The impairment of the prefrontal cortex due to high levels of dopamine and norepinephrine in relation to ADHD

Abstract only availableAttention- Deficit/ Hyperactivity Disorder (ADHD) affects many people from various backgrounds; however, not much is known about the disorder aside from clinical symptoms. Researchers are just beginning to dissect ADHD and its effects on the brain, specifically in the prefrontal cortex (PFC) region. The PFC controls attention, motivation, planning, and most importantly working memory. Working memory is temporary storage for short-term memory; it is essential for sequencing tasks and assists with internalized language. The working hypothesis implicates increased levels of Dopamine (DA) and Norepinephrine (NE) in the impairment of PFC cells, leading to inhibition of working memory, and the development of disorder. The interaction of pyramidal neurons in the various layers of the PFC is studied in order to discover the impact of the network level plasticity on the disorder. This interdisciplinary research examines the relative impact of DA and NE, and the relevant pathway interactions on affected cells. Relevant neurophysiological experimentation data is used to examine mechanisms of ADHD in rat PFC, and to develop a computational model of the pyramidal neurons located in the six layers of the PFC. An analysis of the cognitive effects of ADHD via computational modeling may predict brain function, uncover emergent properties, and assist in the development of treatment. Reliable computational modeling will help save money and time as well as avoid the frequent use of human trial subjects.NSF-REU Program in Biosystems Modeling and Analysi

Mathematical modeling of obsessive compulsive disorder

Abstract only availableWe all at some point become fixated with certain actions or ideas. However, for the two to three percent of the world population with obsessive compulsive disorder (OCD), these fixations become so intense that the individual is debilitated. The exact obsessions the patients experience vary from case to case, but most obsessions fall within five categories: contamination, hoarding, ordering / symmetry, religious, and danger. Suffers of OCD usually recognize that their obsessions are unreasonable and illogical, yet are unable to prevent them. To alleviate these obsessions, the patients perform compulsions or ritualistic acts. Functional imaging studies have consistently implicated the caudate nucleus, the anterior cingulate gyrus, and the orbitofrontal cortex as the major causes of OCD. All three parts of the brain show hyperactivity in OCD patients and decreased activity of patients post treatment. The caudate nucleus is a part of the basal ganglia and is connected to the neocortex through a series of thalamocortical loops. These loops start in certain parts of the neocortex, such as the anterior cingulate gyrus and the orbitofrontal cortex, and run through the basal ganglia to the thalamus and then back to the neocortex. OCD patients appear to become stuck in one of these loops. In an attempt to better understand the loops, a mathematical model is being constructed to represent the OCD network pathway. GEneral NEural SImulation System (GENESIS) is a computer program being employed in the construction of the network. Currently, the framework for the OCD model has been constructed. This model will be enhanced in the coming months to create a more biologically realistic model. We hope to be able to show the reoccurring loop of OCD patients. Ultimately, a better understanding of the thalamocortical loop may lead to better treatment of OCD.NSF-REU Biosystems Modelin

How do we know that we have Obsessive-Compulsive Disorder?

Abstract only availableThe brain is a network of neurons that control our pleasure, emotion, motivation and is important for all types of learning. The objective of the overall research in the OCD's group is to examine the changes in brain circuit, or neuroplasticity that cause Obsessive-Compulsive Disorder (OCD). Such interdisciplinary study requires information of many types: neuroanatomy (relevant regions), neurophysiology (cellular firing) and neurochemistry (neurotransmitters). The specific objectives were to assist with hypothesis development for OCD, to systematically collect information listed above and to work with modelers to develop a computational model for OCD in primates. The basis of this research is the hypothesis that the normal interactions of prefrontal cortical neurons with basal ganglia, thalamus, and amygdala are altered due to OCD, although the primary alterations and interactions remain unknown. Examination of the neuroplastic processes in these pathways will help uncover mechanisms of OCD. This analysis is facilitated by a two-tiered mathematical model for the representation of the brain circuits. At the cellular level (first tier), models can serve to highlight the mechanisms of neuroplasticity affecting firing of the neurons in the circuit. At the network level (second tier) the interactive effects between the brain regions can be studied. Data from primate and rat literature will be used to develop the model. A reliable computation model will help analyze the underlying causes systematically to comprehend the cellular/molecular mechanisms of OCD. After validation, the model can be used for predictive purposes including drug design and to further our understanding of the brain.NSF-REU Program in Biosystems Modeling and Analysi

Modeling firing patterns of medium spiny neurons

Abstract only availableThe alternation in firing patterns of medium spiny neurons of the Nucleus Accumbens , a key structure in the brain's reward pathway, due to chronic and acute cocaine use was investigated through change of ion channel and receptor properties. Cocaine causes cellular changes both in the proteomic and genomic level in medium spiny neurons by increasing the concentration of the neurotransmitter Dopamine in the synaptic region; therefore generating a biologically realistic model of the nucleus accumbens is necessary. Medium spiny neurons exhibit bistability, meaning that they pass through up (polarized) and down (hyperpolarized) phases of membrane potential periodically. Only in the up state will a cell fire a train of action potentials. First step in the long term project of studying cocaine addiction is modeling this complex firing pattern and quantifying what can cause it to change. This task required figuring out all the key ion channels and receptors that mediate bistability, the equations that govern their behavior, and finally putting everything together in a computer program called GENESIS.NSF-REU Biosystems Modelin

A functional computer modeling framework for post-traumatic stress disorder

Abstract only availablePost-traumatic stress disorder (PTSD) is a unique psychiatric condition in which the patient experiences diverse and intrusive psychological symptoms as a direct result of experiencing a traumatic event. As yet, no cure is available for PTSD, though some symptoms are treatable. A detailed, biologically realistic model of the specific neurological areas involved in generating the symptoms of PTSD would be useful in medical efforts to cure the condition. This model will aid in understanding of the mechanisms involved in producing the symptoms of PTSD as well as helping to identify crucial gaps in our knowledge of the brain systems involved in PTSD, thus providing goals for future research. The goal of this project was to identify the specific brain regions and circuits that would need to be included in a computer model for PTSD, and to begin creating this model. Modeling was begun using the GENESIS software package, which allows modeling of intracellular reactions, cellular potentials, signal transmission, and intercellular synaptic transmission. Thus large brain systems can be modeled in extreme detail. A multi-level framework for future GENESIS modeling was developed by generating a skeleton model that includes basic neurons and brain structures. This model can incorporate more detailed information at all levels from genetic and proteomic to intercellular and circuitry-related as this information becomes available.NSF-REU Biosystems Modelin

Computational model of extracellular glutamate in the nucleus accumbens predicts neuroadaptations by chronic cocaine

Notice: this is the author's version of a work that was accepted for publication in Neuroscience. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuroscience, Vol. 158, Issue #4 (2008) doi:10.1016/j.neuroscience.2008.11.014 . http://journals.elsevier.com/03064522/neuroscience/Chronic cocaine administration causes instability in extracellular glutamate in the nucleus accumbens that is thought to contribute to the vulnerability to relapse. A computational framework was developed to model glutamate in the extracellular space, including synaptic and nonsynaptic glutamate release, glutamate elimination by glutamate transporters and diffusion, and negative feedback on synaptic release via metabotropic glutamate receptors (mGluR2/3). This framework was used to optimize the geometry of the glial sheath surrounding excitatory synapses, and by inserting physiological values, accounted for known stable extracellular, extrasynaptic concentrations of glutamate measured by microdialysis and glutamatergic tone on mGluR2/3. By using experimental values for cocaine-induced reductions in cystine-glutamate exchange and mGluR2/3 signaling, the computational model successfully represented the experimentally observed increase in glutamate that is seen in rats during cocaine-seeking. This model provides a mathematical framework for describing how pharmacological or pathological conditions influence glutamate transmission measured by microdialysis

Coregulation of Ion Channel Conductances Preserves Output in a Computational Model of a Crustacean Cardiac Motor Neuron

This item also falls under Society for Neuroscience copyright. For more information, please visit http://www.jneurosci.org/cgi/content/full/30/25/8637?maxtoshow=&hits=10&RESULTFORMAT=1&author1=nair&andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT&eaf . Link active as of 1/29/2011. Link maintenance is the responsibility of the Society for Neuroscience.Digital Object Identifier 10.1523/JNEUROSCI.6435-09.2010Similar activity patterns at both neuron and network levels can arise from different combinations of membrane and synaptic conductance values. A strategy by which neurons may preserve their electrical output is via cell type-dependent balances of inward and outward currents. Measurements of mRNA transcripts that encode ion channel proteins within motor neurons in the crustacean cardiac ganglion recently revealed correlations between certain channel types. To determine whether balances of intrinsic currents potentially resulting from such correlations preserve certain electrical cell outputs, we developed a nominal biophysical model of the crustacean cardiac ganglion using biological data. Predictions from the nominal model showed that coregulation of ionic currents may preserve the key characteristics of motor neuron activity. We then developed a methodology of sampling a multidimensional parameter space to select an appropriate model set for meaningful comparison with variations in correlations seen in biological datasets

Finding alternative methods of treating post-traumatic stress disorder [abstract]

Abstract only availablePost-traumatic stress disorder is a mental condition that affects many veterans and others who have been through a traumatic experience. One widely used method to combat PTSD is debriefing, which is an interview between the therapist/psychologist and the patient(s) that is to discuss the traumatic event. However, recent studies are not only showing that debriefing does not work as well as previously thought, but debriefing may actually be aiding in the onset of PTSD by effectively putting the subject(s) through more fear conditioning by talking about the experience. We wish to further investigate this by trying to investigate the link of fear conditioning to PTSD using 'fear circuit' models report in the literature. We also study the effect of different levels of fear conditioning on PTSD, as well as what can be done to inhibit the onset of PTSD. Data from rat studies will be used in the analysis. We will use computer models of certain neurons in the amygdala and prefrontal cortex (the two main structures of the fear circuit) to study changes to their firing properties with conditioning. This could possibly be related to data from imaging studies of normal and PTSD patients. One objective is to look for possible sites for drug actions such as ways to inhibit or weaken synapses in the fear circuit or to improve the effectiveness of another treatment for PTSD known as extinction. This research is still ongoing and it will take more time before we hope to yield results

Biology and mathematics-can they coexist [abstract]

Abstract only availableIn today's society, the desire for new and better medications for the brain is abundant. For long, biologists have thought that mathematical modeling could not produce physiologically accurate responses. Recently, however, pharmaceutical companies have pushed for the development of these models because of their cost effectiveness and their potential to produce accurate results. Computational tools such as MCell and DReAMM can be used to generate results that can be compared with experimentally determined data. For example, these tools were used to simulate the release of glutamate in a synaptic cleft in 3D. The glutamate in a specific region of this synaptic cleft was measured with respect to time and compared to data that has been experimentally determined. These two methods, biological and mathematical, produced a similar result which reinforces the fact that mathematical modeling can be used in the future to help produce accurate physiological responses.College of Engineering Undergraduate Research Optio

Modeling the lateral amygdala during fear acquisition [abstract]

Abstract only availableFaculty Mentor: Dr. Satish S. Nair, Electrical EngineeringThe lateral nucleus of the amygdala (LA) has been shown to play an important role in the acquisition of fear. In rat experiments performed by our collaborator and others, a conditioned stimulus (CS), such as tone, was paired with an unconditioned stimulus (US), such as shock, during fear learning. After the fear conditioning, when the tone was given without the shock, rats continued to freeze and indicate fear. For better understanding of this fear acquisition, we studied the neuroplasticity mechanisms that underlie learning and created a model that corresponds to the experiments. Studies published on the neuroplasticity mechanisms of fear conditioning revealed that NMDA receptors (NMDARs), AMPA receptors (AMPARs), and L-type voltage-gated calcium channels (VGCCs) are particularly involved in learning fear by increasing channel conductance and allowing more calcium to flow into the postsynaptic cell by the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). We incorporated these findings in a computational model, which consists of two pyramidal neurons and an interneuron, and implemented learning rules to modulate the synaptic weights. Model predictions exhibit trends similar to those observed in experiments by our collaborator. As the model becomes more accurate, it will allow us to predict the consequence of changes in the channels, the synaptic weights and other parts of the cell that experiments have not yet revealed