DMM: A MULTIGROUP, MULTIREGION, ONE-SPACE-DIMENSIONAL COMPUTER PROGRAM USING NEUTRON DIFFUSION THEORY. PART I. THE THEORY. Final Report

DMM is a program using one-space-dimensional multigroup diffusion theory to calculate the reactivity or critical conditions and flux distribution of a multiregion reactor. Calculations of fission-produced xenon and samarium and time variation due to production and depletion of isotopes are an essential part of this program. The adjoint fluxes may also be computed, and the program includes the calculation of the nuclear constaants from fairly simple input combined with a library of cross sections. The present code is written for the Remington Rand 1103A. Operating instructions are presented in Part II. (auth

SIRT1-FOXO3a Regulate Cocaine Actions in the Nucleus Accumbens

Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action.National Institute on Drug AbuseNational Alliance for Research on Schizophrenia and Depression (U.S.)UNCF-Merc

SIRT1-FOXO3a Regulate Cocain Actions in the Nucleus Accumbens

Previous studies have shown that chronic cocain administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocain (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocain causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) familty to be a downstream mechanis through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action

Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocain and Morphine Action

Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological conditions remains poorly understood. Here, we establish an essential role for brain reward region. We show that chronic cocain administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor ΔFosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocain and morphine. In contrast, the local knockdown of SIRT1 from the NAc of floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point towards novel signaling pathways involved in drug action

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior

Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here, we show that repeated cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. We show further, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1, or local knockout of Rac1 from floxed Rac1 mice, is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 mutant, or light activation of a photoactivatible form of Rac1, blocks the ability of repeated cocaine to produce this effect. Downregulation of Rac1 activity in nucleus accumbens likewise promotes behavioral responses to cocaine, with Rac1 activation producing the opposite effect. These findings establish an important role for Rac1 signaling in mediating structural and behavioral plasticity to cocaine

Remodeling neuroendocrine receptors to enhance cognitive function and decrease stress-induced anxiety and memory impairments with herpes simplex viral vectors

Glucocorticoids (GCs) a hormone released from the adrenal glands during the stress response modulates hippocampal function, a brain region important for memory and learning. The modulatory affects of GCs on hippocampal function are thought to be mediated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The GRs plays a critical role in mediating the impairing effects of GCs on hippocampal function. Conversely, activation of MRs facilitates hippocampal function. Mineralocorticoid receptors (MRs) have extremely high affinity for corticosteroid and are consequently tonically occupied. As a result of MRs' high affinity and tonic occupation its functional dynamic range was considered to be minimal. Thus, the contribution of this receptor in modulating the cognitive effects of stress was considered to be trivial. An important question addressed by my thesis was: (1) is it possible to modulate the dynamic range of a receptor that is tonically occupied and (2) if so what are the functional consequences of increasing MR's dynamic range during the acquisition, consolidation, and retrieval phase of a spatial and non spatial hippocampal-dependent task, during basal and high corticosteroid conditions. Using herpes simplex vectors, simultaneously manipulated both MR and GR signaling in the dentate gyrus of the hippocampus, which in turn increased MR signaling. My studies revealed an enhancement in spatial and nonspatial memory consolidation in animals overexpressing MR protein. Moreover, rats overexpressing MR or a negative transdominant GR (TD) were spared from the disruptive effects of high GCs on the retrieval of spatial and nonspatial memory. Thus, this thesis illustrates the potential of viral vectors overexpressing MR to mediate cognitive function. In addition, I evaluated the functional impact of an increase in MR's dynamic range on measures of anxiety. Anxiety-related disorders are closely linked to stress. GCs, acting through GR or MR can influence neuropsychiatric disorders. In the present thesis, I bilaterally over-expressed either one or two copies of the MR gene in the dentate gyrus of the hippocampus and determined its effect on the open field (OF) and elevated plus maze (EPM), two established models of anxiety. I demonstrated that overexpression of two copies of MR ("MR/MR") blocked the stress induced decline in open arm exploration. These results demonstrate that over-expression of MR in the hippocampus blocks the anxiolytic effects of stress and suggest that MR may serve as a potential molecular target for novel therapeutic agents. The results from my thesis support the use of viral vectors to safely and efficiently deliver selective genes to the CNS of living animals; facilitating the study of very sensitive behaviors such as learning/memory and anxiety

A Geometric Perspective on First-Passage Competition

Thesis (Ph.D.)--University of Washington, 2012We study the macroscopic geometry of first-passage competition on the integer lattice Zd, with a particular interest in describing the behavior when one species initially occupies the exterior of a cone. First-passage competition is a stochastic process modeling two infections spreading outward from initially occupied disjoint subsets of Zd. Each infecting species transmits its infection at random times from previously infected sites to neighboring uninfected sites. The infection times are governed by species-specific probability distributions, and every vertex of Zd remains permanently infected by whichever species infects it first. We introduce a new, simple construction of first-passage competition that works for an arbitrary pair of disjoint starting sets in Zd, and we analogously define a deterministic first-passage competition process in the Euclidean space Rd, providing a formal definition for a model of crystal growth that has previously been studied computationally. We then prove large deviations estimates for the random Zd-process, showing that on large scales it is well-approximated by the deterministic Rd-process, with high probability. Analyzing the geometry of the deterministic process allows us to identify critical phenomena in the random process when one of the two species initially occupies the entire exterior of a cone and the other species initially occupies a single interior site. Our results generalize those in a 2007 paper of Deijfen and Haggstrom, who considered the case where the cone is a half-space. Moreover, we use our results about competition in cones to strengthen a 2000 result of Haggstrom and Pemantle about competition from finite starting configurations

DMM: A Multigroup, Multiregion, One-Space-Dimensional Computer Program Using Neutron Diffusion Theory. Part 1 - The Theory

DMM is a program using one-space-dimensional multigroup diffusion theory to calculate the reactivity or critical conditions and flux distribution of a multiregion reactor. Calculations of fission-produced xenon and samarium and time variation due to production and depletion of isotopes are an essential part of this program. The adjoint fluxes may also be computed, and the program includes the calculation of the nuclear constaants from fairly simple input combined with a library of cross sections. The present code is written for the Remington Rand 1103A. Operating instructions are presented in Part II. (auth