Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

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Genome-wide atlas of gene expression in the adult mouse brain

Chronic exposure to stress hormones, whether it occurs during the prenatal period, infancy, childhood, adolescence, adulthood or aging, has an impact on brain structures involved in cognition and mental health. However, the specific effects on the brain, behaviour and cognition emerge as a function of the timing and the duration of the exposure, and some also depend on the interaction between gene effects and previous exposure to environmental adversity. Advances in animal and human studies have made it possible to synthesize these findings, and in this Review a model is developed to explain why different disorders emerge in individuals exposed to stress at different times in their lives.

Effects of stress throughout the lifespan on the brain, behaviour and cognition

The molecular pathology of Alzheimer's disease.

Converging lines of evidence suggest that progressive accumulation of the amyloid beta-protein (A beta) plays a central role in the genesis of Alzheimer's disease, but it was long assumed that A beta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. Over the past decade, data have emerged from the use of synthetic A beta peptides, cell culture models, beta-amyloid precursor protein transgenic mice and human brain to suggest that pre-fibrillar, diffusible assemblies of A beta are also deleterious. Although the precise molecular identity of these soluble toxins remains unsettled, accumulating evidence suggests that soluble forms of A beta are indeed the proximate effectors of synapse loss and neuronal injury. Here we review recent progress in understanding the role of soluble oligomers in Alzheimer's disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2006.04426.x

A beta oligomers - a decade of discovery.

Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

https://www.jneurosci.org/content/jneuro/25/34/7709.full.pdf

Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory

The present invention relates to methods and probes for detecting relative levels of multiple nucleic acid sequences of interest. The invention includes a method to detect the relative amounts of at least two target nucleic acid sequences in at least one sample by use of a corresponding set of detectably labelled oligonucleotide probes for each of the at least two target nucleic acid sequences, and detecting the hybridization of each of the corresponding sets of oligonucleotide probes to its respective target nucleic acid sequence. The invention also includes a method to detect the relative amounts of multiple target messenger RNAs in at least one microscopy sample by in situ hybridization using sets of oligonucleotide probes. Also disclosed are methods to provide corresponding sets of oligonucleotide probes for target nucleic acid sequences.

Oligonucleotide probe sets and uses thereof

Neuroinformatics: A new tool for studying the brain

Publisher Summary This chapter asserts that even the most active neuroscientist spends more working hours in reading, reviewing, and writing scientific reports than on direct experimental effort. Despite the obvious recognition by all participants in the profession of neuroscience, there have been only a few changes in the habits of scientific information gathering, sharing, and analyzing that have been the traditional standards of neuroscientists. The chapter presents some of the steps that are being taken to harness the flow of scientific data and develop within the community of neuroscientists some means of information handling that rival the sophistication of the instruments and methods by which data are acquired. A program to encourage such research efforts has recently been promulgated by several of the NIH institutes with ultimate international applications in mind. Software is being developed to create and distribute an interactive Brain Object Database of the nervous system oriented within species on the templates representing the pages of a classical brain structural atlas.

Chapter 34 New solutions for neuroscience communications are still needed

Publisher Summary This chapter discusses the multi-dimensional database requirements of brain information in the era of rapid gene identification. The chapter illustrates that even before the recent revolutions in methods to detect Expressed Sequence Tags (ESTs) of brain enriched or brain specific genes, the neurosciences had been moving rapidly, to accumulate data at rates clearly exceeding even a wise scientist's ability to organize and recall. The accelerated pace of molecular discovery has produced estimates that perhaps 97% of the ESTs associated with the major brain genes of mice are already in hand. In addition, the chapter explains the initial steps to harness the flow of neuroscientific data. It also discusses new instruments and methods by which molecular geneticists can now acquire and compare data of utmost pertinence to the brain

Chapter 1.1 The multi-dimensional database requirements of brain information in the era of rapid gene identification

Central nervous system diseases constitute a major target for drug development. Genes expressed by the nervous system may represent half or more of the mammalian genome, with literally tens of thousands of gene products. Better methods are therefore required to accelerate the pace of mapping gene expression patterns in the mouse brain and to evaluate the progressive phenotypic changes in genetic models of human brain diseases. Recent studies of mouse models of amyotrophic lateral sclerosis and Alzheimer's disease illustrate how such data could be used for drug development.

Warren G. Young

Papers

Oligonucleotide probe sets and uses thereof

Neuroinformatics: A new tool for studying the brain

Chapter 34 New solutions for neuroscience communications are still needed

Chapter 1.1 The multi-dimensional database requirements of brain information in the era of rapid gene identification

Neuroinformatics tools for visualizing gene expression in the brain