Robert Berman - US grants

stimulus /response; fetal alcohol syndrome; developmental neurobiology; disease /disorder prevention /control; early diagnosis; pathologic process; embryo /fetus toxicology; sensory deprivation; hippocampus; temporal lobe /cortex; visual stimulus; dendrites; neuroanatomy; psychological reinforcement; experimental designs; laboratory rat; behavior test;

DESCRIPTION (Adapted from applicant's abstract): The search for markers associated with the risk of developing major depression (i.e., associated with a personal history of Major Depressive Disorder (MDD), or a family history of MDD in first-degree relatives) has been relatively unsuccessful to date. Furthermore, there is a lack of reliable trait markers for unipolar major depression. Preliminary data from the investigator's group, presented herein, shows that euthymic, unmedicated subjects with a personal history of major depression commonly experience marked, but transient, depressive reactions induced by catecholamine depletion; whereas, historical controls without a personal or family history do not experience significant mood changes when undergoing catecholamine depletion. Therefore, a depressive reaction induced by catecholamine depletion may represent a reliable marker for a history of prior depression, a vulnerability marker for the development of a consequent depression, and/or a marker of previous treatment. The following aim will begin clarifying the significance of the above findings. Aim: To demonstrate that catecholamine depletion induces a depressive reaction in euthymic, unmedicated subjects with a frequency and intensity that reflects the relative risk of developing a future depressive episode: subjects with a personal history of MDD > subjects without a personal history of MDD but with a positive family history of MDD in first-degree relatives > subjects with neither a personal nor family history of MDD. This aim represents a replication and extension of preliminary findings. Preliminary Data Gathering: Should initial observations be further substantiated, this study will also provide preliminary data for determining the clinical correlates of an induced relapse (e.g., number of previous episodes, age of onset, duration of remission, and, previous use of antidepressant medications or electroconvulsive therapy). Furthermore, preliminary data will be gathered to assess the prognostic utility of this challenge paradigm (i.e., correlation with future clinical relapse). In order to assess feasibility of the latter aim, subjects from each group will be followed prospectively for the duration of the study.

DESCRIPTION: (Adapted from the Investigator's Abstract): Evidence now indicates a critical role for increased intracellular calcium levels in cellular damage and neuronal death after traumatic brain injury (TBI). A major source of increased intracellular calcium is calcium influx through voltage sensitive calcium channels (VSCC). Six major subtypes of VSCC's have been identified, including L, N, P, Q, R and T. Each of these channels has been demonstrated in the mammalian nervous system, and each could contribute importantly to the movement of calcium after TBI. The relative contributions of each calcium channel subtype to calcium-induced neuronal pathology are currently unknown. Such information is vital because the identification of a specific channel or channels that mediate the majority of calcium flux could lead to the development of targeted channel blocking drugs with substantial neuroprotective activity. The proposed experiments will examine the contribution of each VSCC subtype to the histopathological and neurobehavioral consequences of TBI. Specific VSCC blockers will be administered after TBI produced using the lateral fluid percussion injury procedure in rats. The ability of each VSCC to provide histological and neurobehavioral (i.e., cognitive and motor) protection will be compared and evaluated. In addition, the relative roles of each channel subtype in mediating calcium flux from the extracellular compartment will be examined directly by measuring changes in extracellular calcium levels after TBI using the techniques of in vivo microdialysis and calcium sensitive microelectrodes. Calcium-dependent phosphorylation of calcium calmodulin-dependent kinase II (CaMKII) will be examined qualitatively and quantitatively as an index of increased intracellular calcium levels after TBI using immunohistochemistry. Specifically, the ability of VSCC blockers to reduce or prevent increases in intracellular levels of phosphorylated CaMKII after TBI will be evaluated. This research will provide important insights into the mechanisms of brain injury, and specifically the role of disruption of calcium homeostasis. New information about the relative contributions of specific VSCC's to the pathophysiology of TBI will be obtained, and the neuroprotective potential of novel neuronal VSCC blockers will be assessed using histological, biochemical and behavioral techniques. Calcium channel blockers are already in development for various forms of brain injury. This research will therefore provide clinically relevant information concerning the feasibility of their application for the treatment of brain injury in humans, and may indicate new directions for their continued therapeutic development.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affective carriers of premutation forms of the FMR1 gene. FXTAS results in progressive development of tremor, ataxia and neuropsychological problems, including anxiety, memory impairment and dementia. Both the gene and the pathogenic trigger (RNA toxicity) responsible for FXTAS are known;therefore, this disorder represents a promising candidate for development of targeted gene therapies. Development of an effective therapy requires a thorough understanding the cellular mechanisms of the disease, identification of molecular targets for therapy, and development of novel therapeutics that can reach those targets. Project 2 proposes to develop valid mouse models of FXTAS that will allow us, in concert with Project 1, 3 and 4, to systematically explore the underlying disease mechanisms of FXTAS and to identify molecular targets for new therapies. Specifically, we will develop and use transgenic mice that are constructed to model the gene mutation that causes FXTAS (i.e., expanded CGG trinucleotide repeat). We will then use these mice to (1) define critical periods in development for disease onset, (2) identify therapeutic windows for treatment, (3) establish the potential for halting or reversing FXTAS by targeted gene therapies, and (4) test novel therapeutics in mice for their potential to prevent or reverse the development of FXTAS. We will use our existing knock-in mice with expanded CGG trinucleotide .repeats to study the development of disease in mice, and to test novel gene-targeted (i.e., antisense DMA, RNAi) and pharmacological treatments (e.g., lithium, memantine). Additional inducible (tet-on) transgenic mice models will be developed that will enable us to turn off activation of the mutant CGG trinucleotide repeat during development to establish when suppression of abnormal gene expression can halt or reverse disease progression, as well as identify the specific cell types and mechanisms that cause FXTAS. This project, in concert with the other projects within this Consortium, will generate the essential knowledge about the causes of and potential treatments for FXTAS that will provide the foundation for the development of treatments that can halt or reverse the disease.

DESCRIPTION (provided by applicant): The goal is to establish critical developmental ages and molecular targets for treating pathology in Fragile X premutation carriers (PM) and in Fragile X-associated tremor/ataxia (FXTAS) using CGG knock-in mice (CGGex KI) and doxycycline-inducible dox-CGG99 mice. The Fragile X gene (FMR1) is polymorphic for the number of CGG trinucleotide repeats in the 5'-untranslated region. Repeat sizes in the general population range between 5-55 CGG repeats. In Fragile X syndrome (FXS) repeat expansions exceed 200, silencing expression of FMR1 and its protein product FMRP, resulting in mental retardation. Carriers of the FMR1 PM have between 55-200 repeats and were originally thought to be free of pathology. However, several neurological disorders occur in carriers of the PM, including anxiety, depression and mild motor and cognitive impairments. The incidence of the PM in the general population is high, with estimates of 1:250 for females and 1:800 for males, or more than 1.5 million PM carriers in the United States alone. Approximately 40% of male and 8-11% of female PM carriers are also at risk for developing FXTAS, a late onset neurodegenerative disorder causing tremor, ataxia, brain pathology, cognitive loss, dementia and early death in some individuals. Therefore, there is a need to define critical ages when pathology begins, developmental windows when the disorder may be halted or reversed, and the cellular and molecular mechanisms that can be used as therapeutic targets for symptomatic PM carriers and patients with FXTAS. To address these important questions we have developed powerful in vivo and in vitro mouse models of PM and FXTAS, including dox-inducible mice in which expression of a CGG99 repeat expansion can be activated by doxycycline (dox) and then inactivated following dox withdrawal. These mice will be used to establish critical developmental periods when disease processes begin and developmental periods when disease might be halted or reversed. We will also establish whether pathology in astrocytes, neurons or both is necessary and sufficient to cause disease. Finally, we will use these mouse models to test novel treatment strategies using gapmer antisense oligonucleotides (AONs) that may improve neurological function in symptomatic carriers of the PM and in patients with FXTAS.

The project provides partial support for participation in the program "Large-N Methods in Kaehler Geometry" held at the Simons Center for Geometry and Physics (Stony Brook University) from April 20 to June 19, 2015. The large N limit of the project title refers to 1/h where h is Planck's constant, a very small physical constant that measures the importance of quantum mechanical effects in a physical process. Quantum effects are important at the atomic level, but not for macroscopic objects such as cars, whose motion is described by classical mechanics (Newton's laws). As h tends to 0, or N = 1/h tends to infinity, quantum mechanical models tend to classical counterparts. Analogous situations arise in many areas of mathematics and physics whenever there is a large parameter N so that the N tends to infinity limit shares the principal features of the limit as quantum mechanics tends to classical mechanics. In geometry, N represents the degree of a polynomial. In Kaehler geometry, there are special metrics known as Bergman metrics that are analogous to polynomials of degree N. Any metric may be approximated by the polynomial-like Bergman metrics of degree N. The conference is devoted to the many uses of this approximation in geometry and physics, ranging from quantum gravity to the quantum Hall effect.

In Kaehler geometry, the geometric quantization of a Kaehler manifold is the space of holomorphic sections of the Nth power of a positive Hermitian line bundle L over a Kaehler manifold whose curvature form is the Kaehler form. In the Tian-Yau-Donaldson program of relating stability to extremal metrics, a central role is played by the approximation of general Kaehler metrics in the class by Bergman metrics of degree N. The Bergman metrics of degree N are special Kaehler metrics induced by holomorphic embeddings of M into complex projective space of dimension by bases of holomorphic sections of the Nth power of L. The holomorphic embedding is essentially the map z -> B(N, w, z) where B is the Bergman kernel, i.e., the orthogonal projection onto the space of holomorphic sections of the Nth power of L. Bergman kernels and metrics arise in physics as well as geometry. For instance, the Laughlin wave function of the fractional quantum Hall effect on a curved surface is intimately related to the Bergman kernel, with N given by the number of electrons on the surface. Bergman kernels and metrics also give a new approach to defining probability measures on the space of all Kaehler metrics, which is expected to be related to quantum gravity. This program focuses on holomorphic stochastic geometry and mathematical physics.

Conference web site:
scgp.stonybrook.edu/scientific/programs/fall-2014-spring-2015-program-details/large-n-limit-problems-in-kahler-geometry