Medical Sciences Commons^™

Neural Responses To Naturalistic Clips Of Behaving Animals Under Two Different Task Contexts, Samuel A. Nastase, Yaroslav O. Halchenko, Andrew C. Connolly, M. Ida Gobbini, James V. Haxby

Dartmouth Scholarship

The human brain rapidly deploys semantic information during perception to facilitate our interaction with the world. These semantic representations are encoded in the activity of distributed populations of neurons (Haxby et al., 2001; McClelland and Rogers, 2003; Kriegeskorte et al., 2008b) and command widespread cortical real estate (Binder et al., 2009; Huth et al., 2012). The neural representation of a stimulus can be described as a location (i.e., response vector) in a high-dimensional neural representational space (Kriegeskorte and Kievit, 2013; Haxby et al., 2014). This resonates with behavioral and theoretical work describing mental representations of objects and actions as being …

Closed-Loop Stimulation Of Temporal Cortex Rescues Functional Networks And Improves Memory, Yousseff Ezzyat, Paul A. Wanda, Deborah F. Levy, Allison Kadel, Ada Aka, Isaac Pedisich, Michael R. Sperling, Ashwini D. Sharan, Bradley C. Lega, Alexis Burks, Robert E. Gross, Cory S. Inman, Barbara C. Jobst, Mark A. Gorenstein

Dartmouth Scholarship

Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target …

Anxiety Associated Increased Cpg Methylation In The Promoter Of Asb1: A Translational Approach Evidenced By Epidemiological And Clinical Studies And A Murine Model, Rebecca T. Emeny, Jens Baumert, Anthony S. Zannas, Sonja Kunze, Simone Wahl, Stella Iurato

Dartmouth Scholarship

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n= 1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited …

5-Hydroxymethylcytosine Localizes To Enhancer Elements And Is Associated With Survival In Glioblastoma Patients, Kevin C. Johnson, E. Andres Houseman, Jessica E. King, Katharine M. Von Herrmann, Camilo E. Fadu, Brock C. Christensen

Dartmouth Scholarship

Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. Here, we resolve genome-wide 5-methylcytosine and 5-hydroxymethylcytosine in glioblastoma through parallel processing of DNA with bisulfite and oxidative bisulfite treatments. We apply a statistical algorithm to estimate 5-methylcytosine, 5-hydroxymethylcytosine and unmethylated proportions from methylation array data. We show that 5-hydroxymethylcytosine is depleted in glioblastoma compared with prefrontal cortex tissue. In addition, the genomic localization of 5-hydroxymethylcytosine in glioblastoma is associated with features of dynamic cell-identity regulation such as tissue-specific transcription and super-enhancers. Annotation of 5-hydroxymethylcytosine genomic distribution reveal significant associations with RNA regulatory processes, immune function, stem cell maintenance and …

Non-Alcoholic Fatty Liver Disease Induces Signs Of Alzheimer’S Disease (Ad) In Wild-Type Mice And Accelerates Pathological Signs Of Ad In An Ad Model, Do-Geun Kim, Antje Krenz, Leon E. Toussaint, Kirk J. Maurer

Dartmouth Scholarship

Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world's population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD.

Methods: WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another …

Immunomodulatory Activity Of Interferon-Beta, Lloyd H. Kasper, Anthony T. Reder

Dartmouth Scholarship

Multiple sclerosis (MS) is a complex disorder of the central nervous system that appears to be driven by a shift in immune functioning toward excess inflammation that results in demyelination and axonal loss. Beta interferons were the first class of disease-modifying therapies to be approved for patients with MS after treatment with this type I interferon improved the course of MS on both clinical and radiological measures in clinical trials. The mechanism of action of interferon-beta appears to be driven by influencing the immune system at many levels, including antigen-presenting cells, T cells, and B cells. One effect of these …

Prolonged Febrile Seizures Cause Reversible Reductions In White Matter Integrity☆, M. Yoong, K. Seunarine, M. Martinos, R. F. Chin, C. A. Clark, R. C. Scott

Dartmouth Scholarship

Prolonged febrile seizures (PFS) are the commonest cause of childhood status epilepticus and are believed to carry a risk of neuronal damage, in particular to the mesial temporal lobe. This study was designed to determine: i) the effect of prolonged febrile seizures on white matter and ii) the temporal evolution of any changes seen.

33 children were recruited 1 month following PFS and underwent diffusion tensor imaging (DTI) with repeat imaging at 6 and 12 months after the original episode of PFS. 18 age-matched healthy control subjects underwent similar investigations at a single time point. Tract-based spatial statistics (TBSS) was …

Neuroinflammation And Psychiatric Illness, Souhel Najjar, Daniel M. Pearlman, Kenneth Alper, Amanda Najjar, Orrin Devinsky

Dartmouth Scholarship

Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. While systemic autoimmune diseases are well-documented causes of neuropsychiatric disorders, synaptic autoimmune encephalitides with psychotic symptoms often go under-recognized. Parallel to the link between psychiatric symptoms and autoimmunity in autoimmune diseases, neuroimmunological abnormalities occur in classical psychiatric disorders (for example, major depressive, bipolar, schizophrenia, and obsessive-compulsive disorders). Investigations into the pathophysiology of these conditions traditionally stressed dysregulation of the glutamatergic and monoaminergic systems, but the mechanisms causing these neurotransmitter abnormalities remained elusive. We review the link between autoimmunity and neuropsychiatric disorders, and the human and experimental evidence …

Impairment Of Trkb-Psd-95 Signaling In Angelman Syndrome, Cong Cao, Mengia S. Rioult-Pedotti, Paolo Migani, Crystal J. Yu, Rakesh Tiwari, Keykavous Parang, Mark R. Spaller

Dartmouth Scholarship

Angelman syndrome (AS) is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP) in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF) …

Strain-Dependent Variation In The Early Transcriptional Response To Cns Injury Using A Cortical Explant System, David J. Graber, Brent T. Harris, William F. Hickey

Dartmouth Scholarship

While it is clear that inbred strains of mice have variations in immunological responsiveness, the influence of genetic background following tissue damage in the central nervous system is not fully understood. A cortical explant system was employed as a model for injury to determine whether the immediate transcriptional response to tissue resection revealed differences among three mouse strains. Immunological mRNAs were measured in cerebral cortex from SJL/J, C57BL/6J, and BALB/cJ mice using real time RT-PCR. Freshly isolated cortical tissue and cortical sections incubated in explant medium were examined. Levels of mRNA, normalized to β-actin, were compared using one way analysis …

Progressive Changes In Microglia And Macrophages In Spinal Cord And Peripheral Nerve In The Transgenic Rat Model Of Amyotrophic Lateral Sclerosis, David J. Graber, William F. Hickey, Brent T. Harris

Dartmouth Scholarship

The role of neuroinflammation in motor neuron death of amyotrophic lateral sclerosis (ALS) is unclear. The human mutant superoxide dismutase-1 (hmSOD1)-expressing murine transgenic model of ALS has provided some insight into changes in microglia activity during disease progression. The purpose of this study was to gain further knowledge by characterizing the immunological changes during disease progression in the spinal cord and peripheral nerve using the more recently developed hmSOD1 rat transgenic model of ALS. Using immunohistochemistry, the extent and intensity of tissue CD11b expression in spinal cord, lumbar nerve roots, and sciatic nerve were evaluated in hmSOD1 rats that were …

Prion Protein Glycosylation Is Not Required For Strain-Specific Neurotropism, Justin R. Piro, Brent T. Harris, Koren Nishina, Claudio Soto, Rodrigo Morales, Judy R. Rees, Surachai Supattapone

Dartmouth Scholarship

In this study, we tested the hypothesis that the glycosylation of the pathogenic isoform of the prion protein (PrP^Sc) might encode the selective neurotropism of prion strains. We prepared unglycosylated cellular prion protein (PrP^C) substrate molecules from normal mouse brain by treatment with PNGase F and used reconstituted serial protein cyclic misfolding amplification reactions to produce RML and 301C mouse prions containing unglycosylated PrP^Sc molecules. Both RML- and 301C-derived prions containing unglycosylated PrP^Sc molecules were infectious to wild-type mice, and neuropathological analysis showed that mice inoculated with these samples maintained strain-specific patterns of PrP …

The Cns Role Of Toll-Like Receptor 4 In Innate Neuroimmunity And Painful Neuropathy, Flobert Y. Tanga, Nancy Nutile-Mcmenemy, Joyce A. Deleo

Dartmouth Scholarship

Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and …