Mapping reward mechanisms by intracerebral self-stimulation in the rhesus monkey (Macaca mulatta).

The objective of the study was to identify brain structures that mediate reward as evidenced by positive reinforcing effects of stimuli on behavior. Testing by intracerebral self-stimulation enabled monkeys to inform whether activation of ~2900 sites in 74 structures of 4 sensorimotor pathways and 4 modulatory loop pathways was positive, negative or neutral. Stimulation was rewarding at 30% of sites, negative at 17%, neutral at 52%. Virtually all (99%) structures yielded some positive or negative sites, suggesting a ubiquitous distribution of pathways transmitting valence information. Mapping of sites to structures with dense versus sparse dopaminergic (DA) or noradrenergic (NA) innervation showed that stimulation of DA-pathways was rewarding or neutral. Stimulation of NA-pathways was not rewarding. Stimulation of association areas was generally rewarding; stimulation of purely sensory or motor structures was generally negative. Reward related more to structures' sensorimotor function than to density of DA-innervation. Stimulation of basal ganglia loop pathways was rewarding except in lateral globus pallidus, an inhibitory structure in the negative feedback loop; stimulation of the cerebellar loop was rewarding in anterior vermis and the spinocerebellar pathway; and stimulation of the hippocampal CA1 loop was rewarding. While most positive sites were in the DA reward system, numerous sites in sparsely DA-innervated posterior cingulate and parietal cortices may represent a separate reward system. DA-density represents concentrations of plastic synapses that mediate acquisition of new synaptic connections. DA-sparse areas may represent innate, genetically programmed reward-associated pathways. Implications of findings in regard to response habituation and addiction are discussed.

Creating neuroscience ontologies.

The insufficiency of terminological standards in neuroscience is increasingly recognized as a serious obstacle to interoperability. Adoption of a controlled vocabulary is a successful solution for small numbers of groups that work closely together but is impractical for large numbers of groups who represent diverse areas of research, index information by various legitimate nomenclatures, or publish in different languages. Interoperability among such disparate databases requires a translation mechanism, or "mediator," to enable communication and data sharing among databases. Shared ontologies are essential components of a mediator. An ontology codifies the relations between terms of multiple nomenclatures and the concepts they represent. Neuroanatomy is central to neuroscience, and neuroanatomical terminology represents a core portion of the vocabulary of neuroscience. We have created in NeuroNames an ontology of 2500 neuroanatomical concepts referenced by 15,000 terms in seven languages. NeuroNames is the mediator for BrainInfo, a portal to neuroanatomy on the Web. We hope that a description of our experience in establishing interoperability between BrainInfo and other neuroscience Web sites may be useful to others engaged in the development of ontologies for neuroscience.

NeuroNames 2002.

NeuroNames is a nomenclature designed as a tool for indexing digital databases of neuroscientific information. It can be used, for example, as the entry point to a digital dictionary of neuroanatomy, to a brain atlas, or to a database of information referenced to specific brain structures. The user can query with terms from many different nomenclatures. One can create a neuroanatomic ontology from NeuroNames by relating an appropriate subset of terms to a conceptual model represented by structures illustrated in a brain atlas. At the conceptual core of NeuroNames are primary structures, the elementary units of the brain in the spatial domain. Each primary structure is associated with a set of synonyms that represent the structure in the symbolic domain. One of the synonyms is designated the default name for use in verbal definitions of other structures. A unique abbreviation based on the default name is provided for labeling images. Neuroscientists classify structures in different contexts reflecting different attributes of interest. Thus, the name of a given structure can appear in any number of hierarchical contexts. In NeuroNames all primary structures are now represented in at least two hierarchies. The first is a nine-level "Brain Hierarchy," in which volumetric structures are grouped by proximity to form successively larger units that represent the brain at different levels of dissection. Secondly, primary structures are categorized in a three-level "spatial attribute hierarchy" used to color- code them for visual display. Grouped structures in the nine-level volumetric hierarchy are designated superstructures, each of which has synonyms, a default term, and an abbreviation. All names of structures not in the hierarchy are designated ancillary terms and are defined in words using the default names of hierarchy structures. With NeuroNames as entry point, we have developed BrainInfo (http://braininfo.rprc.washington.edu), a website that allows searchers to proceed intuitively in a few steps to descriptions and images of specific structures. Currently NeuroNames resides in a Microsoft ACCESS database and includes some 12,200 terms in seven languages.

Behavioral responses of longtailed macaques to different cage sizes and common laboratory experiences.

The authors tested the effects of varying cage size on the behavior of 10 female and 10 male Macaca fascicularis by singly caging them for 2 weeks in each of 5 cage sizes, ranging from approximately 20% to 148% of regulation size. Behavior in the regulation cage size, a size 23% smaller, and a size 48% larger did not differ in any analysis. Locomotion was significantly less in the 2 smallest cage sizes. Abnormal behavior occurred only 5% of the time, did not increase as cage size decreased, and did not change significantly over nearly 3 years. Disruption of the normal activity budget in the laboratory environment proved to be a useful indicator of psychological well-being. Moving to a new room and, to a lesser extent, moving into a new, clean cage, regardless of size, was associated with disrupted sleep the 1st night and suppressed activity, especially self-grooming, the next day.

Urinary cortisol responses of longtailed macaques to five cage sizes, tethering, sedation, and room change.

Urinary free cortisol responses to five cage sizes, cage level, room change, tethering adaptation, chronic catheterization, and ketamine sedation were measured in 14 female and 14 male wild-born adult Macaca fascicularis. Urinary free cortisol, a physiological measure of psychological well-being that can be collected unobtrusively, provided a measure of the animals' general adrenocortical response to various conditions over a time course of hours. Urinary free cortisol values in response to stimulation with adrenocorticotropic hormone (ACTH) validated the measure as a reflection of blood values. Cortisol values were expressed as a ratio to creatinine, which normalized for differences in urinary output and body weight (muscle mass). Cage size (20-140% of regulation floor area) and housing level (upper vs. lower cage) had no effect on stress, as measured by cortisol excretion. Room change elicited a slight increase in cortisol excretion for the first day, but not to a level suggesting stress. Sedation, surgery, some aspects of tethering adaptation, and chronic catheterization produced urinary cortisol evidence of stress. Even so, animals varied in their responses and all showed adaptation. Males and females did not differ in normal mean values but females tended to have higher cortisol levels in response to potential stressors investigated in this study. Cortisol levels continued to decline gradually throughout the study. © 1993 Wiley-Liss, Inc.

Sex differences in compatibility of pair-housed adult longtailed macaques.

This research was designed to evaluate the effects of same-sex pair housing on the psychological well-being of adult wild-born longtailed macaques (Macaca fascicularis). We studied behavioral compatibility and stress as measured by urinary cortisol excretion in 15 pairs of each sex. Before they were housed together, the pairs were categorized by noncontact pairedpreference testing as preferred, nonpreferred, or randomly assigned partners. Every aspect of data analysis indicated that the success of pairing was strongly related to gender. Whereas 100% of female pairs were compatible, only eight of the 15 male pairs were still together after two weeks, and only five (33%) showed a degree of compatibility resembling that of females. The psychological well-being of virtually all females seemed to be improved during the physical contact paired-housing conditions; they spent more than one-third of the day engaged in social grooming. Paired adult males had much lower interaction rates than adult females. On average, males were initially somewhat stressed by the introduction to a cagemate as indicated by increased urinary cortisol excretion. The noncontact preference testing procedure was no more predictive of pair success than random assignment. For males, the presence of fighting combined with the absence of grooming during the first 90 min opportunity for physical contact ("introduction") was associated with pair incompatibility, but not to a statistically significant extent. For research protocols permitting social grouping of this species, the social contact requirement of the USDA Animal Welfare Rules usually can be met for adult females by pair housing. For males, pairing with other adult males often is unsuccessful; by our estimates, at least 20% of males cannot be pair-housed with other males. These sex differences in response to same-sex adults are consistent with the known socioecology of macaques. Further research is necessary to determine whether adult males have a lower need for social contact than females, or whether their needs are better met by other types of social contact. © 1994 Wiley-Liss, Inc.

Relations among whole blood serotonin and sex, age, diet, and social status in Macaca nemestrina.

Whole blood serotonin (WBS) determinations were made in 56 pigtailed macaques (Macaca nemestrina) with approximately equal numbers in three age groups: young-adult (4-5 years), middle-aged (13-14 years), and old (over 18 years). The animals were housed in ten living groups with one female and male of each age group in each living group. Half of the groups were fed a diet high in lipid, cholesterol, simple sugars, and sodium; the other half received a restricted diet. Three determinations per animal showed WBS levels to be stable at two times of day and at a 1-week interval, and individual differences were stable over several months' time. The mean WBS concentrations in M. nemestrina were found to be considerably higher than those reported for other species. The mean levels in females were almost 25% higher than in males. No significant effects of age, diet, or dominance status were detected.

NeuroNames: an ontology for the BrainInfo portal to neuroscience on the web.

BrainInfo ( http://braininfo.org ) is a growing portal to neuroscientific information on the Web. It is indexed by NeuroNames, an ontology designed to compensate for ambiguities in neuroanatomical nomenclature. The 20-year old ontology continues to evolve toward the ideal of recognizing all names of neuroanatomical entities and accommodating all structural concepts about which neuroscientists communicate, including multiple concepts of entities for which neuroanatomists have yet to determine the best or 'true' conceptualization. To make the definitions of structural concepts unambiguous and terminologically consistent we created a 'default vocabulary' of unique structure names selected from existing terminology. We selected standard names by criteria designed to maximize practicality for use in verbal communication as well as computerized knowledge management. The ontology of NeuroNames accommodates synonyms and homonyms of the standard terms in many languages. It defines complex structures as models composed of primary structures, which are defined in unambiguous operational terms. NeuroNames currently relates more than 16,000 names in eight languages to some 2,500 neuroanatomical concepts. The ontology is maintained in a relational database with three core tables: Names, Concepts and Models. BrainInfo uses NeuroNames to index information by structure, to interpret users' queries and to clarify terminology on remote web pages. NeuroNames is a resource vocabulary of the NLM's Unified Medical Language System (UMLS, 2011) and the basis for the brain regions component of NIFSTD (NeuroLex, 2011). The current version has been downloaded to hundreds of laboratories for indexing data and linking to BrainInfo, which attracts some 400 visitors/day, downloading 2,000 pages/day.

The INIA19 Template and NeuroMaps Atlas for Primate Brain Image Parcellation and Spatial Normalization.

The INIA19 is a new, high-quality template for imaging-based studies of non-human primate brains, created from high-resolution, T(1)-weighted magnetic resonance (MR) images of 19 rhesus macaque (Macaca mulatta) animals. Combined with the comprehensive cortical and sub-cortical label map of the NeuroMaps atlas, the INIA19 is equally suitable for studies requiring both spatial normalization and atlas label propagation. Population-averaged template images are provided for both the brain and the whole head, to allow alignment of the atlas with both skull-stripped and unstripped data, and thus to facilitate its use for skull stripping of new images. This article describes the construction of the template using freely available software tools, as well as the template itself, which is being made available to the scientific community (http://nitrc.org/projects/inia19/).

A symmetrical Waxholm canonical mouse brain for NeuroMaps.

NeuroMaps (2010) is a Web-based application that enables investigators to map data from macaque studies to a canonical atlas of the macaque brain. It currently serves as an image processor enabling them to create figures suitable for publication, presentation and archival purposes. Eventually it will enable investigators studying any of several species to analyze the overlap between their data and multimodality data mapped by others. The purpose of the current project was to incorporate the Waxholm canonical mouse brain (Harwylycz, 2009) into NeuroMaps. An enhanced gradient echo (T2*) magnetic resonance image (MRI) of the Waxholm canonical brain (Johnson et al., 2010) was warped to bring the irregular biological midplane of the MRI into line with the mathematically flat midsagittal plane of the Waxholm space. The left hemisphere was deleted and the right hemisphere reflected to produce a symmetrical 3D MR image. The symmetrical T2* image was imported into NeuroMaps. The map executing this warp was applied to four other voxellated volumes based on the same canonical specimen and maintained at the Center for In-Vitro Microscopy (CIVM): a T2-weighted MRI, a T1-weighted MRI, a segmented image and an image reconstructed from Nissl-stained histological sections of the specimen. Symmetric versions of those images were returned to the CIVM repository where they are made available to other laboratories. Utility of the symmetric atlas was demonstrated by mapping and comparing a number of cortical areas as illustrated in three conventional mouse brain atlases. The symmetric Waxholm mouse brain atlas is now accessible in NeuroMaps where investigators can map image data to standard templates over the Web and process them for publication, presentation and archival purposes: http://braininfo.rprc.washington.edu/MapViewData.aspx.

Development of the area postrema: an immunohistochemical study in the macaque.

The organization and chemical development of the area postrema (AP) in the macaque monkey was studied by immunohistochemistry imaged with conventional and confocal microscopy from day 40 of gestation to adulthood. The thin ependyma of the adult was found to develop from a thick continuous structure beginning in the second trimester. It was later invaded by tyrosine hydroxylase immunoreactive (TH+) and dopamine beta-hydroxylase immunoreactive (DBH+) cells and fibers, suggesting a possible route for release of neurotransmitter directly into ventricular cerebrospinal fluid. Other TH+ and/or DBH+ fibers were found in close approximation to blood vessels. Prominent vascularity of the parenchyma of AP was present late in the first trimester (fetal day (Fd)57 in the macaque) and increased further until birth. By contrast, the underlying solitary nucleus was hypervascular at Fd57, but its vascularity rapidly declined by late in the second trimester. TH+ neurons first appeared late in the first trimester, and DBH+ neurons appeared in the second trimester; these findings are consistent with the view that catecholaminergic cells in AP are the earliest members of the A2 noradrenergic group. Catecholaminergic cells or fibers in AP contained little labeling for synaptic vesicular proteins, suggesting that the release of neurotransmitter there may not involve a synaptic mechanism. Synapses were first observed in mid-second trimester, and most were associated with GABA+ fibers.

The neuroscience information framework: a data and knowledge environment for neuroscience.

With support from the Institutes and Centers forming the NIH Blueprint for Neuroscience Research, we have designed and implemented a new initiative for integrating access to and use of Web-based neuroscience resources: the Neuroscience Information Framework. The Framework arises from the expressed need of the neuroscience community for neuroinformatic tools and resources to aid scientific inquiry, builds upon prior development of neuroinformatics by the Human Brain Project and others, and directly derives from the Society for Neuroscience's Neuroscience Database Gateway. Partnered with the Society, its Neuroinformatics Committee, and volunteer consultant-collaborators, our multi-site consortium has developed: (1) a comprehensive, dynamic, inventory of Web-accessible neuroscience resources, (2) an extended and integrated terminology describing resources and contents, and (3) a framework accepting and aiding concept-based queries. Evolving instantiations of the Framework may be viewed at http://nif.nih.gov , http://neurogateway.org , and other sites as they come on line.