content is observed in the I93M mutant. We have determined the solution structure of S18Y and mapping its interaction with ubiquitin by chemical shift perturbation approach. The electrostatic surface potential analysis reveals that the interaction between ubiquitin and UCH-L1-S18Y is primarily electrostatic in nature, with negatively charged residues on the surface of UCH-L1-S18Y interacting with the positively charged residues on the basic face of ubiquitin. Although the active site and the L8 loop in UCH-L1-S18Y adopts conformations similar to that observed in the crystal structure of UCH-L1-WT, both the altered hydrogen bond network and surface charge distributions have demonstrated that the S18Y substitution could lead to profound structural changes. In particular, the difference in the dimeric interfaces of the wild-type and the S18Y mutant has shown that mutation can significantly affect the distribution of the surface-exposed residues involved in the dimeric interface. Such observed difference might weaken the stability of the UCH-L1 dimer and hence may explain the reduced dimerization-dependent ligase activity of UCH-L1-S18Y in comparison to UCH-L1-WT.postprin

Aldose reductase deficiency protects the retinal neurons in a mouse model of retinopathy of prematurity

Poster Presentation: P64PURPOSE: Retinopathy of prematurity (ROP) is a common retinal disease occurred in premature babies. It is found to be related to oxidative stress while dysfunction of the neural retina has also been documented. We previously showed that genetic deletion or pharmacological inhibition of aldose reductase (AR), a rate- limiting enzyme in the polyol pathway, prevented ischemia-induced retinal ganglion cell (RGC) loss and oxidative stress. Here, we assessed the effects of AR deletion on retinal neurons using a mouse model of ROP. METHODS: Seven-day-old mouse pups were exposed to 75% oxygen for five days and returned to room air. The pathological neuronal changes were examined and compared between wild-type (WT) and AR-deficient retinae on P14 and P17 (P, postnatal). Retinal thickness was measured and immunohistochemistry for calbindin, calretinin, PKCα, Tuj1, glial fibrillary acidic protein (GFAP), nitrotyrosine (NT), as well as poly(ADP-ribose) (PAR) was performed. RESULTS: After hyperoxia exposure, significantly reduced inner nuclear layer (INL) and inner plexiform layer (IPL) thickness were found in both genotypes. The intensity of calbindin staining for horizontal cells in INL was reduced in the WT retinae but not in AR-deficient retinae. In addition, significant reduction was found in calretinin-positive amacrine cell bodies in central INL especially in WT retinae. Serious distortion was also observed in the three calretinin-positive strata along IPL in the WT retinae but not AR-deficient retinae on P17. Moreover, increased GFAP intensity across IPL indicating Müller cell processes was observed in AR-deficient retinae on P14 and in WT retinae on P17. Furthermore, increased NT immunoreactivity in INL and nuclear or para-nuclear PAR staining along GCL were observed in WT retina while these changes were not apparent in AR-deficient retina. CONCLUSION: Our observations demonstrated morphological changes of retinal neurons in the mouse model of ROP and indicated that AR deficiency showed neuronal protection in the retina, possibly through modulating glial responses and reducing oxidative stress.postprin

Protective effects of lycium barbarum polysaccharides on cerebral edema and blood-brain barrier disruption after ischemic stroke

Young Investigators Symposium I (Y3) - Di YangBACKGROUND: Ischemic stroke is a destructive cerebrovascular disease and one of the leading causes of death worldwide. The long term disability after stroke induces heavy burden both to the patients and the society. Yet, no effective neuroprotective agents are available. The polysaccharides extracted from the fruits of wolfberry, Lycium barbarum (LBP), showed neuroprotective and immune-modulative functions. We aim to evaluate the protective effects of LBP in experimental stroke using a focal cerebral ischemia/reperfusion (I/R) model. METHODS: C57BL/6N mice were subjected to 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. Prior to ischemia induction, animals were treated with either vehicle (PBS) or LBP daily for 7 days. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement and immunohistochemical analysis as well as Western blot experiments. Evans blue (EB) extravasation experiment was performed to determine blood-brain barrier (BBB) disruption after MCAO. RESULTS: LBP treatment significantly improved neurological scores and decreased infarct size, hemispheric swelling and water content as well as reduced EB extravasation. In addition, fewer apoptotic cells were identified in the LBP-treated brains by TUNEL assay. Immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were also significantly decreased in LBP-treated brains. We further observed a reduction of nuclear factor-κB translocation and IκB expression after LBP treatment. CONCLUSION: Seven-day LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin water channel up-regulation and glial activation. The protective effects of LBP might partially act through its anti-inflammatory effects. The present study suggests that LBP may be used as a preventive neuroprotectant for ischemic stroke.postprin

Adiabatic dynamic causal modelling

This technical note introduces adiabatic dynamic causal modelling, a method for inferring slow changes in biophysical parameters that control fluctuations of fast neuronal states. The application domain we have in mind is inferring slow changes in variables (e.g., extracellular ion concentrations or synaptic efficacy) that underlie phase transitions in brain activity (e.g., paroxysmal seizure activity). The scheme is efficient and yet retains a biophysical interpretation, in virtue of being based on established neural mass models that are equipped with a slow dynamic on the parameters (such as synaptic rate constants or effective connectivity). In brief, we use an adiabatic approximation to summarise fast fluctuations in hidden neuronal states (and their expression in sensors) in terms of their second order statistics; namely, their complex cross spectra. This allows one to specify and compare models of slowly changing parameters (using Bayesian model reduction) that generate a sequence of empirical cross spectra of electrophysiological recordings. Crucially, we use the slow fluctuations in the spectral power of neuronal activity as empirical priors on changes in synaptic parameters. This introduces a circular causality, in which synaptic parameters underwrite fast neuronal activity that, in turn, induces activity-dependent plasticity in synaptic parameters. In this foundational paper, we describe the underlying model, establish its face validity using simulations and provide an illustrative application to a chemoconvulsant animal model of seizure activity

Regulatory role of proheparanase with peri-synaptic heparan sulfate proteoglycan and AMPA-type glutamate receptor in synaptic plasticity

Poster Presentation: P59AMPA-type glutamate receptors (AMPAR) govern excitatory synaptic transmission. Perineuronal heparan sulfates (HS) have been implicated in controlling the open-state of AMPAR. Our finding of neuronal heparanase expression in adult rats led us to test (1) if neuronal heparanase is secreted and (2) if the secreted form acts on perineuronal HS to modulate synaptic plasticity. Neuronal secretion of heparanase was triggered by phorbol ester of rat hippocampal neurons in culture. Western blot analysis of the secreted product revealed enzymatically inactive proheparanase, but not the enzymatically active heparanase. Synaptosomes prepared from phorbol ester-treated rat cortexslices showed enrichment in proheparanase; co-immunoprecipitation studies further showed association of AMPAR subunits (GluA1 and GluA2/3) with both syndecan-3 (a transmembrane HS-proteoglycan) and proheparanase, suggesting their partnership in the peri-synaptic environment. Treatment of hippocampal neurons in culture with recombinant proheparanase triggered internalization of proheparanase, perineuronal HS-proteoglycans and AMPARs, suggesting their clustering as a functional complex. Heparitinase pre-treatment of hippocampal neuron cultures reduced proheparanase-induced internalization of AMPARs, suggesting that the HS moiety is critical for effecting the partnership. Treatment of hippocampal slices with recombinant proheparanase resulted in down-regulation of both basal synaptic strength and LTP at Schaffer collateral synapses. These results reveal a novel role of neuronal proheparanase in resetting AMPAR and perineuronal HS levels at the synapse and thus the modulation of synaptic plasticity.postprin

Population based models of cortical drug response: insights from anaesthesia

A great explanatory gap lies between the molecular pharmacology of psychoactive agents and the neurophysiological changes they induce, as recorded by neuroimaging modalities. Causally relating the cellular actions of psychoactive compounds to their influence on population activity is experimentally challenging. Recent developments in the dynamical modelling of neural tissue have attempted to span this explanatory gap between microscopic targets and their macroscopic neurophysiological effects via a range of biologically plausible dynamical models of cortical tissue. Such theoretical models allow exploration of neural dynamics, in particular their modification by drug action. The ability to theoretically bridge scales is due to a biologically plausible averaging of cortical tissue properties. In the resulting macroscopic neural field, individual neurons need not be explicitly represented (as in neural networks). The following paper aims to provide a non-technical introduction to the mean field population modelling of drug action and its recent successes in modelling anaesthesia

The influence of dopamine on prediction, action and learning

In this thesis I explore functions of the neuromodulator dopamine in the context of autonomous learning and behaviour. I first investigate dopaminergic influence within a simulated agent-based model, demonstrating how modulation of synaptic plasticity can enable reward-mediated learning that is both adaptive and self-limiting. I describe how this mechanism is driven by the dynamics of agentenvironment interaction and consequently suggest roles for both complex spontaneous neuronal activity and specific neuroanatomy in the expression of early, exploratory behaviour. I then show how the observed response of dopamine neurons in the mammalian basal ganglia may also be modelled by similar processes involving dopaminergic neuromodulation and cortical spike-pattern representation within an architecture of counteracting excitatory and inhibitory neural pathways, reflecting gross mammalian neuroanatomy. Significantly, I demonstrate how combined modulation of synaptic plasticity and neuronal excitability enables specific (timely) spike-patterns to be recognised and selectively responded to by efferent neural populations, therefore providing a novel spike-timing based implementation of the hypothetical ‘serial-compound’ representation suggested by temporal difference learning. I subsequently discuss more recent work, focused upon modelling those complex spike-patterns observed in cortex. Here, I describe neural features likely to contribute to the expression of such activity and subsequently present novel simulation software allowing for interactive exploration of these factors, in a more comprehensive neural model that implements both dynamical synapses and dopaminergic neuromodulation. I conclude by describing how the work presented ultimately suggests an integrated theory of autonomous learning, in which direct coupling of agent and environment supports a predictive coding mechanism, bootstrapped in early development by a more fundamental process of trial-and-error learning

Large scale neural dynamics of rhythmic sensorimotor coordination and stability

Coordination Dynamics posits that the stability of coordinated patterns of movement may be a key variable for organizing neural activity underlying coordinated action. In support, recent findings suggest that premotor areas play an important role in maintaining pattern stability. The present EEG study investigates how changes in neural activation (assessed via event-related power) are affected both by rate and stability of coordination. Nineteen participants coordinated finger taps with an auditory metronome in either a synchronized or syncopated pattern presented at five different rates (1.00, 1.25, 1.50, 1.75, and 2.00 Hz). Premotor areas demonstrated increases in event-related synchronization (neural deactivation) within the alpha band following slow, synchronized movements. Stepwise increases in rate led to greater desynchronization (neural activation) throughout the entire duration of the movement cycle. During syncopation medial premotor regions remained desynchronized during movement. Moreover, medial premotor was more involved during synchronization with subsequent increases in movement rate. Counter to previous findings, medial premotor did not modulate changes in coordination stability. We suggested that medial premotor regions are involved in processes related to the coincidence of the finger tap and auditory tone. These findings support premotor cortex\u27s role in motor inhibition, timing, and execution