Medicine and Health Sciences Commons^™

Target Validation And Pharmacological Characterization Of Novel Nmdar Modulators, Kiran Sapkota

Theses & Dissertations

The N-methyl-D aspartate receptors (NMDARs) are ligand-gated ion channels, which play important roles in learning and memory. Excessive activity of NMDARs is implicated in damage due to stroke and neurodegenerative diseases, whereas hypoactivity of NMDARs contributes to schizophrenia. The initial goal of my dissertation is to evaluate the potential role of the GluN2D-containing NMDARs in neuropathological, behavioral and cognitive alterations associated with schizophrenia and characterize the pharmacology and mechanisms of action of NMDAR modulators which could potentially be used to modulate these receptors in schizophrenia.

A subanesthetic dose of the NMDAR antagonist ketamine elicits symptoms of schizophrenia. This property led …

Selective Suppression Of The Α Isoform Of P38 Mapk Rescues Late-Stage Tau Pathology, Nicole Maphis, Shanya Jiang, Guixiang Xu, Olga N. Kokiko-Cochran, Saktimayee M. Roy, Linda J. Van Eldik, D. Martin Watterson, Bruce T. Lamb, Kiran Bhaskar

Sanders-Brown Center on Aging Faculty Publications

Background: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer’s disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1.

Method: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice.

Results: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 …

Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations And Cortical-Subcortical Coupling During Movements: Preliminary Evidence In Subjects With Parkinson’S Disease, Andrea Canessa, Nicolo G. Pozzi, Gabriele Arnulfo, Joachim Brumberg, Martin M. Reich, Gianni Pezzoli, Maria F. Ghilardi, Cordula Matthies, Frank Steigerwald, Jens Volkman, Ioannis U. Isais

Publications and Research

Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson’s disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon …

Very Rapid Onset Cannabis Dependence Risk In Relation To Co-Occurring Use Of Other Psychoactive Drugs, Olga A. Vsevolozhskaya, Fernando A. Wagner, James C. Anthony

Biostatistics Presentations

Background: Epidemiological estimates for lifetime cumulative incidence indicate that for every 9-11 who start using cannabis, one becomes a case of the cannabis dependence syndrome (CDS) – i.e., roughly 9%-11%. More recent estimates clarify that CDS risk might be much lower among ’cannabis only’ users, due in part to the fact that many ’cannabis only’ users try the drug a few times and never again. We turned to Hill functional analysis in order to study CDS probability soon after 1st cannabis use, estimated across strata defined by the number of recent days of cannabis use, with an acknowledgment that a …

Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang

Dissertations & Theses (Open Access)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce …

Consensus Paper: Cerebellar Development., K Leto, M Arancillo, Ebe Becker, A Chiang, Et Al.

Faculty Publications

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.

Maguk Scaffolds Organize A Key Synaptic Complex In Horizontal Cell Processes Contacting Photoreceptors, Alejandro Vila, Ph.D.

Dissertations & Theses (Open Access)

Synaptic processes and plasticity of synapses are mediated by large suites of proteins. In most cases, many of these proteins are tethered together by synaptic scaffold proteins. Scaffold proteins have a large number and typically a variety of protein interaction domains that allow many different proteins to be assembled into functional complexes. As each scaffold protein has a different set of protein interaction domains and a unique set of interacting partners, the presence of synaptic scaffolds can provide insight into the molecular mechanisms that regulate synaptic processes. In studies of rabbit retina, we found SAP102 and Chapsyn110 selectively localized in …

Methylphenidate And Memory And Attention Adaptation Training For Persistent Cognitive Symptoms After Traumatic Brain Injury: A Randomized, Placebo-Controlled Trial, Brenna C. Mcdonald, Laura A. Flashman, David B. Arciniegas, Robert J. Ferguson, Li Xing, Jaroslaw Harezlak, Gwen C. Sprehn, Flora M. Hammond, Arthur C. Maerlender, Carrie L. Kruck, Karen L. Gillock, Kim Frey, Rachel N. Wall, Andrew J. Saykin, Thomas W. Mcallister

Center for Brain, Biology, and Behavior: Faculty and Staff Publications

The purpose of this multicenter, prospective, randomized, placebo-controlled study was to evaluate and compare the efficacy of two cognitive rehabilitation interventions (Memory and Attention Adaptation Training (MAAT) and Attention Builders Training (ABT)), with and without pharmacologic enhancement (i.e., with methylphenidate (MPH) or placebo), for treating persistent cognitive problems after traumatic brain injury (TBI). Adults with a history of TBI at least four months prior to study enrollment with either objective cognitive deficits or subjective cognitive complaints were randomized to receive MPH or placebo and MAAT or ABT, yielding four treatment combinations: MAAT/MPH (N=17), ABT/MPH (N=19), MAAT/placebo (N=17), and ABT/placebo (N=18). …

Understanding The Differences Between Neuronal Calcium Sensor Proteins: A Comparison Of Neurocalcin Delta And Hippocalcin, Jeffrey M. Viviano

Graduate School of Biomedical Sciences Theses and Dissertations

Many neuronal functions, including learning and memory are driven by changes in intracellular Ca2+concentrations. The Neuronal Calcium Sensor (NCS) family of proteins is responsible for mediating the response to calcium. They are typically comprised of 4 EF hands; of which EF 2, 3, and 4 bind calcium.

Hypothesis: NCS proteins carry out unique, non-overlapping functions, and that specific characteristics of the family can be mapped to precise regions of the proteins.

Results: The effect on the following properties were investigated primarily on two highly similar NCS proteins, Neurocalcin Delta (NCALD) and Hippocalcin (HPCA): (1) Response to calcium was determined through …

The Scripps Research Institute Summer Undergraduate Research Fellowship, Ezana Assefa

Trick to the Treat of Internships and Research

This program is a 10-week internship designed for undergraduates interested in the scientific field to engage in current research. Students have the option of requesting to work under three mentors, one of which they will be paired. Students will work in the lab with the principal investigator and other members of the lab. Along with working in the lab, students in the program will also attend bi-weekly talks/lectures from researchers, grad students, and professionals at TSRI as well as participating in two presentations and a final poster or oral presentation.

Interleukin-17a Promotes Cd8 T Cell Cytotoxicity To Facilitate West Nile Virus Clearance, Amber M. Paul, Dhiraj Acharya, Penghua Wang, Jianfeng Dai, David Gate

Publications

CD8 T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a/) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 T cells isolated from Il17a/ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in …

Zombies, Predatory Wasps And Consciousness, James K. Peterson

Annual Symposium on Biomathematics and Ecology Education and Research

No abstract provided.

Family Based Treatment For Adults With Anorexia Nervosa Using Insights From Neurobiology, The Center For Balanced Living

Learning Showcase 2016: A Celebration of Discovery, Transformation and Success

Anorexia Nervosa (AN) is a biologically-based brain disorder, which has the highest death rate of all mental illnesses. No effective treatments exist for adults with severe and enduring AN (5-7+ years). Brain imaging studies at University of California San Diego on AN temperament, cognition and eating show common traits related to neural function. The temperaments are characterized by increased trait anxiety and state anxiety related to food and eating, high incidence of co-morbid anxiety disorders, high punishment sensitivity and low reward reactivity, elevated intolerance of uncertainty and exaggerated harm avoidance (HA). HA is a multifaceted temperament trait that contains elements …

Structural Dichotomy Of The Mind; The Role Of Sexual Neuromodulators, Ion G. Motofei, David L. Rowland

Journal of Mind and Medical Sciences

The mind (mental function) and sexuality represent two distinct environmental functions, but which are supported within the brain by a common (somatic-autonomic) neurobiological substrate. As a consequence, mental function takes on autonomic characteristics from the sexual-autonomic system (like autonomy, duality), while sexual function takes on features from mental functioning (such as lateralization). In this paper we discuss the lateralized action of two classes of sexual neuromodulators: hormones and pheromones. This process of lateralization is assimilated with the structural dichotomy of the mind.

A relatively similar process but related to informational dichotomy of the mind will be presented in a forthcoming …

Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic And Ca2+-Handling Deficits In Alzheimer's Disease Models, Erez Eitan, Emmette R. Hutchison, Krisztina Marosi, James Comotto, Maja Mustapic, Saket M. Nigam, Caitlin Suire, Chinmoyee Maharana, Gregory A. Jicha, Dong Liu, Vasiliki Machairaki, Kenneth W. Witwer, Dimitrios Kapogiannis, Mark P. Mattson

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50–150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca²⁺ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of Aβ but have an …

From The Handbook Of The Laszlo Institute Of New Paradigm Research And The Intelligence Of The Cosmos , Inner Traditions, September 2017, Ervin Laszlo

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Consciousness: Where We Are At, Imants Barušs

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

It is useful every couple of years to take a bird’s eye view of consciousness studies and reflect on what we see. When I look, I still see two streams, one of which is the social and political framework for the study of consciousness, and the other of which is the substance of what we know about consciousness. The former is still largely defined by the extent to which the scientific study of consciousness has been freed from a materialist agenda. The latter includes recent research into the clarity of cognitive functioning in the absence of sufficient neurological support for …

Growth And Happiness In The Human Personality, Rien Havens, Allan Combs

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

This paper explores stages and styles of meaning making in a population at Kegan’s (1982) developmental levels 3 through 5. It is a qualitative study of the relationship between adult personality development and how individuals speak about meaning and well-being in their lives. Nineteen participants ranging widely in age and socioeconomic class were selected informally through connections with the researchers, and snowball sampling. They were chosen from an original group of 50, based on informal interviews suggesting that they had achieved Kegan’s developmental levels of “Socialized Mind” (stage 3), or especially “Self-Authoring Mind” (stage 4) or “Self-Transforming Mind” (stage 5). …

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Joe Subbiondo

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Allan Combs

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Ervin Laszlo

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Jim Smith

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Stanley Krippner

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Shelli Joye

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

Reduced Efficacy Of Anti-AΒ Immunotherapy In A Mouse Model Of Amyloid Deposition And Vascular Cognitive Impairment Comorbidity, Erica M. Weekman, Tiffany L. Sudduth, Carly N. Caverly, Timothy J. Kopper, Oliver W. Phillips, David K. Powell, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID …

The Pribram – Bohm Hypothesis Part Ii: The Physiology Of Consciousness, Shelli R. Joye

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

A physiology of consciousness is elaborated, based upon implications of the Pribram-Bohm hypothesis (developed in Part I of this series). The model presented here is in sharp contrast to the prevailing conviction among neuroscientists that consciousness will eventually be discovered to be a physiological epiphenomenon of neuronal electrical impulses firing in the brain. In contrast, the Pribram-Bohm theory holds that consciousness, inherent in what Bohm views cosmologically as “the Whole,” manifests as a dynamic conscious energy resonance bridging the explicate space-time domain with the nonlocal, transcendent flux domain termed the “implicate order.” Presented in Part I, the Pribram-Bohm hypothesis posits …

Integral In-Dwelling: A Prepositional Theology Of Religions, Bruce Alderman

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

The concept of generalized co-presence is a central one in the gram- mar of Bhaskar’s metaRealist metaphysics. As a term denoting the radical relationality and mutual indwelling of beings in the cosmos, generalized co- presence finds analogues in the holographic principle of Morin’s Complex Thought, Wilber’s nondual inflection of holarchy, as well as multiple religious archetypes of divine interindependence. In this paper, I will explore the potential of this concept for framing a “deep participatory,” Complex Integral Realist model of interreligious relationship that can amplify the integrative potential of the metaRealist, Integral, and participatory approaches to this topic that have …

Why Consciousness Matters: Insights From A New Generation, Kathleen Noble

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

The University of Washington-Bothell is home to a transdisciplinary and integral minor in consciousness that is the first and only such program at a public research university. This study reports a content analysis of reflection essays submitted by 122 students who completed at least four of the five courses that comprise the minor between 2012 and 2016. Results indicate that students derived significant benefits from this approach to the study of consciousness, including a deep appreciation for the depth and breadth of the mind and the need to release their understanding of consciousness from the constraints of scientific materialism. They …

Commentaries On Deepak Chopra And Menas Kafatos’ Book, “You Are The Universe”; 2017, Harmony Books., Simon Senzon

CONSCIOUSNESS: Ideas and Research for the Twenty-First Century

No abstract provided.

The Off-Label Use, Utility And Potential Value Of Tdcs In The Clinical Care Of Particular Neuropsychiatric Conditions, Marom Bikson, Bhaskar Paneri, James Giordano

Publications and Research

No abstract provided.