The mammalian central nervous system (CNS) contains a remarkable array of neural cells, each with a complex pattern of connections that together generate perceptions and higher brain functions. Here we describe a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes and pathways. We illustrate the use of this atlas to derive novel insights into gene function in neural cells, and into principal steps of CNS development. The atlas, library of BAC vectors and BAC transgenic mice generated in this screen provide a rich resource that allows a broad array of investigations not previously available to the neuroscience community.

Background and Purpose-One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. Methods-The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. Results-The results of these discussions are reported herein. Conclusions-The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.

Background and Purpose-This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review-The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Conclusions-Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these. (Stroke. 2009;40:e694-e702.)

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.

During the past decade, substantial progress has been made in delineating clinical features of the epilepsies and the basic mechanisms responsible for these disorders. Eleven human epilepsy genes have been identified and many more are now known from animal models. Candidate targets for cures are now based upon newly identified cellular and molecular mechanisms that underlie epileptogenesis. However, epilepsy is increasingly recognized as a group of heterogeneous syndromes characterized by other conditions that co-exist with seizures. Cognitive, emotional and behavioral co-morbidities are common and offer fruitful areas for study. These advances in understanding mechanisms are being matched by the rapid development of new diagnostic methods and therapeutic approaches. This article reviews these areas of progress and suggests specific goals that once accomplished promise to lead to cures for epilepsy.

It has been postulated that the developing sympathetic innervation of rat eccrine sweat glands changes from adrenergic to cholinergic under the influence of its target. In agreement with previous evidence that the sympathetic innervation of adult rat sweat glands is cholinergic, we found that choline acetyltransferase (CAT)-immunoreactive nerve fibers are present in adult glands, and that gland-rich chunks of adult footpads contain CAT enzyme activity. We were therefore interested in determining when CAT activity is first expressed in the developing gland innervation. Low levels of acetylating activity were observed in rat footpads as early as postnatal day 4, when sympathetic fibers first contact the glands. A greater than fourfold increase in CAT specific activity occurred between postnatal days 11 and 21. Neonatal treatment of rats with the adrenergic neurotoxin 6-hydroxydopamine (6-OHDA) eliminated most of the CAT activity in 14 and 19 d footpads. In contrast, the acetylating activity observed prior to day 11 was unaffected by neonatal 6-OHDA treatment, and only slightly reduced by the selective CAT inhibitor, naphthylvinylpyridine. These results indicate that the sympathetic fibers that innervate rat sweat glands do not acquire detectable levels of CAT activity until a full week after they contact the glands.

Neuropeptide Y (NPY) is widely distributed in the sympathetic nervous system, where it is colocalized with norepinephrine. We report here that NPY-immunoreactive neurons are also abundant in three cranial parasympathetic ganglia, the otic, sphenopalatine, and ciliary, in the rat. Neuropeptide Y (NPY) is structurally related to members of the pancreatic polypeptide family but appears to be localized exclusively in central and peripheral neurons (1, 2). In the periphery, NPY is present in sympathetic neurons that innervate the vasculature (3, 4), heart (5, 6), urogenital tract (3, 7), and iris (8). A number of biological actions have been reported for NPY, including a potent vasoconstrictor action on peripheral and cerebral vessels (3, 4, 9) and inhibition of synaptic transmission in the vas deferens, uterus, urinary bladder, and heart (3, 10, 11). NPY may therefore act as a neuromodulator in the sympathetic nervous system. NPY-immunoreactive sympathetic neurons contain the catecholamine-synthetic enzymes tyrosine hydroxylase [TyrOHase; L-tyrosine,tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] and dopamine ,3-hydroxylase [3,4-dihydroxyphenethylamine,ascorbate:oxygen oxidoreductase (l3-hydroxylating), EC 1.14.17.1], indicating that NPY is colocalized with norepinephrine in these neurons (3,(12)(13)(14). In contrast, there is little overlap between populations of sympathetic neurons that contain NPY and those that contain vasoactive intestinal polypeptide (VIP) (12, 14). The minority population of sympathetic neurons that contain VIP has been found to lack catecholamine-synthetic enzymes; as is the case for VIP-containing parasympathetic neurons, there is evidence that at least some of the neurons in this population are cholinergic (12,15,16). The notion has emerged from these studies that coexpression of NPY with norepinephrine, and of VIP with acetylcholine, is an organizational principle in the autonomic nervous system (14).To explore further the relationship between NPY expression and the expression ofother neurotransmitter phenotypes in autonomic neurons, we have examined cranial parasympathetic neurons for the presence of NPY. The present work shows that NPY-immunoreactive neurons are abundant in rat cranial parasympathetic ganglia and examines the colocalization of NPY immunoreactivity with TyrOHase, VIP, and the cholinergic enzyme choline acetyltransferase (ChoAcTase; acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6) in these neurons.MATERIALS AND METHODS Cytochemistry. The NPY antiserum (Amersham) was raised in rabbit against synthetic porcine NPY. The VIP antiserum, a gift from P. Hogan (Harvard Medical School), was raised in rabbit against a carbodiimide conjugate of synthetic VIP (Boehringer Mannheim) to bovine serum albumin. The TyrOHase antiserum, a gift from J. Thibault, was raised in rabbit against TyrOHase purified from rat pheochromocytoma tumors (17). The ChoAcTase antiserum, a gift from F. Eckenstein, was raised in mouse against ChoAcTase purified from pig ...