Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Stochastic neural network dynamics: synchronisation and control

Biological brains exhibit many interesting and complex behaviours. Understanding of the mechanisms behind brain behaviours is critical for continuing advancement in fields of research such as artificial intelligence and medicine. In particular, synchronisation of neuronal firing is associated with both improvements to and degeneration of the brain’s performance; increased synchronisation can lead to enhanced information-processing or neurological disorders such as epilepsy and Parkinson’s disease. As a result, it is desirable to research under which conditions synchronisation arises in neural networks and the possibility of controlling its prevalence. Stochastic ensembles of FitzHugh-Nagumo elements are used to model neural networks for numerical simulations and bifurcation analysis. The FitzHugh-Nagumo model is employed because of its realistic representation of the flow of sodium and potassium ions in addition to its advantageous property of allowing phase plane dynamics to be observed. Network characteristics such as connectivity, configuration and size are explored to determine their influences on global synchronisation generation in their respective systems. Oscillations in the mean-field are used to detect the presence of synchronisation over a range of coupling strength values. To ensure simulation efficiency, coupling strengths between neurons that are identical and fixed with time are investigated initially. Such networks where the interaction strengths are fixed are referred to as homogeneously coupled. The capacity of controlling and altering behaviours produced by homogeneously coupled networks is assessed through the application of weak and strong delayed feedback independently with various time delays. To imitate learning, the coupling strengths later deviate from one another and evolve with time in networks that are referred to as heterogeneously coupled. The intensity of coupling strength fluctuations and the rate at which coupling strengths converge to a desired mean value are studied to determine their impact upon synchronisation performance. The stochastic delay differential equations governing the numerically simulated networks are then converted into a finite set of deterministic cumulant equations by virtue of the Gaussian approximation method. Cumulant equations for maximal and sub-maximal connectivity are used to generate two-parameter bifurcation diagrams on the noise intensity and coupling strength plane, which provides qualitative agreement with numerical simulations. Analysis of artificial brain networks, in respect to biological brain networks, are discussed in light of recent research in sleep theor

Voltage-Gated Sodium Channel Nav1.6 S-Palmitoylation Regulates Channel Functions and Neuronal Excitability

Indiana University-Purdue University Indianapolis (IUPUI)The voltage-gated sodium channels (VGSCs) are critical determinants of neuronal excitability. They set the threshold for action potential generation. The VGSC isoform Nav1.6 participates in various physiological processes and contributes to distinct pathological conditions, but how Nav1.6 function is differentially regulated in different cell types and subcellular locations is not clearly understood. Some VGSC isoforms are subject to S-palmitoylation and exhibit altered functional properties in different S-palmitoylation states. This dissertation investigates the role of S-palmitoylation in Nav1.6 regulation and explores the consequences of S-palmitoylation in modulating neuronal excitability in physiological and pathological conditions. The aims of this dissertation were to 1) provide biochemical and electrophysiological evidence of Nav1.6 regulation by S-palmitoylation and identify specific S-palmitoylation sites in Nav1.6 that are important for excitability modulation, 2) determine the biophysical consequences of epilepsy-associated mutations in Nav1.6 and employ computational models for excitability prediction and 3) test the modulating effects of S-palmitoylation on aberrant Nav1.6 activity incurred by epilepsy mutations. To address these aims, an acyl-biotin exchange assay was used for Spalmitoylation detection and whole-cell electrophysiology was used for channel characterization and excitability examination. The results demonstrate that 1) Nav1.6 is biochemically modified and functionally regulated by S-palmitoylation in an isoform- and site-specific manner and altered S-palmitoylation status of the channel results in substantial changes of neuronal excitability, 2) epilepsy associated Nav1.6 mutations affect different aspects of channel function, but may all converge to gain-of-function alterations with enhanced resurgent currents and increased neuronal excitability and 3) S-palmitoylation can target specific Nav1.6 properties and could possibly be used to rescue abnormal channel function in diseased conditions. Overall, this dissertation reveals S-palmitoylation as a new mechanism for Nav1.6 regulation. This knowledge is critical for understanding the potential role of S-palmitoylation in isoform-specific regulation for VGSCs and providing potential targets for the modulation of excitability disorders.2022-05-0

Serotonergic modulation of the ventral pallidum by 5HT1A, 5HT5A, 5HT7 AND 5HT2C receptors

Introduction: Serotonin's involvement in reward processing is controversial. The large number of serotonin receptor sub-types and their individual and unique contributions have been difficult to dissect out, yet understanding how specific serotonin receptor sub-types contribute to its effects on areas associated with reward processing is an essential step. Methods: The current study used multi-electrode arrays and acute slice preparations to examine the effects of serotonin on ventral pallidum (VP) neurons. Approach for statistical analysis: extracellular recordings were spike sorted using template matching and principal components analysis, Consecutive inter-spike intervals were then compared over periods of 1200 seconds for each treatment condition using a student’s t test. Results and conclusions: Our data suggests that excitatory responses to serotonin application are pre-synaptic in origin as blocking synaptic transmission with low-calcium aCSF abolished these responses. Our data also suggests that 5HT1a, 5HT5a and 5HT7 receptors contribute to this effect, potentially forming an oligomeric complex, as 5HT1a antagonists completely abolished excitatory responses to serotonin application, while 5HT5a and 5HT7 only reduced the magnitude of excitatory responses to serotonin. 5HT2c receptors were the only serotonin receptor sub-type tested that elicited inhibitory responses to serotonin application in the VP. These findings, combined with our previous data outlining the mechanisms underpinning dopamine's effects in the VP, provide key information, which will allow future research to fully examine the interplay between serotonin and dopamine in the VP. Investigation of dopamine and serotonins interaction may provide vital insights into our understanding of the VP's involvement in reward processing. It may also contribute to our understanding of how drugs of abuse, such as cocaine, may hijack these mechanisms in the VP resulting in sensitization to drugs of abuse

Structures and functions of the post-mortem brain: an experimental evaluation of the residual properties of fixed neural tissues

Does brain function irreversibly cease after death? Billions of years of evolution and hundreds of thousands of years of human development have inculcated within us an intuition that death is a deep pit from which thoughts and behaviour cannot emerge. This dissertation serves to challenge the assumption of neurofunctional loss after death by employing modern technology to observe alternative mechanisms by which information can be processed by fixed, post-mortem neural tissues. The central aim of the thesis was to measure periodic, electric potential differences (μV) characteristic of the psychological definition of “response” within neuroanatomical loci while the fixed tissues were exposed to patterned current, complex electromagnetic fields, chemical probes, and other experimental conditions. The findings presented here show that fixed post-mortem tissues express regional, electrical anisotropies which can be modulated by various applications of electrochemical energy and that the areas surrounding the hippocampus are most responsive. We show that neuropathology secondary to repeated and protracted seizure activity can be detected in post-mortem rat brains with coupled depressions of low-frequency signal periodicities. Our findings demonstrate that injections of current into coronal sections of fixed human brain tissue are most potent when patterned to simulate neuronal spike-trains and the dominant frequency of the equivalent living tissue subsection. We also show that fixed, post-mortem brain tissues act as electromagnetic filters, expressing signals non-randomly and preferentially within the right cerebral hemisphere. Further findings indicate that receptor agonist-antagonist probes (e.g., glutamate and ketamine) as well as other chemical applications can induce regional electrical responses as well as habituation-type phenomena over repeated exposure. iv These responses are paired and can be inversely related to photon emission from the tissue proper as inferred by photomultiplier tube measurements. The bases of the electrochemical responses are thought to be due to phenomena associated with pH and ionic gradients in general as inferred by our experiments with post-mortem rat brains. The aforementioned experimental results are then synthesized to produce a working hypothesis upon which further research can be based. We conclude that the brain’s structure-function relationship is sufficient to elicit post-mortem responses characteristic of a composite material of otherwise unknown potential.Doctor of Philosophy (PhD) in Biomolecular Science

Mutation analysis of GABAergic neuroinhibitory genes in childhood genetic generalised epilepsies.

Epilepsy affects over 450,000 people in the UK and there are over 50 epilepsy phenotypes; genetic generalised epilepsy (GGE) account for up to 30% of seizure types. It is established that GGE and other neurological disorders are, in some cases, caused by channelopathies within post-synaptic inhibitory neurotransmitter systems such as GAB A (epilepsy) and Glycine (hyperekplexia). GAB A is the primary inhibitory neurotransmitter in the brain and is synthesised from glutamate by GAD65 and 67, and is released from the pre-synaptic nerve terminal into the synaptic cleft, where it binds to post-synaptic GABA receptors and initiate neuroinhibition. This inhibition is removed by post-synaptic GABA transporters (GAT1 and GAT3) that uptake GABA back into the cell for re-packaging in presynaptic vesicles or breakdown by transamination. Abnormalities in this system have been linked to diseases including anxiety, psychosis, Parkinsons’s Disease and epilepsy. GABAergic animal models have demonstrated a tendency to seizure, including GABA transporter and enzyme models in relation to epilepsy.Given the above, the aim of this study was to identify GGE causing variants in four GABAergic genes. GGE patient samples (n=101) were recruited from 3 global centres and screened for variations in GAT1, GAT3, GAD65, GAD67 using high-throughput LightScanner analysis and bi-directional Sanger sequencing. Control population studies («=480) were carried out and analysis of online databases to determine the frequency of variants. Twenty novel or very rare variants were identified in 48 patient samples representing a detection rate of 6.8%, where a clustering of phenotypes included a predisposition towards absence seizures. The biological consequences of these variants were predicted using three online predictive programmes, multiple phylogenetic alignments and 3D structural modelling. Mutation expression constructs were prepared and expression levels were validated by immunocytochemistry. Functional characterisation of these variants will hopefully improve genetic diagnosis in GGE and determine causality of GABAergic absence seizures

Role of the inward rectifying potassium channel, Kir4.1, in astrocyte physiology and neuronal excitability

During neuronal activity extracellular potassium concentration ([K+]out) becomes elevated and if uncorrected causes neuronal depolarization, hyperexcitability, and seizures. Clearance of K+ from the extracellular space, termed K+ spatial buffering, is considered to be an important function of astrocytes. Results from a number of studies suggest that maintenance of [K+]out by astrocytes is mediated by K+ uptake through Kir4.1 channels. Furthermore, a missense variation in the Kir4.1 gene is linked to seizure susceptibility in mice and humans. To study the role of this channel in astrocyte physiology and neuronal excitability we have generated a conditional knockout (cKO) of Kir4.1 directed to astrocytes via human GFAP promoter, gfa2. Kir4.1 cKO mice die prematurely and display severe ataxia and stress-induced seizures. Histological analysis of Kir4.1 cKO brain and spinal cord revealed white matter vacuolization suggestive of oligodendrocyte pathology. Immunostaining studies confirmed removal of Kir4.1 from cKO astrocytes and oligodendrocytes, indicating that these cell types arise from a common GFAP-expressing precursor. Passive astrocytes in Kir4.1 cKO hippocampus appeared normal in morphology and coupling ability; however, we observed a significant loss of complex astrocytes suggestive of Kir4.1 role in astrocyte development. Whole-cell patch clamp revealed large depolarization (>35 mV) of Kir4.1 cKO astrocytes and oligodendrocytes. Complex cell depolarization appears to be a direct consequence of Kir4.1 removal. In contrast, passive astrocyte depolarization seems to arise from an indirect process that may involve a change in Na+/K+-ATPase function. Kir4.1 cKO passive astrocytes displayed a marked impairment of both K+ and glutamate uptake induced by neuronal stimulation. Surprisingly, membrane and action potential properties of CA1 pyramidal neurons, as well as basal synaptic transmission due to single pulse stimulation appeared unaffected, while spontaneous neuronal activity was reduced in the Kir4.1 cKO. However, increased synaptic stimulation (100 pulse train) revealed greatly elevated (>20%) post-tetanic potentiation and short-term potentiation in Kir4.1 cKO hippocampus. Our findings implicate that through its involvement in astrocyte development and K+ buffering, Kir4.1 participates in the modulation of synaptic strength thereby modulating neuronal spontaneous activity and synaptic plasticity

Brain Injury

The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. The collective contribution from experts in brain injury research area would be successfully conveyed to the readers and readers will find this book to be a valuable guide to further develop their understanding about brain injury