Human Brain Software

Flash Brain Anatomy

This course gives you access to a full online course and software to learn more about the brain than you ever thought possible in a short amount of time. This software contains detailed, 3D brain models, animations to display concepts, hundreds of educational courses, a neuroanatomy atlas, and compatibility with most web browsers. You will also have access to a full online suite of tutors. Neuroanatomy is one of the hardest parts of anatomy to learn, and learning the brain will really be a lot easier if you had a detailed model to base your knowledge off. This software makes the brain as simple as possible, while also giving you a way to learn it throughly. This model simplifies a very complex subject that most people struggle with Don't be one of the people that doesn't know what to do with the brain model! This course is designed to teach you everything about the brain while keeping the lessons manageable and learning at your own pace. Read more...

Flash Brain Anatomy Summary

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Highly Recommended

The interface is user friendly with its intuitive layout. Also, the addition of the prompt, with expert advice sets it apart from all the other similar programs. The Flash Brain Anatomy installation process is clean and without any unpleasant surprises like hidden toolbars, adds or anything like that. However, the installation process takes a bit longer than expected and you actually have to go through ten steps before the installation is complete, but that can hardly be considered a downside though.

I personally recommend to buy this software. The quality is excellent and for this low price and 100% Money back guarantee, you have nothing to lose.

Only a Glimpse The Complexity of the Human Brain

This chapter provides just a tiny sample of the complexity of the variegated structures and chemical functions that flexibly, often creatively, manage the ongoing functions of the human brain. The massive scope of the brain's ability to make connections within itself boggles the mind. Paul The amazing capacities of the human brain to operate with such wide variability are all the more incredible when one considers that no two brains are exactly alike. Gerald Edelman and Giulio Tononi (2000) have emphasized how each brain is much more flexible in its capacities, and more individualized than the most advanced computer ever made.

Has the human brain stopped evolving

A written culture in a large, settled, differentiated, civilised community placed greater demands on learning and memory than life in a small, undifferentiated, preliterate nomadic tribe. Today, people from nomadic tribes can adjust to modern city life within a generation or two, showing that their brains have all the requisite capacity. The simplest inference is that civilised culture has evolved during the past 5000 years without any further significant changes in the human brain. However, there is probably no one alive today whose ancestors have, without exception, avoided all significant contact with civilisation. Perhaps many Homo sapiens 10,000 years ago could not have coped with the learning and memory demands of even rudimentary civilisation, let alone the modern city but natural selection has eliminated them. Therefore, it is possible that the progress of H. sapiens towards civilisation has entailed continuing expansion of the brain. error and less than the standard deviation...

Distinctive features of human brain function

Human brains are bigger relative to body size, and much more complicated in terms of numbers of synaptic connections, than the brains of other mammals. However, being bigger and more multiply connected does not mean that they are better at everything than the brains of other species. For example, dogs process olfactory information far more efficiently and elaborately than humans. Salient examples of human capabilities are hand control, facial recognition and language we discussed hand control and its evolutionary significance earlier. The human brain is apparently hard-wired to attend and respond to the sight of human faces. As a result, it is able to learn very early in life to respond to particular faces, especially those of adult carers. The memories of particular faces seem to be stored towards the front of the brain in the temporal lobes. However, actual recognition of a face within the field of vision involves a region called the fusiform gyrus, where the occipital and temporal...

Cns Complexity And Drug Discovery

The human brain contains approximately 100 billion neurons and expresses greater than 60 of known human genes. In comparison, the nervous system of the threadworm, C. eleqans. a model system for studying genomic function, has a mere 302 neurons, 3 x 10 6 the number in the human brain. Neurons in C. eleqans are interconnected via 600 electrical and 5000 chemical synapses (5). The C. eleqans genome codes for approximately 1000 G-protein coupled receptors (GPCRs), 90 ligand-gated ion channels, 80 potassium-selective ion channels and 228 nuclear receptors providing a virtually infinite number of postgenomic molecular substrates through which neuronal function can be regulated (6,7). Understanding this complexity at the level of the human brain and postgenomic interactions between genes and their products (epigenetics 8) is a key challenge in understanding human CNS disease pathophysiology and in designing new drugs that are safer and more efficacious to treat these diseases. The...

Fact Add looks very much like a willpower problem but it isnt Its essentially a chemical problem in the management

Most individuals who suffer chronically from an impaired ability to pay attention are able to focus their attention very well on activities that interest them. So why can't they pay attention during other activities that they recognize as important To answer this riddle, we have to look more carefully at the many aspects of attention, recognizing that processes of attention in the human brain are more complex and subtle than we might have imagined. One way to understand the complexity of attention is to listen carefully to patients with ADHD as they describe their struggles with inattention. Meet a patient of mine, a teenaged hockey player whom I'll call Larry

Cortical Spreading Depression

Also be aware that needling of the cortex is effective, and it seems inescapable that more complex surgical manipulations of similar, susceptible tissue are likely to be effective if, as seems clear from the recent findings in patients 4 , CSD does indeed occur in the human brain. There is also experimental evidence that spreading depression occurs in the spinal cord 9 . What determines susceptibility, by which is meant the frequency of occurrence of CSD (rather than vulnerability to damage from depolarisa-tions), is an important theme of this review. The factors which are currently believed to affect this are species differences, location in the brain, haemodynamic and metabolic conditions in the cortex, anaesthesia, and systemic metabolic variables (essentially - in the present state of knowledge - plasma glucose). All of these factors are best considered after we have first reviewed the basic electrophysiological, haemodynamic and metabolic properties of CSD. Studies of normal,...

Ab aggregation and neurotoxic oligomers

A number of reports have described the biochemical characterization of the soluble Ab extracted from human AD brain. The presence of sodium dodecyl sulfate (SDS)-stable dimers and trimers in the soluble fraction of human brain and in extracts of amyloid plaques suggests that SDS-stable, low n oligomers of Ab are the fundamental building blocks of insoluble amyloid deposits and could be the earliest mediators of neuronal dysfunction 20 . Recent studies have described the physiological characterization of Ab dimers isolated from AD brains that inhibit long-term potentiation (LTP), a physiological correlate of memory, and reduce dendritic spine density in normal rodent hippocampus 21 . In addition, the dimers disrupt memory of a learned behavior when directly injected into the brains of normal rats.

The Biological Significance of CSD

For neurosurgeons studying and caring for acute brain injury, the only certainties are that PIDs, when identified, should be controlled, and that there is more to be learned about the effects of CSD on the human brain before we can reach a view on whether to attempt to control it.

Taihung Duong PhD Chap 6 Cellular Communication

Taihung ( Peter ) Duong is Associate Professor of Anatomy and Cell Biology at the Indiana University School of Medicine, Terre Haute, and Director of the Terre Haute Center. He received a B.A. degree in Biology from Whittier College in 1977 and a Ph.D. degree in Anatomy from the University of California at Los Angeles (UCLA) in 1989. He completed 2 years in a postdoctoral fellowship in neuroanatomy at the UCLA Mental Retardation Research Center before joining the faculty at the Indiana University School of Medicine in 1991. His research interests are brain aging and Alzheimer disease.

Oligomeric Ab Causes Neurotoxicity

There is convincing evidence that oligomeric Ap species exist in vivo. Water soluble Ap oligomers have been detected in human brain and are elevated 12-fold in AD brain (67). Using antibodies that preferentially bind oligomeric species of Ap, Lambert and colleagues demonstrated the presence of ADDLs in temporal and frontal cortices from AD brain, but not in control brains or AD cerebellum, a region not susceptible to AD-related damage (61). Oligomeric Ap species were detected in CSF samples (59). Chinese hamster ovary cells stably transfected with APP cDNA express SDS-stable Ap species including monomer, dimer, and trimer, which were identified by sequencing and affinity for specific Ap antibodies. These Ap oligomeric species may assemble shortly after Ap synthesis in intracellular vesicles as they are detected in cell lysates and isolated microsomes and they co-migrate with proteins associated with subcellular vesicles (59).

Muscarinic receptor expression in the brain

M1, M2 and M4 mAChRs are the predominate mAChR subtypes expressed in the brain (Levey et al., 1991). M3 and M5 are also expressed throughout the brain, but in low abundance. Approximately 40 of total mAChRs in the cortex of the rodent brain represent M1, 37 M2 and approximately 15 M4 (Levey et al., 1991). In the human brain, M1 is the primary receptor in the frontal, temporal, parietal and occipital cortical areas, representing 35-60 of total mAChRs (Flynn et al., 1995). M2 is more abundant in the occipital cortex of human brain (36 ) than in the frontal, temporal or parietal cortex (approximately 20 ). M4 represents only approximately 20 of total mAChRs in the human brain cortex.

FACT Underactivity of the brains management networks is typical of persons with ADD Effective medications increase

The human brain weighs about three pounds and is composed of approximately 100 billion neurons, tiny cells only one millionth of an inch across. These neurons are the building blocks of the brain. Each neuron has a cell body on which develop tens of thousands of tiny branches called dendrites these dendrites receive information from other neurons. Each neuron also has one extension, called an axon, for sending information out to other cells these can range in length from less than a millimeter to over a meter long. Part A of Figure 2 shows a neuron and some of its dendrites emerging from the dense matrix of intertwined neurons in the brain.

Two Interconnected Halves

In the past, the left hemisphere of the human brain was recognized as dealing primarily with language data, while the right hemisphere was seen as dealing primarily with visual and spatial operations. A different picture emerges from more recent studies. Robert Ornstein (1997) has reviewed research suggesting that the right hemisphere tends to deal more with getting the big picture, the wider range of possible meanings, whereas the left hemisphere is better suited for dealing with more detailed and focused sequential information. In his view, these two hemispheres work together, with the right side more suited to recognizing the contextual forest while the left deals more with details of particular trees. Information flow in the brain thus involves not only circuits that pull together information from local and regional centers across modalities of perception, but also circuits that criss-cross the hemispheres to sort out and integrate constantly shifting details, sequences, and...

Cytochemical signature of the nucleus basalis

In the human brain, Ch4 neurons express ChAT, the vesicular acetylcholine transporter, acetyl cholines-terase (AChE), calbindin-d28k, the high affinity nerve growth factor receptor trkA, and the low affinity p75 nerve growth factor receptor (NGFr) (Geula et al., 1993b Kordower et al., 1994 Gilmor et al., 1999). A minority of Ch4 neurons are NGFr-negative and, at least in the rat, project preferentially to the amygdala (Mufson et al., 1989 Henderson and Evans, 1991 Heckers et al., 1994). The nucleus

Inputs and neurotransmitter circuitry of the nucleus basalis

The concurrent visualization of ChAT and TH showed the presence of TH-positive (presumably dopaminergic) asymmetric synapses onto ChATpositive cholinergic Ch4 neurons (Smiley and Mesulam, 1999). Reliable serotonin immunoreactiv-ity has been difficult to obtain in the human brain. In the monkey brain, we detected a dense plexus of serotonin-immunoreactive axons within the nucleus basalis (Smiley et al., 1999b). The primate nucleus basalis therefore provides a site for extensive choli-nergic-monoaminergic interactions.

Topography and distribution of cortical cholinergic projections

In the monkey brain, individual cortical areas receive their major cholinergic input from different sectors of the nucleus basalis-Ch4 complex. Thus, Ch4am provides the major source of cholinergic input to medial cortical areas including the cingulate gyrus Ch4al to frontoparietal cortex, opercular regions, and the amygdaloid nuclei Ch4i to laterodorsal frontoparietal, peristriate and mid-temporal regions and Ch4p to the superior temporal and temporopolar areas (Mesulam et al., 1983a). The experimental methods that are needed to reveal this topographic arrangement cannot be used in the human brain. However, indirect evidence for the existence of a similar topographical arrangement can be gathered from patients with Alzheimer's disease. We described two patients in whom extensive loss of cholinergic fibers in temporopolar but not frontal opercular cortex was associated with marked cell loss in the posterior (Ch4p) but not the anterior (Ch4am + Ch4al) sectors of Ch4 (Mesulam and Geula,...

In the Prefrontal Cortex Working Memory Circuits

The prefrontal cortex is a relatively small component of the human brain it takes up slightly less than one-third of the brain's total volume. This central management center is connected directly with every functional unit of the brain, those that Specific cells that execute the functions of working memory have been identified in the living brain. For example, the late Patricia Goldman-Rakic (1987) found specific cells in the prefrontal cortex for spatial working memory the ability to remember where something occurs in a tiny region of the lateral prefrontal cortex. Her studies were done with monkeys, animals whose brains are organized almost identically to the human brain.

Trajectory of cholinergic pathways from the nucleus basalis to the cerebral cortex

The cerebral cortex and amygdala in the human brain. A medial pathway joins the white matter of the gyrus rectus, curves around the rostrum of the corpus callosum to enter the cingulum, and merges with fibers of the lateral pathway within the occipital lobe. It supplies the parolfactory, cingulate, peri-cingulate and retrosplenial cortices. The lateral pathway is subdivided into a capsular division traveling in the white matter of the external capsule and a peri-Sylvian division traveling within the claustrum. Branches of the peri-Sylvian division supply the fronto-parietal operculum, insula, and superior temporal gyrus. Branches of the capsular division innervate the remaining parts of the frontal, parietal and temporal neocortex. These cholinergic pathways have been represented within a three-dimensional MRI volume in a manner that helps to determine the location of subcortical cerebrovascular lesions that are likely to interrupt the cholinergic projections to the cerebral cortex...

Cholinergic synapses in the cerebral cortex

In the rat and cat cerebral cortex, ChAT-immuno-reactive fibers are almost exclusively unmyelinated, display numerous varicosities, and make mostly symmetrical synapses on the perikaryon, dendritic shaft and spines of pyramidal as well as nonpyramidal neurons (Wainer et al., 1984 Frotscher and Leranth, 1985 DeLima and Singer, 1986). The cerebral cortex of the rat also contains cholinergic varicosities not associated with identifiable synapses, leading to the inference that cholinergic neurotransmission may partially rely on volume transmission (Umbriaco et al., 1994). In the temporal cortex of the human brain, almost two thirds of ChAT-positive synapses formed identifiable synaptic specializations. These were usually quite small and symmetric and were located predominantly on the dendritic shafts and spines of pyramidal neurons (Smiley et al., 1997).

The Development of Executive Functions in the Brain

Another important but slowly evolving element is myelination, the development of a protective surface coating that insulates the fibers that carry messages within the brain and elsewhere in the body. Myelin functions much as insulation around an electrical wire it protects from short circuits and can enhance up to a hundredfold the speed with which messages can zip along the brain's networks, sometimes reaching transmission speeds of two hundred miles per hour. While most myelination of the human brain occurs before age two, the process continues well into the fourth decade of life. The more complex structures of the brain, those that exercise more central management functions, are not fully myelinated until considerably later than other brain structures that are less complex (Sampaio and Truwit 2001).

ADAR Substrates in the Central Nervous System 41 Glutamate Gated Ion Channels 411 AMPA Receptors

The first example of A-to-I editing in mammalian mRNAs was identified in transcripts encoding the GluR-2 subunit of the AMPA receptor in which a genomically-encoded glutamine codon (CAG) was altered to an arginine codon (CIG) (Melcher et al. 1995 Rueter et al. 1995 Sommer et al. 1991 Yang et al. 1995). The substitution of a positively-charged arginine residue for a neutrally-charged glutamine residue at the apex of the membrane reentrant pore loop (M2) changes the conductance properties of channels containing an edited GluR-2(R) subunit (Verdoorn et al. 1991). Heteromeric AMPA channels that contain the edited GluR-2(R) subunit are relatively impermeant to Ca2+ ions and show a linear current-voltage (I-V) relationship, whereas channels that lack or contain a non-edited GluR-2(Q) subunit show a double-rectifying I-V relationship and an increased Ca2+ conductance (Dingledine et al. 1992 Hollmann et al. 1991 Sommer et al. 1991 Verdoorn et al. 1991). Quantitative PCR analyses of adult rat,...

The Ventral Striatum in the Human

Although experimental studies in the rat were instrumental to the discovery of the ventral striatum and ventral pallidum, it is important to emphasize that additional studies in other mammals including primates (Alheid and Heimer, 1988 Martin et al., 1991 Heimer et al., 1999 Haber and Johnson Gdowsky, 2004) have contributed significantly to our understanding of the ventral stria-topallidal system in the human brain. The diagrams in Fig. 3.1 depict a series of coronal sections through the human forebrain from the level of the rostral part of ventral striatum (i.e., the accumbens, Fig. 3.1 A) to the level of the caudal amygdala (Fig. 3.1D). Just in front of the crossing of the anterior commissure (Fig. 3.1 A), the caudate nucleus and putamen are continuous with each other underneath the anterior part of the internal capsule. This broad continuity of striatal structures, which includes the accumbens (Fig. 3.2), is sometimes referred to as the fundus striati. Although the term fundus...

The Heterogeneity of Ventral Striatum Small Celled Islands

Among the most intriguing contributors to the heterogeneity of ventral striatum are the small-celled islands, referred to as terminal islands by Sanides (1957). It is amazing to learn that the small-celled islands have generally been ignored in studies and discussions of the human brain, although they were described in great detail half a century ago. Some exceptions to this rule, however, deserve attention. Talbot et al. (1988a) published a detailed review of the islands of Calleja in different animals, and Meyer and her colleagues (1989) produced a broader study that included the entire basal forebrain in several mammals, including the human, where the small-celled islands are especially prominent. The cells of the small-celled islands are quite variable. Some of the islands contain predominantly very small glia-like, or granular, neurons similar to those in the famous islands of Calleja of macrosmatic animals, whereas other islands, such as parvicellular islands (Fig. 3.7), contain...

Parallel Corticosubcortical Reentrant Circuits Basal Ganglia Loops

FIGURE 3.7 Photomicrographs of neurons in ventral striatum from the Kluver-Barrera stained frontal section through the human brain shown in Figure 3.2 (K1-B4). Panel A illustrates the locations of the various types of neurons of the small-celled (interface) islands. The box in A is enlarged in B. Although Kluver-Barrera sections are not optimally suited for cytoarchitectural studies, they do provide a clear picture of the various cell types that intermingle with striatal neurons in the accumbens. Cells belonging to granular (gran) and parvicellular (parv) interface islands are shown. A group of larger, likely pallidal, neurons (pall) is also shown in B. (Modified from Heimer et al., 1999, reprinted with permission.) FIGURE 3.7 Photomicrographs of neurons in ventral striatum from the Kluver-Barrera stained frontal section through the human brain shown in Figure 3.2 (K1-B4). Panel A illustrates the locations of the various types of neurons of the small-celled (interface) islands. The...

Atrial Natriuretic Peptide

As with endothelin, recent studies suggest that a family of natriuretic peptides may exist in different tissue compartments, including brain, heart and kidney (78-80). Human brain natriuretic peptide (BNP) demonstrates considerable amino acid sequence homology with circulating ANP, and appears to be processed from its own distinct precursor protein (78). Several investigators have described another 32 amlno-acld form of ANP, urodilatln, which is localized to kidney tubules and collecting ducts (80). Initial results suggest that urodllatin is generated as a post-translational product of a different processing system from that of ANP (80). It has been suggested that urodllatin may act specifically in the renal collecting ducts, while ANP acts on renal vessels, proximal tubules and the juxtaglomerular apparatus, since only urodilatln has been detected in the urine (80).

Indirect Pathways From Striatum To Thalamus

This conclusion was initially based on comparison of tissue in GPe with that in either SNR or GPi using immunochemical assay or staining for various neuropeptides. It has generally been found that the neuropil in the target nuclei for the direct pathway (GPi or SNR) contains high levels of substance P (SP) and or dynorphin (DYN), while that in the target nucleus of the indirect pathway (GPe) contains high levels of enkephalin (ENK)* (Haber and Elde, 1981 Graybiel, 1986 Reiner et al., 1999). The difference between nuclei of the direct and indirect pathways is not, however, an absolute categorical one. In histological studies, the inner part of GPi stains moderately for ENK and strongly for SP, and GPe stains sparsely for SP and intensely for ENK (Haber and Elde, 1981 Marshall et al., 1983 Graybiel, 1986 Reiner et al., 1999 Mounir and Parent, 2002). Some of the ENK in GPe may derive from neurons intrinsic to that structure, rather than from striatal projections (Voorn et...

Cholinergic mechanisms in the striatum

Striatal projection neurons in the human brain. This figure demonstrates how two sets of striatal projection neurons can have opposite functions because of their wiring into direct and indirect neuronal circuits that exert opposite feedback effects in the motor cortex (Smith et al., 1998 Wichmann and DeLong, 1998). Plus signs indicate excitatory neurotransmission, whereas minus signs indicate inhibitory neurotransmission. The activity in these pathways is believed to be balanced, normally. This balance is very sensitive to dopamine levels, since dopamine excites the direct pathway via D1 receptors, increasing movement, and it inhibits the indirect pathway via D2 receptors, also increasing movement. Anything that decreases dopamine (e.g., Parkinson's disease) leads to an indirect direct pathway imbalance and less movement, and anything that increases dopamine (e.g., excess levodopa) leads to a direct indirect pathway imbalance and more movement. Cholinergic effects on these two...

Discovery Of The 5ht4 Receptor In The Gi Tract

In the central nervous system (CNS) of guinea-pigs and rats, 5-HT4 receptors are expressed in two anatomical and functional structures the extrapyramidal motor system and the mesolimbic system 6,7 . In human brain, the presence of 5-HT4 receptors has been shown in basal ganglia and in the caudate putamen nuclei, where the density is the highest 8 .

Oxidative Stress And Brain Ischemia

The adult human brain constitutes approximately 2 of total body weight but requires approximately 25 of the cardiac output. Because of its high oxygen consumption, the brain is especially vulnerable to oxidative stress. Furthermore, the brain's antioxidant capacity is very low due to low levels of enzymes, such as catalase and glutathione peroxidase, and high levels of iron and unsaturated fatty acids. Following ischemic injury, oxidative stress is a major cause of secondary injury through direct oxidant effects, as well as through activation of a variety of cell-death-signaling pathways (29). Especially in the setting of ischemia followed by reperfusion, pronounced oxidation occurs because large amounts of ROS in oxygenated blood enter the brain through recanalized vessels and through production in activated inflammatory cells. However, even in the absence of reperfusion, the ischemic brain can accumulate ROS. The mitochondrial respiratory chain is one of the main sites of cellular...

GFV1 virus See goldfish virus

Species in the genus Gammaretrovirus. Seen by electron microscopy in a disseminated T-lymphoblastic lymphosarcoma in a captive gibbon ape, Hylobates lar. The tumor cells in culture grew as free-floating cells, releasing virus particles, which are non-transforming in vitro but in gibbons induce leukemia. Antigenically related to the simian sarcoma virus. Several strains have been isolated and their origins are indicated by suffixes, thus -H for Hall's Island near Bermuda -SF for San Francisco -Br for brain extract from gibbons injected with extract of human brain from kuru patients and -SEATO for Seato Laboratory, Bangkok. All are closely related by protein serology and nucleic acid homology. The GALVs as a group are related to murine leukemia viruses, especially the endogenous virus of the Asian mouse, Mus caroli. No GALV isolates have been made from wild gibbon apes.

The Nonisocortical Character Of The Limbic Lobe

FIGURE 4.4 Medial views of the human brain depicting the components of the limbic lobe in colors. Note the inner ring of allocortices in dark green, light purple, and dark purple, and the outer ring in light green, denoting the agranular, dysgranular, and dyslaminate cortices. Reprinted from Heimer and Van Hoesen (2006) with permission. (Artwork provided by Medical and Scientific Illustration, Crozet, VA, USA.) See color plate. FIGURE 4.4 Medial views of the human brain depicting the components of the limbic lobe in colors. Note the inner ring of allocortices in dark green, light purple, and dark purple, and the outer ring in light green, denoting the agranular, dysgranular, and dyslaminate cortices. Reprinted from Heimer and Van Hoesen (2006) with permission. (Artwork provided by Medical and Scientific Illustration, Crozet, VA, USA.) See color plate. area is not shown in Fig. 4.4 so that the hippocampus can be visualized, but it is shown in Fig. 4.5. forming Brodmann's area 28. Also...

The Olfactory System Of The Limbic Lobe

The impetus for Broca's comparative study of the limbic lobe is not known with certainty. However, Broca had a lifetime interest in comparative anatomy, its functional correlates, and anthropology. The relative variation of the olfactory apparatus among species surely caught his attention, and the insertion of the olfactory tracts into the cortex he named the limbic lobe would be a compelling reason for him to undertake further study. He attributed olfactory sensation to the limbic lobe, but as Schiller (1979) points out in his excellent biography of Broca, he was cautious and, perhaps, even skeptical that the cortex of the whole limbus subserved only this function. Schiller's translations of the original text and Broca's notes reveal a critical, and somewhat contemporary-sounding, synthesis that comes very close to attributing visceral and emotion-related functions, along with olfaction, to the limbic lobe. This, along with the conceptual juxtaposition of olfaction and limbic...

Editing Within Repetitive Elements

In 1990s, experimental evidence for a significant amount of inosine in total RNA has emerged. In the decade to follow, we have witnessed an impressive growth in the number of known editing sites within the coding sequence (editing of which might modify the encoded protein), especially as deep-sequencing methods have been introduced in the past 2 years (see below). However, these are far from being able to account for the total inosine levels observed the currently known editing sites within the coding region amount to about 400 sites. Thus, they represent roughly 1 150,000 of all nucleotides in exons. The editing efficiency is spread between 0 and 100 , with average efficiency less than 50 , so one expects not more than 1 300,000 inosine to adenosine ratio in total mRNA. This rough estimate is at odds with an observed ratio of 1 17,000nt in rat's brain (Paul and Bass 1998) and results showing up to one inosine per 2,000 nt in poly-adenylated mRNA from human brain (Blow et al. 2004)....

Stroke Neuroprotective Clinical Trials Lessons from Past Failures

In the preclinical stage, therapies are often tested on healthy, young animals under rigorously controlled laboratory conditions, and, most often, the treatment is not adequately tested (for example, by multiple investigators in different stroke models) before it is brought to clinical trial. Whereas experimental animals are bred for genetic homogeneity, genetic differences and factors such as advanced age and co-morbidities (hypertension, diabetes) in patients may alter their therapeutic response. Moreover, despite similarities in the basic pathophysiology of stroke between species, there are important differences in brain structure, function, and vascular anatomy. The human brain is gyrated, has greater neuronal and glial densities, and is larger than the rodent brain. Some rodents (gerbils) lack a complete circle of Willis (gerbils), while others (rats) have highly effective collaterals between large cerebral vessels. As a result, there are important differences in the size,...

T2Weighted Imaging of Remyelination

A recent study of mice undergoing demyelination and then remyelination of the spinal cord suggests that T2 images show remyelination-associated changes 32 . Mice were treated with either placebo or rHIgM22, an antibody demonstrated to promote remyelination. The authors found that mice treated with rHIgM22 and demonstrating remyelination had smaller lesions on T2-weighted images, and less T2 intensity. In another study of the mouse cuprizone model, where demyelination and remyelination have a very predictable time course, the authors 25 also found that T2 increased in the demyelination phase and declined (though not back to normal) after remyelination. While this may not prove that decreased T2 signal in human brain correlates with remyelination, it fits with our understanding of how T2 imaging works and is provocative.

Shotgun and Protein Profiling

The discriminatory pattern that separates the control from the testing group is usually related to the small subset of proteins or peptides present in the barely visible electrophoretic spots, or it shows up as small spec-trometric peaks hiding in the background of the spectra. To find a spot or a peak of difference and to separate these two groups, a massive amount of data must be analyzed that for most instances exceeds the capacity of the human brain. In these instances, the proteomics practitioner must be assisted by pattern recognition software that helps in the preliminary evaluation of data. Such software is an integral tool of pro-teomics protocols.

Blood Pressure Management

Manipulation of blood pressure becomes necessary in many ischemic stroke patients, as patients with ongoing ischemia and fixed stenotic arterial lesion(s) may require blood pressure management to feed the ischemic penumbra. Conversely, patients with cerebral edema may require blood pressure lowering to reduce the detrimental effect of increased cerebral blood flow (CBF). In the normal human brain, CBF is kept relatively constant by the mechanism of cerebral autoregulation. This applies throughout a range of CPP from approximately 40 to 140 mm Hg. Beyond this range, the autoregulatory capacity is overwhelmed, and at pressures below 40 mm Hg further ischemia ensues. At pressures above 140 mm Hg, cerebral edema often worsens. Both of these circumstances assume an intact autoregulatory capacity, which may be significantly impaired in acute stroke patients. Older patients, or patients with chronic hypertension, often have poor vasoreactivity of

Plasticity of brain function

Like most terminally differentiated cells, mature neurones cannot divide. In most vertebrate brains, neurones are not replaced when they die, so their number in the brain decreases with advancing age. After their late teens, humans lose brain neurones at the rate of about a million a day. This sounds alarming, but the human brain contains something like a million million neurones altogether. Nevertheless, losses can accumulate significantly over a long life-time. If the brain had less plasticity, if new circuits were less capable of compensating for damage, then senile dementia might develop much earlier.

Histochemical Detection of Apoptotic Neurons

Short of electron microscopic examination, the most reliable method for detection of apoptotic cytological features in neurons is light microscopic examination of optimally fixed and stained plastic-embedded tissue sections with a high-power objective. In experimental adult animals, this is accomplished by perfusing anesthetized rats or mice with heparinized saline followed by 3 glutaraldehyde in 0.1 M phosphate buffer (pH 7.3) containing 0.45 mmol L Ca2+ or with other glutaraldehyde-based fixatives. The brain is then removed from the skull and fixed for an additional 24-48 h before further dissection, dehydration in graded ethanol solutions, and embedding in Epon with propylene oxide as an intermediary solvent. One-micrometer-thick plastic sections are cut and then stained with toluidine blue. For embryonic brains or appropriately small (1-2 mm thick) samples of human brain, immersion

The driving forces for the evolutionary increase in brain size

Evolutionary psychologists have suggested that the large human brain, like the peacock's tail, is the result of sexual selection. Ancestral peahens were more attracted to mates with bigger and more ornate tails. Therefore, size and ornateness of tail were selected for. Therefore, we now have peacocks with ludicrously exuberant tails. By analogy, hominid females were more attracted to mates with bigger brains. Therefore, bigger brains were selected for. Therefore, we now have humans with ludicrously big and complicated brains. On the face of it, this seems plausible. Sexual selection has been held to account for evolutionary super-growth in various animal features. However, sexual selection only favours exaggerated development of features in the male. It is the peacock, not the peahen, that has the dazzling tail. In humans, the ratio of brain size to body size is essentially the same in both sexes. Moreover, even if brainier males did attract more mates in the evolutionary past, this...

Macrosystem Outputs to Mesopontine Cholinergics Summarized

Whereas macrosystem-basal forebrain cholinergic reentrant loops are organized in a parallel, if not precisely segregated, fashion reminiscent of the cortico-basal ganglia-thalamocortical loops (see Chapter 3 and following), the macrosystem outputs that descend to the vicinity of the mesopontine tegmental cholinergics in the PPTg merge and interdigitate extensively there. From the vicinity of the PPTg and LDTg, where such convergence is particularly striking, not only cholinergic but also GABAergic and glutamatergic projections ascend toward the ventral mesencephalon, basal forebrain, and thalamus, where they terminate in particularly robust fashion. Furthermore, robust cau-dalward projections from the vicinity of the PPTg to brainstem motor effector sites also have been reported. Thus, the neuroanatomy suggests that convergent macrosystem outputs gain access in the mesopontine tegmentum, via either direct connections or interneuronal relays, to robust projections that ascend to the...

Functional Magnetic Resonance Imaging

Neuroimaging techniques, such as single photon emission tomography (SPECT), positron emission tomography (PET), and fMRI, provide a means of mapping regional neuronal activity in vivo in the intact human brain. Blood oxygen level-dependent (BOLD) fMRI uses echo-planar imaging (EPI) to detect changes in the oxygenation state of the blood (8). Recent studies of the monkey brain combined BOLD-sensitive fMRI with electrophysiological measurements to demonstrate that the BOLD signal primarily measures the input and processing of neuronal information within a brain region (2). Since the BOLD signal is an intrinsic signal, BOLD-sensitive fMRI does not require the injection of a contrast agent. Compared to PET and SPECT, BOLD-sensitive fMRI does not involve exposure to radiation, is widely available, and offers a higher spatial and temporal resolution. Moreover, event-related fMRI protocols allow studies to investigate changes in the BOLD signal related to a single movement, whereas SPECT and...

Magnetic Resonance Spectroscopy

MRS provides chemical information on tissue metabolites (3,4). The molecules that can be studied by MRS in human brain tissue are hydrogen 1 ( H) and phosphorus 31 (31P). Magnetic resonance sensitivity is far greater for protons than it is for phosphorus (3). Therefore, most commercial MR scanners are capable of only proton MRS. Spectra are usually obtained from localized brain regions. The brain region is defined on a single slice by placing a small voxel, on the order of 1 or 2 cm2, in the area of interest. The compounds that can be observed in proton spectra are primarily identified by their frequency (i.e., their position in the spectrum), expressed as the shift in frequency in pars per million (ppm) relative to a standard. A normal spectrum shows peaks from N-acetyl groups, especially N-acetylaspartate (NAA) at 2.0 ppm, creatine (Cr), and phosphocreatine at 3.0 ppm, and cho-line-containing phospholipids (Ch) at 3.2 ppm (3). An additional peak at 1.3 ppm arises from the methyl...

Oxidative Stress Yields DNA Damage

Oxidative damage is not necessarily present in significant amounts in the normal brain (Arnett et al. 2005), presumably because mediators of oxidative stress are balanced by endogenous antioxidant systems. In the rodent, under normal physiological conditions, however, increases in basal levels of oxidative DNA damage have been detected in the brain during aging (Cardozo-Pelaez et al. 1999 Hamilton et al. 2001 Rutten et al. 2003). Furthermore, in the aging human brain, DNA damage has been found in the promoter regions of genes encoding proteins that are downregu-lated in the aged brain, suggesting that DNA damage accumulates in the brain over time (Lu et al. 2004). Accumulation of DNA damage during the aging process may contribute to age-related neurodegeneration the extent and consequences, however, of nonpathological DNA damage in the brain have yet to be determined.

The Transfer of Information between Circuits

Furthermore, it is necessary to acknowledge another recent finding that is difficult to reconcile with the neuroanatomy. Georges and Aston-Jones (2001 2002 see also Dumont and Williams, 2004) demonstrated a short-latency excitation of the VTA following electrical and chemical stimulation at a single, focal site in the ventrolateral part of the bed nucleus of the stria terminalis. As just noted, the anatomy appears consistent with few, if any, direct projections from the central division of the extended amgydala to the VTA. However, as just noted, great numbers of VTA-projecting neurons form a densely packed column centered on the medial forebrain bundle that invades numerous forebrain structures, including the lateral and medial hypothalamus, sublenticular region, lateral and medial preoptic regions, diagonal band, septal nuclei, ventral pallidum, and ventral parts of the bed nuclei of the stria terminalis (Geisler and Zahm, 2005). Many of the neurons in this column are thought to be...

Role of acetylcholine in disorders of consciousness

The cholinergic system is implicated in a broad range of disorders of the human brain, including those associated with development (Rett's syndrome, autism and schizophrenia for example), and in old age (Alzheimer's and Parkinson's disease, dementia with Lewy bodies (DLB), and progressive supranuclear palsy, for example). Amongst these, autism and DLB are particular examples of brain disorders, which include as central feature disturbances in consciousness.

Extending the cellbrain analogy

Some parts of the brain are necessary for overseeing basic physiological functions, e.g. respiratory muscle contractions and the beating of the heart. No vertebrate could survive without these functions. Other parts of the human brain are devoted to specifically human functions such as facial recognition, communication of emotions, language and abstract thought. The basic-physiology parts of the brain can be regarded as analogous to housekeeping genes, and the higher-function parts to luxury genes.

Cellular Effectors of Axon Injury 411 Cytotoxic CD8 T Cells

The in vivo imaging evidence for a direct association between CTLs and injured axons is less clear. One example of contact between a demyelinated axon and a CD3-positive lymphocyte exhibiting polarization of granzyme B-containing granules toward the immunological synapse was reported in an acute MS lesion 178 , suggesting that CTLs may mediate at least some axon injury in the demyelinated human brain. However, further work will be required to show whether this type of contact is frequent, whether it produces axon injury, and whether interference with such contact leads to axon preservation. Nonetheless, other CNS inflammatory diseases provide compelling evidence for direct axon and neuron injury mediated by CTLs. For example, while Rasmussen's encephalitis is associated with autoantibodies against a glutamate receptor subunit 10 , much of the disease pathology is consistent with a CTL-mediated process 25 , and CD8v T cells are frequently found in contact with and polarized toward MHC...

Lincomycin and Clindamycin

Clindamycin is rapidly removed from serum to body tissues and fluids and it penetrates well into saliva, sputum, respiratory tissue, pleural fluid, soft tissues, prostate, semen, bones, and joints (62), as well as into fetal blood and tissues. No data exist to show that significant concentrations are achievable in the human brain, cerebrospinal fluid, or eye.

New insights in to the neurochemistry of consciousness

In exploring a 'cholinergic hypothesis of consciousness', this chapter depends on assumptions and correlations which are admittedly highly speculative. In the first place, a broad range of human cerebral pathologies could be linked to consciousness, since so many human brain activities involves conscious awareness, from sensory perception to higher cognitive functions. Disorders such as blindsight, schizophrenia, narcolepsy, delirium, depression, Alzheimer's disease, frontotemporal dementia, epilepsy, stroke, and a range of developmental diseases associated with mental retardation have been or could be examined from this perspective. Secondly, correlations between any two variables, as in this instance between brain pathology and function do not necessarily imply any causative linkage. However, what is striking in the two diseases under discussion is that the prominent cholinergic abnormality in the one (autism) and neurochemical correlate of disturbed consciousness in the other (DLB)...

Role Of Bradykinin B1 Receptors In Pain

Peripheral nerve injury and inflammatory damage is known to produce inflammatory responses in the spinal cord, as well as at the site of injury, that are conducive for B1 receptor induction (58-60). Activation of B1 receptors either on central terminals of primary afferents and or second order neurons of the dorsal horn may subserve a CNS mechanism. All of the components of the kinin system have been localized in the CNS (61). Intrinsic kininergic neurons have been detected in the spinal cord dorsal and ventral horns (62). B1 receptors have been immunolocalized to A-delta and C-fibers as well as intrinsic neurons of the dorsal horn (43,45,63). They have also been localized to neurons in various human brain regions (64).

Cholinoceptive neurons of the cerebral cortex

The density and staining intensity of AChE-rich cortical neurons is higher in the human brain than in any other species that we have studied, including the macaque and baboon. These neurons also display a most unusual ontogenetic profile their AChE-rich Fig. 1. Anterior orbitofrontal cortex of the human brain. AChE histochemistry. Varicose cholinergic axons (coming from Ch4) are contacting AChE-rich cholinoceptive cell bodies. Magnification 10x. Fig. 1. Anterior orbitofrontal cortex of the human brain. AChE histochemistry. Varicose cholinergic axons (coming from Ch4) are contacting AChE-rich cholinoceptive cell bodies. Magnification 10x. staining pattern is not detectable as late as the 10th year of life and becomes fully established during adulthood. These AChE-rich neurons are ChATnegative and, therefore, non-cholinergic. Paralimbic and limbic areas of the human brain receive a very dense cholinergic input, but have very few AChE-rich neurons. Furthermore, AChE-rich intracortical...

I63Social Attachment The Role of the Hypothalamus in Behavioral Deficits

Experimental studies revealed that the hypothalamic nucleus paraventricularis (NPV) and the nucleus supraopticus (NSO), producing oxytocin (OT) and vasopressin (VAS), regulate emotional responses, social attachment, cognitive functions, sleep, and appetite (Barden, 2004 Ehlert et al., 2001 Manaye et al., 2005). OT and VAS are relayed from the human brain into the bloodstream via the posterior pituitary. The presence of receptors for both peptides throughout the forebrain, limbic system, thalamus, brain stem, and spinal cord (Raggenbass, 2001) indicates that hypotha-lamic neuropeptides modulate the function of many brain regions. Developmental changes in the distribution and expression of receptors suggest that the hypothalamic peptides play a significant role both in brain development and function (Shapiro and Insel, 1989). OT is required for the development of social memory. In OT knockout mice, the loss of social memory could be rescued by OT treatment (Ferguson et al., 2000). VAS...

DNA Repair Counters DNA Damage

It has been suggested that neurons preferentially repair transcriptionally active regions of the genome, but as opposed to what occurs during TCR, neurons appear to repair the transcribed and nontranscribed strands with equal efficiency. This type of repair has been termed differentiation-associated repair (Nouspikel and Hanawalt 2000, 2002). Intriguingly, genes involved in TCR and differentiation associated repair appear to be important to neuronal development and survival in the rodent and human brain. Mutations in XP genes, with the exception of XPC and XPE (which are not thought to be required for TCR) result in a wide range of neurological phenotypes usually characterized by either neuronal loss during development or progressive neurodegeneration in specific neuronal populations (Brooks 2002 Hayashi et al. 2004 Itoh et al. 1999 Kohji et al. 1998 McMurray 2005). Interestingly, astrocytes from XPA- - mice are seemingly resistant to cell death evoked by chloroacetaldehyde (CAA)...

Histopathology Of Global Ischemia

The thalamic reticular nucleus is another region of recognized pathology in human brain following brief intervals of cardiac arrest (18 ), with parallels in many animal models (7,17,19-21). Lesions can occur after brief insults and progress surprisingly quickly, showing evidence of irreversible damage within minutes of recirculation (20,22). However, factors that determine the marked variability of reticular nucleus involvement in either clinical or experimental ischemia remain undefined ( 18 ).

Limits Topography And Related Concepts

Medial Limbic Lobe

FIGURE 4.1 Schematic drawing of the medial surface of the human brain depicting the limbic lobe. The cortical areas of the parahippocampal gyrus have been removed to show the location of the underlying laterobasal-cortical amygdala and hippocampus. Reprinted from Heimer and Van Hoesen (2006) with permission. (Artwork provided by Medical and Scientific Illustration, Crozet, VA, USA.) FIGURE 4.1 Schematic drawing of the medial surface of the human brain depicting the limbic lobe. The cortical areas of the parahippocampal gyrus have been removed to show the location of the underlying laterobasal-cortical amygdala and hippocampus. Reprinted from Heimer and Van Hoesen (2006) with permission. (Artwork provided by Medical and Scientific Illustration, Crozet, VA, USA.) further buttress the segregation of limbic lobe cortex from the isocortex. In this context, it is important to revisit Vogt's theory of pathoklise (Vogt and Vogt, 1922 Vogt, 1925), which, to quote the late Pierre Gloor (1997),...

Basal forebrain cholinergic neurons and their cortical projections

The cholinergic basal nuclear complex has been identified in a number of placental mammalian species using ChAT immunohistochemistry. Of these, the cholinergic BF system shows the highest degree of development in the human brain (Hedreen et al., 1984 Saper and Chelimsky, 1984), in particular with the growth and differentiation of the caudal aspects of the cholinergic basal nuclear complex, i.e., the nucleus of Meynert (Mesulam and Geula, 1988 Butcher and Semba, 1989 Fig. 2A, B). The number of cholinergic neurons in the nucleus of Meynert (or Ch4) is estimated to be approximately 200,000 in each hemisphere (Arendt et al., 1985). Compared to the nucleus of Meynert, the medial septum is simple, and its cholinergic neurons may contain lesser amounts of ChAT mRNA (Kasashima et al., 1998). The cholinergic BF system has been identified in a number of nonhuman primates, including New World monkeys such as blackcapped capuchin (Cebus apella Kordower et al., 1989) and common marmoset...

Squalamine And Endothelial Cells

The specificity of squalamine for endothelial cells was evaluated in culture with bovine retina (BREC) and rat brain (RBE-4) endothelial cells at different concentrations, and compared to results with rat (9L glioma), rabbit (VX2 carcinoma), and human brain tumor (H80) cells (66). The endothelial cell lines were grown in DMEM media containing 10 fetal bovine serum, 1 L-glutamine, 25 mM HEPES, and genticine and 20 ng mL vascular endothelial growth factor (VEGF) in the presence or absence of squalamine. The growth factor was added to the cells prior to the addition of squalamine to the cell cultures. Squalamine exposure was observed to specifically inhibit VEGF-stimulated endothelial cell proliferation for BREC cells, but not the growth of any of the tumor lines (Fig. 4). The degree of inhibition of VEGF-stimulated BREC cells, or RBE-4 cells found with squalamine, increased with increasing squalamine concentration. For example, the net growth of BREC cells was inhibited by more than 30...

Systematic Surveys for MiRNA Editing Sites

A-to-I editing of a pri-miRNA was first reported in 2004 (Luciano et al. 2004). PCR amplification and sequencing of the region surrounding the pri-miR-22 hairpin revealed editing at several positions in mouse brain and human brain, lung, and testis (Fig. 2a). However, editing frequency was very low less than 10 . While the biological consequence of this editing is still unclear, its discovery demonstrated the existence of miRNA editing and sparked further studies. In 2006, Blow et al. attempted to isolate, PCR amplify, and sequence all 231 human pri-miRNAs registered in miRBase and their corresponding genomic DNA from ten different tissues adult human brain, heart, liver, lung, ovary, placenta, skeletal muscle, small intestine, spleen, and testis (Blow et al. 2006). They succeeded for 99 pri-miRNAs. In 2008, these results were extended by a second systematic survey (Kawahara et al. 2008). Known editing sites indicated that adenosines are particularly prone to editing when located in...

The Triune Brain Concept And The Controversy Surrounding It

Almost as soon as MacLean's triune brain was proposed, it came under fire. Several reviewers of the concept questioned its compatibility with modern views of evolutionary neurobiology (Durant, 1985 LeDoux, 1991 Butler and Hodos, 1996 Reiner, 1997). As it turned out, while MacLean was developing his idea in the late 1960s and early 70s (MacLean, 1970), the field of comparative neuroanatomy was undergoing a revolution of its own. As is usually the case in neuroscience, the revolution was triggered by improved technology, in this case, histotechnical advances heralding the emergence of new experimental methods to trace neuronal connections (see Basic Science Box 1). Application of these new techniques to a number of mammalian and nonmammalian species in the 1960s and 1970s revealed that the blueprint of forebrain organization is similar in all vertebrates (Karten, 1969 Nauta and Karten, 1970 Ebbesson, 1980 Butler and Hodos, 1996). In other words, homologues of MacLean's limbic system are...

Disease Models Involving Neovascularization And Squalamine

The rat 9L glioma is widely used as a model for human brain tumors, and for evaluation of the consequences of chemotherapy (82-85). Carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea BCNU) is an approved agent for the treatment of human brain tumors, and is active in the rat 9L glioma model. BCNU displays cumulative toxicity in animals and humans, so that, when given systemically in animals, a single dose is the common dosage. Systemic squalamine was compared in the rat 9L glioma model to BCNU treatment, when the 9L glioma was transplanted either in the rat brain or in the rat flank. In the latter instance, the blood-brain barrier is not encountered, and drug delivery is less in doubt.

Discovery of the Extended Amygdala

As just indicated the idea of a centromedial amygdala-bed nucleus of stria terminalis continuum, which originated with J. B. Johnston's pioneering studies almost a century ago, was quickly forgotten, in all likelihood because it proved difficult to identify and illustrate the attenuated cellular continuities between the centromedial amygdala and the bed nucleus of stria terminalis. An additional breakthrough was needed, and, as is often the case in neuroanatomy, it came with a histotechnical advance in this case, in the form of de Olmos's (1969) cupric silver method. For some unknown reason the cupric-silver method exhibits chemical specificity for a special type of neuron and neuropil, restricted to the central amygdaloid nucleus, the lateral bed nucleus of stria terminalis, and identical neuronal elements bridging the gap between these two structures, not only in the sublenticular region as shown in Fig. A but also in the stria terminalis. amygdala (Fig. 3.10) are not part of the...

PARP1 in the Pathobiology of Ischemic Stroke

It is now clearly established that cerebral ischemia overactivates PARP-1 in several cell types of the ischemic region and significantly contributes to the extension of ischemic damage. PARP-1 activation occurs not only in injured neurons but also in endothelial and glial cells as well as in pericytes and infiltrating leukocytes. Consistent with PARP-1 involvement in ischemic brain damage, enzymatic activity of PARP-1 in gerbils subjected to transient (5 min) ischemia increases in the injured tissue 4.3- and 1.7-fold at 1 and 24 h of reperfusion, respectively (Nagayama et al. 2000). Prolonging duration of ischemia (10 min) leads to significant increases of PARP-1 activity up to the seventh day of reperfusion (Strosznajder et al. 2003). Accordingly, various studies report PAR accumulation in the ischemic brain tissue. In a focal and transient model of brain ischemia in mice, PAR formation is highly increased in the nuclei of cells of cerebral cortex compared to those present in the...

Larry Fowler and Wieslaw Furmaga

These instruments become data factories that produce enormous amounts of information, transcending the capacity of the human brain. The need to store and analyze such a large amount of data has stimulated the advancement of new bioinformatics tools that contribute significantly to the development of omics disciplines. Despite its short history, this comprehensive methodology has proved its effectiveness by advancing our understanding of physiological and pathological processes, which brings hope for more accurate diagnosis and treatment of diseases.1

Unbound compound concentrations and the free drug hypothesis

Based on the described neuroanatomy, the three key matrices for evaluating compound concentrations to determine the extent and or rate of CNS penetration are blood, CSF, and brain tissue. Due to the nearly universal analysis of plasma to determine systemic concentrations of small molecules, total plasma compound concentration (Cp) will henceforth be substituted for total blood concentration, which is the product of Cp and compound blood-to-plasma ratio.

Proteomics Instrumentation

The entire process of the spectrometric spectra evaluation provides a basis for discovering single biomarkers and for a diagnostic strategy called proteomics pattern diagnostics.35 The SELDI mass spectrometer along with provided software was tested during development and validation of the spectral patterns as a diagnostic marker for ovarian,36 prostate,37 and breast cancer.38 As a result, a large amount of very complex data was obtained that could not be evaluated by classical statistics. To validate whether spectrometric peak patterns can be utilized in cancer diagnosis, an artificial neuronal network algorithm was used, integrated with the SELDI software packet. An artificial neural network is a statistical tool that imitates the learning ability of the human brain. PRoPeak software provided by Bio-Rad is based on an artificial neural network and is able to learn to recognize universal elements based on repeated analysis of the complex data from at least two experimental groups....

Constitutive Gpcr Activation Disease And Inverse Agonist Utility

CB1 receptors regulate release of multiple central and peripheral transmitters 69 . High constitutive activity of CB1 receptors has been reported in both rat and human brain 42 , a finding that is recapitulated in native receptor bearing cell systems 70 . Thus, a therapeutic utility for CB1 inverse agonists is possible for a variety of indications. The most advanced CB1 inverse agonist, rimonabant (SR141716A) produced sustained weight loss in phase III clinical trials 71-74 . Though there are multiple reports that characterize the inverse agonist profile of SR141716A 75,76 and references therein , the perspective is not universally supported. It has been suggested that cross talk between CB1 and adenosine A1 receptors is responsible for the apparent capacity of SR141716A to block basal CB1 function. Thus, in GTPgS binding studies in rat cerebellar membranes, SR141716A could not prevent constitutive activity when tonic A1 signaling was blocked. In guinea pig small intestine,...

Evidence for Immunopathogenic Heterogeneity in Multiple Sclerosis

Analyzing large samples of human brain biopsies and autopsies during early disease revealed patterns of demyelination that were homogenous in multiple active lesions of the same patient but differed between patients 62 . Active demy-elinating lesions were classified into four patterns based on plaque geography, myelin protein expression, pattern of oligodendrocyte pathology, and presence of immune complex deposition (Fig. 3). Only T cells and macrophages dominated the

Issn 08932336

When the President of Humana Press first suggested that a series on methods in the neurosciences might be useful, one of us (AAB) was quite skeptical only after discussions with GBB and some searching both of memory and library shelves did it seem that perhaps the publisher was right. Although some excellent methods books had recently appeared, notably in neuroanatomy, it was a fact that there was a dearth in this particular field, a fact attested to by the alacrity and enthusiasm with which most of the contributors to this series accepted our invitations and suggested additional topics and areas. After a somewhat hesitant start, essentially in the neurochemistry section, the series has grown and will encompass neurochemistry, neuropsychiatry, neurology, neuropathology, neurogenetics, neuroethology, molecular neurobiology, animal models of nervous disease, and no doubt many more neuros. Although we have tried to include adequate methodological detail and in many cases detailed...

About Lennart Heimer

This book represents in large part the legacy of its lead author, Lennart Heimer, who, as a young man, tested the waters of art, sport, and engineering and might well have excelled as a professional in any of them. Although it was the study of medicine to which he ultimately committed, even that, as it turned out, was but a threshold over which he passed to enter the realm of experimental neuroanatomy that finally captured and held him for the rest of his life. those structures that regulate the emotions and motivation. By 1972 he assumed a professorship at the University of Virginia and as his long and influential career unfolded there, Lennart's thinking evolved ultimately toward what became his most tenaciously held conviction that the segregation of learned thought about human brain and mental disorders into the neurological and psychiatric reflects an unnatural and counterproductive divide. Perhaps this is made most clear in the 1991 Perestroika paper, written with Jose de Olmos,...

Series Preface

The workings of the brain, including the human brain, are a source of endless fascination. In the last generation, experimental approaches to brain research have expanded massively, partly as a result of the development of powerful new techniques. However, the development of concepts that integrate and make sense of the wealth of available empirical data has lagged far behind the experimental investigation of the brain. The series of books entitled Conceptual Advances in Brain Research (CABR) is intended to provide a forum in which new and interesting conceptual advances can be presented to a wide readership in a coherent and lucid way.

Conclusions

There is also a difference between phylogenetic and ontogenetic development. The cholinergic neurons in the ventral telencephalon appear to shift their positions somewhat during evolution, apparently in association with general evolution of the brain. There are indications that in 'lower' species, these choliner-gic neurons are more closely associated with olfactory structures that are located rostrally, whereas in higher species, this association is weaker as the major part of cholinergic neurons are increasingly located more caudally, away from olfactory structures. In particular, remarkable growth is seen in the human brain for the magnocellular basal nucleus, which is the caudalmost part of the cholinergic BF complex. This shift might be related to the gradual decrease in the relative significance of olfaction, along with the development of lateral hemisphere and cerebral cortex, during evolution. This rostral to caudal shift, however, is in stark contrast to the characteristic...

Bsecretase

Discovered using an expression cloning strategy to search a library for genes that increased the secretion of Ap from HEK293 cells overexpressing APPsw. Soon after this report additional strategies were described which resulted in the identification of the same protein, also referred to as asp2 and memapsin 2 . These included the location of ESTs encoding novel aspartyl proteases (52,54,55), and direct purification of the enzyme from human brain using an inhibitor-functionalized affinity column (56). BACE is a 501 amino acid aspartyl protease containing an unusual 80 amino acid C-terminal extension with a predicted TMD 21 amino acids from the C-terminus (Figure 2). The protein has an N-terminal 21 amino acid signal peptide, and

Acetylcholinesterase

In vivo imaging studies of AChE have utilized two approaches, either radiolabeled inhibitors or radiolabeled substrates for AChE. Several inhibitors of AChE have been radiolabeled in order to visualize the brain distribution of AChE using PET, including 11C donepezil and 11C physostigmine. While animal imaging studies with 11C donepezil failed to demonstrate a radioactivity distribution consistent with the known regional brain distribution of AChE, PET imaging studies using 11C physostigmine in normal human subjects successfully displayed a regional distribution of radiotracer similar to that of AChE in postmortem human brain 106 . However, the non-specific binding of 11C physostigmine is relatively high,

Summary

Although cortical spreading depression and peri-infarct depolarisations have been extensively studied in the experimental in vivo models, there is now clear evidence that depolarisations also occur and propagate in the human brain in areas surrounding a focus of traumatic contusion. 6. Whether such events in the injured human brain represent cortical spreading depression or peri-infarct depolarisation is unclear. However, invasive and probably non-invasive monitoring methods are available which may serve to distinguish which event has occurred. 7. Much further work will be needed to examine the relationship of depolarisation events in the injured brain with outcome from cerebral ischaemia or head injury, to examine the factors which influence the frequency of depolarisation events, and to determine which depolarisation events in the human brain augment the injury and should be prevented. depression-like depolarisation. Physiol Rev 81 1065-1096 Strong AJ, Fabricius M, Boutelle MG,...

Conclusion

It is apparent that limbic system proponents and opponents alike are looking for something beyond the limbic system. One of LeDoux's major complaints is that MacLean packaged . . . the entire emotional brain and its evolutionary history into one system. LeDoux maintains that different survival functions must be subserved by different emotional systems that need to be studied separately. To this end, the idea of a limbic system is of little use. A similar idea expressed by some supporters of the limbic system (e.g., Morgane et al., 2005) is that the anatomy of partial functions need to be better pieced together than they have in the past. In this chapter, we have highlighted some reasons for abandoning the limbic system concept and suggest that MacLean's anatomical basis for the limbic system has been significantly undermined by discoveries in the comparative and experimental neuroanatomy of the fore-brain, which were fueled by histotechnical advances in the 1960s and 1970s. These...

Apoptosis

Apoptosis occurs via caspase-dependent as well as caspase-independent mechanisms (Fig. 1.3). Caspas-es are protein-cleaving enzymes (zymogens) that belong to a family of cysteine aspartases constitutively expressed in both adult and especially newborn brain cells, particularly neurons. Since caspase-dependent cell death requires energy in the form of ATP, apopto-sis predominantly occurs in the ischemic penumbra (which sustains milder injury) rather than in the ischemic core, where ATP levels are rapidly depleted 31 . The mechanisms of cleavage and activation of caspases in human brain are believed to be similar to those documented in experimental models of stroke, trauma, and neurodegeneration 32 .Apopto-genic triggers 33 include oxygen free radicals 34 , Bcl2, death receptor ligation 35 , DNA damage, and possibly lysosomal protease activation 36 . Several mediators facilitate cross communication between The normal human brain expresses caspases-1, -3, -8, and -9, apoptosis...

Cingulate Gyrus

The cingulate gyrus is an extensive structure in the human brain. In the past, the cytoarchitectural differences between anterior agranular and posterior granular parts of the cingulate region were emphasized, but more recently, progressing from anterior to posterior, at least four functional divisions are described, including viscero-motor, cognitive-effector, motor, and sensory processing regions (Mega and Cummings, 1997). From a neuropsychiatry point of view most attention has been paid to the anterior part of the cingulate gyrus, which is associated with disorders having much to do with motivation and movement, consistent with the extensive dorsal and ventral striatal connections of this part of the structure.

Neuropathology

Neuropathologically, PSP is characterized by abundant neurofibrillary tangles and or neuropil threads particularly in the striatum, pallidum, subthalamic nucleus, substantia nigra, oculomotor complex, periaqueductal gray, superior colliculi, basis pontis, dentate nucleus, and prefrontal cortex (see Fig. 2). Neuronal loss and gliosis are variable (see Chapter 4) (6,41). Pathological tau in PSP is composed of aggregated four-repeat (E10+) isoforms that accumulate as abnormal filamentous lesions in cells and glia in subcortical and cortical areas (42,43). In the normal adult human brain, there are six different tau isoforms with different microtubule-binding domains and the ratio of tau isoforms with three- (3-R) and four-repeat (4-R) microtubule binding domains is 1 1. In AD, there is amyloid deposition and the six tau isoforms aggregate mainly in neurons, but the 1 1 ratio is maintained. By contrast, in PSP and CBD, there is no amyloid deposition and tau aggregates in neurons and glia...

The amyloid core

NPs have largely been presumed to form late in the disease and to gradually increase in size. Both of these presumptions are in question following the emergence of new technologies for imaging NP growth in vivo. The clinical imaging agent 11LC Pittsburgh compound B (PiB), which recognizes the fibrillar structure of Ap, has revealed that NP cores form in cognitively normal or mildly impaired humans over a fairly brief period 8 . Recent longitudinal studies suggest that the occurrence of PiB labeling in human brain is associated with a subsequent higher rate of cognitive decline and or conversion to AD 9 . The rate of formation of individual amyloid cores has also been studied using two-photon microcopy in Ap-depositing transgenics, where it was found that amyloid cores form and reach their terminal size within 24-48 h 10 . After forming, these plaque cores are remarkably stable and in fact serve as landmarks for detecting the formation of additional NPs.

Clinical Relevance

The induction of tolerance to ischemia by preconditioning was first described in the heart 20 years ago (2). It was later observed in brain that brief ischemic insults that did not induce tissue damage, protected the brain against damage caused by subsequent, more severe, and otherwise lethal ischemia (3 ) . It was first observed in gerbils that 2 min of global ischemia protected hippocampal CA1 neurons from lethal 5 min ischemia 24 to 48 hr later. Similar observations were later made in rats (4,5) and mice (6). Whether the human brain can be preconditioned to tolerate ischemia is unknown. A number of recent clinical studies, however, suggest that a transient ischemic attack (TIA) might serve as a preconditioning stimulus, reducing the severity of subsequent strokes (7-10). In contrast, a more recent study failed to detect an association of prior TIA with lesser stroke severity (11). Distinction between the role of TIA as risk factor or protectant is difficult in humans because TIA is...

Brains and computers

Mammalian brains, particularly human brains, are the most complicated objects known in the universe. Every generation compares the brain to the most complicated piece of technology so far invented. In the 17th century, Leibnitz compared it to a water-mill. At the end of the 19th century, Freud compared it to a hydraulic system. In the 1930s it was compared to a telephone exchange, in the 1960s to a digital computer. Most recently it has been compared to a neural network or parallel-processing system, a development in computer technology partly inspired by (but not necessarily intended to simulate) a living brain. How useful is this analogy signals, recognise patterns, interpolate data, make predictions, guide movement on the basis of visual information, and even synthesise speech. But they are not really like brains. A one-year-old child's visual processing capacity far exceeds that of any computer. Different areas of the human brain detect and interpret form, motion and colour in a...

Brain state

Essentially, the structure of the human brain consists of neurones connected via synapses to form pathways or circuits50. Brain function consists of the activities of these circuits ordered sequences of action potentials, neurotransmitter release events, and postsynaptic responses. Function obviously depends on structure. However, as we showed in chapter 16, structure also depends on function. Neuronal activities alter the strengths of synapses and they also forge new growth in axon termini and the formation of new connections, i.e. new circuits.

Dependent

Brain state bears some comparison to the internal state of a cell (chapter 6), although cellular transport has no obvious counterpart in the brain. Like a cell's internal state, brain state changes from moment to moment. The structures and functions of the numerous circuits, and the control process operating in them, are never constant. Since brains cause minds , it follows that the workings of the mind are underpinned by an ever-shifting pattern of activities and an ever-changing set of connections among the 1015 or so synapses in the human brain.

Autism

Autism is a developmental disorder, involving abnormalities in social function, language and imagination. There is as yet no aetiology-based treatment or cure. Neurotransmitter signaling systems are relevant to symptom aetiology, treatment, and brain development. Transmitters so far implicated in autism include the monoamines-serotonin, dopamine and noradrenaline, together with acetylcholine, GABA, glutamate and several neuro-peptides. Investigations have mainly relied on measurements in blood or cerebrospinal fluid or responses to pharmaceutical agents, and more recently on genetic linkage data and observations using human brain tissue.

Biologic Differences

A component of the cerebral edema associated with an infarct is thought to be vasogenic, due to movement of water across the BBB into the interstitial space of the brain parenchyma. Although the BBB in neonates is generally considered immature and therefore less effective, these concepts have been challenged by advances in developmental neuroanatomy, as well as by recent studies using MRI in rodent models (13). For example, the higher cerebral spinal fluid protein concentration found in neonates, as compared to adults, may not be due to an ineffective BBB, but rather a physiologic mechanism that promotes protein passage across the BBB, which becomes less effective as the brain matures (14). Endothelial tight junctions, which form the basis of the BBB, also undergo developmental changes that might contribute to a developmental decline in passive permeability (15,16).

Parts of the Brain

Figure 14.5 Sagittal section showing some of the major regions of the human brain. The front of the brain is at the left. Figure 14.6 Coronal section through the anterior portion of the cerebrum of the human brain showing some of the elements of the basal ganglia and limbic system. Adapted from Carola, R., J. P. Harley, and C. R. Noback. 1992. Human Anatomy and Physiology. 2nd ed. McGraw-Hill, New York. Figure 14.7 Spatial relationship among components of the basal ganglia (stippled), limbic system (solid), and thalamus (cross-hatched) within the cerebrum of the human brain. The front of the brain is at the right. Adapted from Carola, R., J. P. Harley, and C. R. Noback. 1992. Human Anatomy and Physiology. 2nd ed. McGraw-Hill, New York.

Analgesia

The development of ABT-239 was halted due to cardiovascular liabilities 19 . ABT-239 inhibits 3H dofetilide binding to the hERG potassium channel with a Kj value of 195 nM. ABT-239 has a high clogP of 5.2, which was believed to contribute to the high brain partitioning (B P 34), high bound fraction in human brain homogenates in vitro and phospholipidosis 19 . Naphthalene analogs have even higher clogP and brain to plasma ratios than the corresponding benzofuran analogs 45 . For example, compound 8 has a clogP of 5.9. ABT-834 is a backup compound in clinical trials for ADHD, although the structure has not been disclosed 15,16 . Protective patents related to compound 9 have published, including disclosing the crystal structure of various salt forms 46 . To improve the drug-like properties by lowering the logP, compounds 10 (A-688057) and 11 (A-687136) were identified 47 . Compared to ABT-239, A-688057 showed improved hERG activity (Ki of 9 p.M for dofetilide binding), a...

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