Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity.

Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e., when circuits or cells do not reach their fully mature state.

Total levels of hippocampal histone acetylation predict normal variability in mouse behavior.

Background: Genetic, pharmacological, and environmental interventions that alter total levels of histone acetylation in specific brain regions can modulate behaviors and treatment responses. Efforts have been made to identify specific genes that are affected by alterations in total histone acetylation and to propose that such gene specific modulation could explain the effects of total histone acetylation levels on behavior - the implication being that under naturalistic conditions variability in histone acetylation occurs primarily around the promoters of specific genes.

Methods/results: Here we challenge this hypothesis by demonstrating with a novel flow cytometry based technique that normal variability in open field exploration, a hippocampus-related behavior, was associated with total levels of histone acetylation in the hippocampus but not in other brain regions.

Studying gene expression system regulation at the program level.

Understanding how gene expression systems influence biological outcomes is an important goal for diverse areas of research. Gene expression profiling allows for the simultaneous measurement of expression levels for thousands of genes and the opportunity to use this information to increase biological understanding. Yet, the best way to relate this immense amount of information to biological outcomes is far from clear.

Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake.

The ability of amylin, a pancreatic β-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward.

Measuring the maturity of the fast-spiking interneuron transcriptional program in autism, schizophrenia, and bipolar disorder.

Background: Emerging evidence suggests that fast-spiking (FS) interneurons are disrupted in multiple neuropsychiatric disorders including autism, schizophrenia, and bipolar disorder. FS cells, which are the primary source of synaptic inhibition, are critical for temporally organizing brain activity, regulating brain maturation, and modulating critical developmental periods in multiple cortical systems. Reduced expression of parvalbumin, a marker of mature FS cells, has been reported in individuals with schizophrenia and bipolar disorder and in mouse models of schizophrenia and autism.

Autism and increased paternal age related changes in global levels of gene expression regulation.

A causal role of mutations in multiple general transcription factors in neurodevelopmental disorders including autism suggested that alterations in global levels of gene expression regulation might also relate to disease risk in sporadic cases of autism. This premise can be tested by evaluating for changes in the overall distribution of gene expression levels. For instance, in mice, variability in hippocampal-dependent behaviors was associated with variability in the pattern of the overall distribution of gene expression levels, as assessed by variance in the distribution of gene expression levels in the hippocampus.

Paternal transmission of complex phenotypes in inbred mice.

Background: Inbred mice are genetically identical but nonetheless demonstrate substantial variability in complex behaviors such as activity levels in a novel environment. This variability has been associated with levels of parental care experienced early in development. Although maternal effects have been reported in biparental and uniparental strains, there have been no investigations of paternal effects in non-biparental strains in which offspring are reared exclusively by mothers.

Is there a genomic tone? Implications for understanding development, adaptation and treatment.

This review examines the general hypothesis that cellular plasticity may be related to genomic plasticity. Using a novel approach to microarray analysis, recent studies from our laboratory showed that, in genetically identical mice, variability in the large-scale organization of gene expression was associated with individual differences in behavior. An association of the large-scale organization of gene expression in the hippocampus with behavioral variability suggests that an important aspect of gene expression regulation had gone unrecognized with traditional genomic approaches designed to look for specific differences in gene expression levels.

Putting a KAP on transcription and stress.

Chromatin regulation plays an important role in brain development and the generation of phenotypic diversity. In this issue of Neuron, Jakobsson et al. find that disruption in neurons of KAP1, a key component of transcriptional repressor complexes in the brain, results in increased anxiety-like behavior and sensitivity to stress.

Variation in the large-scale organization of gene expression levels in the hippocampus relates to stable epigenetic variability in behavior.

Background: Despite sharing the same genes, identical twins demonstrate substantial variability in behavioral traits and in their risk for disease. Epigenetic factors-DNA and chromatin modifications that affect levels of gene expression without affecting the DNA sequence-are thought to be important in establishing this variability. Epigenetically-mediated differences in the levels of gene expression that are associated with individual variability traditionally are thought to occur only in a gene-specific manner.

Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution.

T-cell receptor (TCR) with unique major histocompatibility complex (MHC)-unrestricted antigen-binding properties was isolated from a human T-cell clone specific for the tumor antigen MUC1. This TCR binds its epitope on the MUC1 protein without the requirement of processing and presentation. A single-chain Valpha/Vbeta/Cbeta (scTCR) was fused to a CD3 zeta (zeta) chain to allow expression on the surface of cells of the innate (granulocytes, macrophages, natural killer [NK] cells) as well as the adaptive (T and B cells) immune system.