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OBJECTIVE: Mutations in the glucocerebrosidase gene (GBA) represent a significant risk factor for developing Parkinson disease (PD). We investigated the enzymatic activity of glucocerebrosidase (GCase) in PD brains carrying heterozygote GBA mutations (PD+GBA) and sporadic PD brains. METHODS: GCase activity was measured using a fluorescent assay in cerebellum, frontal cortex, putamen, amygdala, and substantia nigra of PD+GBA (n = 9-14) and sporadic PD brains (n = 12-14). Protein expression of GCase and other lysosomal proteins was determined by western blotting. The relation between GCase, α-synuclein, and mitochondria function was also investigated in vitro. RESULTS: A significant decrease in GCase activity was observed in all PD+GBA brain areas except the frontal cortex. The greatest deficiency was in the substantia nigra (58% decrease; p < 0.01). GCase activity was also significantly decreased in the substantia nigra (33% decrease; p < 0.05) and cerebellum (24% decrease; p < 0.05) of sporadic PD brains. GCase protein expression was lower in PD+GBA and PD brains, whereas increased C/EBP homologous protein and binding immunoglobulin protein levels indicated that the unfolded protein response was activated. Elevated α-synuclein levels or PTEN-induced putative kinase 1 deficiency in cultured cells had a significant effect on GCase protein levels. INTERPRETATION: GCase deficiency in PD brains with GBA mutations is a combination of decreased catalytic activity and reduced protein levels. This is most pronounced in the substantia nigra. Biochemical changes involved in PD pathogenesis affect wild-type GCase protein expression in vitro, and these could be contributing factors to the GCase deficiency observed in sporadic PD brains.

Primates are usually found to have richer behavioral repertoires and better cognitive abilities than rodents of similar brain size. This finding raises the possibility that primate brains differ from rodent brains in their cellular composition. Here we examine the cellular scaling rules for primate brains and show that brain size increases approximately isometrically as a function of cell numbers, such that an 11x larger brain is built with 10x more neurons and approximately 12x more nonneuronal cells of relatively constant average size. This isometric function is in contrast to rodent brains, which increase faster in size than in numbers of neurons. As a consequence of the linear cellular scaling rules, primate brains have a larger number of neurons than rodent brains of similar size, presumably endowing them with greater computational power and cognitive abilities.

BACKGROUND: Schizophrenia has been hypothesized to be caused by a hypofunction of glutamatergic neurons. Findings of reduced concentrations of glutamate in the cerebrospinal fluid of patients with schizophrenia and the ability of glutamate-receptor antagonists to cause psychotic symptoms lend support to this hypothesis. N-acetylaspartylglutamate (NAAG), a neuropeptide that is highly concentrated in glutamatergic neurons, antagonizes the effects of glutamate at N-methyl-D-aspartate receptors. Moreover, NAAG is cleaved to glutamate and N-acetylaspartate by a specific peptidase, N-acetyl-alpha-linked acidic dipeptidase (NAALADase). To test the glutamatergic hypothesis of schizophrenia, we studied the NAAG-related glutamatergic variables in postmortem brains from patients with schizophrenia, neuroleptic-treated controls, and normal individuals, with particular emphasis on the prefrontal cortex and hippocampus. METHOD: Different regions of frozen brain tissue from three different groups (patients with schizophrenia, neuroleptic-treated controls, and normal controls) were assayed to determine levels of NAAG, N-acetylaspartate, NAALADase, and several amino acids, including aspartate and glutamate. RESULTS: Our study demonstrates alterations in brain levels of aspartate, glutamate, and NAAG and in NAALADase activity. Levels of NAAG were increased and NAALADase activity and glutamate levels were decreased in the schizophrenic brains. Notably, the changes in NAAG level and NAALADase activity in schizophrenic brains were more selective than those for aspartate and glutamate. In neuroleptic-treated control brains, levels of aspartate, glutamate, and glycine were found to be increased. CONCLUSIONS: The changes in levels of aspartate, glutamate, NAAG, and NAALADase are prominent in the prefrontal and hippocampal regions, where previous neuropathological studies of schizophrenic brains demonstrate consistent changes. These findings support the hypothesis that schizophrenia results from a hypofunction of certain glutamatergic neuronal systems. They also suggest that the therapeutic efficacy of neuroleptics may be related to increased glutamatergic activity.

Abstract This article can be viewed as an attempt to explore the consequences of two propositions. (1) Intentionality in human beings (and animals) is a product of causal features of the brain. I assume this is an empirical fact about the actual causal relations between mental processes and brains. It says simply that certain brain processes are sufficient for intentionality. (2) Instantiating a computer program is never by itself a sufficient condition of intentionality. The main argument of this paper is directed at establishing this claim. The form of the argument is to show how a human agent could instantiate the program and still not have the relevant intentionality. These two propositions have the following consequences: (3) The explanation of how the brain produces intentionality cannot be that it does it by instantiating a computer program. This is a strict logical consequence of 1 and 2. (4) Any mechanism capable of producing intentionality must have causal powers equal to those of the brain. This is meant to be a trivial consequence of 1. (5) Any attempt literally to create intentionality artificially (strong AI) could not succeed just by designing programs but would have to duplicate the causal powers of the human brain. This follows from 2 and 4. “Could a machine think?” On the argument advanced here only a machine could think, and only very special kinds of machines, namely brains and machines with internal causal powers equivalent to those of brains. And that is why strong AI has little to tell us about thinking, since it is not about machines but about programs, and no program by itself is sufficient for thinking.

The widely held hypothesis that enlarged brains have evolved as an adaptation to cope with novel or altered environmental conditions lacks firm empirical support. Here, we test this hypothesis for a major animal group (birds) by examining whether large-brained species show higher survival than small-brained species when introduced to nonnative locations. Using a global database documenting the outcome of >600 introduction events, we confirm that avian species with larger brains, relative to their body mass, tend to be more successful at establishing themselves in novel environments. Moreover, we provide evidence that larger brains help birds respond to novel conditions by enhancing their innovation propensity rather than indirectly through noncognitive mechanisms. These findings provide strong evidence for the hypothesis that enlarged brains function, and hence may have evolved, to deal with changes in the environment.

How do we exercise our will? The erosion of Descartes' concept of the soul in the machine by recent developments in neuroscience leaves us with the challenge of understanding how we control our behaviour and make sense of the world around us. Do our genes and environments determine all that goes on in our brains, or do we create ourselves through what we believe and how we behave? In How Brains Make Up Their Minds, the distinguished US neuroscientist Walter J. Freeman charts the brain's mind, progressing from single nerve cells, through cooperative assemblies of these cells, to the emergence of complex patterns of brain activity. By drawing on new developments in brain imaging and theories of chaos and nonlinear dynamics, he shows how brains create intentions and meanings. The result is an original and stimulating synthesis of neuroscience and philosophy that argues that the power to choose is an essential and inalienable property of brains, and, moreover, the foundation for the development and flourishing of individuals and societies.

The amount of messenger RNA encoding human inducible nitric oxide synthase and the presence and distribution of NADPH diaphorase were determined in tissue sections from multiple sclerosis (MS) and control brains. Levels of human nitric oxide synthase messenger RNA were markedly elevated in MS brains when compared to normal control brains. NADPH diaphorase activity, a histochemical stain reflecting nitric oxide synthase catalytic activity, was detected in reactive astrocytes in active demyelinating MS lesions and at the edge of chronic active demyelinating lesions. Control brains did not contain NADPH diaphorase-positive astrocytes. These results implicate the free radical nitric oxide in the pathogenesis of demyelinating MS lesions.

In the effort to understand the evolution of mammalian brains, we have found that common relationships between brain structure mass and numbers of nonneuronal (glial and vascular) cells apply across eutherian mammals, but brain structure mass scales differently with numbers of neurons across structures and across primate and nonprimate clades. This suggests that the ancestral scaling rules for mammalian brains are those shared by extant nonprimate eutherians - but do these scaling relationships apply to marsupials, a sister group to eutherians that diverged early in mammalian evolution? Here we examine the cellular composition of the brains of 10 species of marsupials. We show that brain structure mass scales with numbers of nonneuronal cells, and numbers of cerebellar neurons scale with numbers of cerebral cortical neurons, comparable to what we have found in eutherians. These shared scaling relationships are therefore indicative of mechanisms that have been conserved since the first therians. In contrast, while marsupials share with nonprimate eutherians the scaling of cerebral cortex mass with number of neurons, their cerebella have more neurons than nonprimate eutherian cerebella of a similar mass, and their rest of brain has fewer neurons than eutherian structures of a similar mass. Moreover, Australasian marsupials exhibit ratios of neurons in the cerebral cortex and cerebellum over the rest of the brain, comparable to artiodactyls and primates. Our results suggest that Australasian marsupials have diverged from the ancestral Theria neuronal scaling rules, and support the suggestion that the scaling of average neuronal cell size with increasing numbers of neurons varies in evolution independently of the allocation of neurons across structures.

Glial cells are thought to derive embryologically from either myeloid cells of the hematopoietic system (microglia) or neuroepithelial progenitor cells (astroglia and oligodendrocytes). However, it is unclear whether the glia in adult brains free of disease or injury originate solely from cells present in the brain since the fetal stage of development, or if there is further input into such adult brains from cells originating outside the central nervous system. To test the ability of hematopoietic cells to contribute to the central nervous system, we have transplanted adult female mice with donor bone marrow cells genetically marked either with a retroviral tag or by using male donor cells. Using in situ hybridization histochemistry, a continuing influx of hematopoietic cells into the brain was detected. Marrow-derived cells were already detected in the brains of mice 3 days after transplant, and their numbers increased over the next several weeks, exceeding 14,000 cells per brain in several animals. Marrow-derived cells were widely distributed throughout the brain, including the cortex, hippocampus, thalamus, brain stem, and cerebellum. When in situ hybridization histochemistry was combined with immunohistochemical staining using lineage-specific markers, some bone marrow-derived cells were positive for the microglial antigenic marker F4/80. Other marrow-derived cells surprisingly expressed the astroglial marker glial fibrillary acidic protein. These results indicate that some microglia and astroglia arise from a precursor that is a normal constituent of adult bone marrow.

Abstract Cell proliferation in the brains of rats and cats was investigated autoradiographically. Two young adult rats were injected intraperitoneally with 2 mc of thymidine‐H 3 and killed after a two weeks' exchange period. Two adult cats were injected intraventricularly with 0.5 mc of thymidine‐H 3 and killed one week later. Labeling of cell nuclei in the brain, presumed to reflect DNA turnover and cellular proliferation, was investigated. In the rats, some neuroglia cells were found labeled in all parts of the brain, suggesting a low rate of glial proliferation. In addition, circumscribed small regions with numerous labeled neuroglia and microglia cells were seen in several brain regions, suggesting the occurrence of local glial proliferative reactions in these presumably normal brains. A few apparently labeled neurons were seen in the neocortex, and a proliferative region of granule cells was identified in the dentate gyrus of the hippocampus. In the cats labeling of glia cells was highest in the midline region, near the point of injection of the radiochemical, with a gradient of decreasing number of labeled cells both laterally and in the anteroposterior direction of the neuraxis. Neurons with apparently labeled nuclei were observed in the midline cortex bilaterally in both animals. These results indicate that glia cells can multiply in the brains of young adult rats and adult cats and they support the possibility that new neurons may be formed in forebrain structures, both in rodents and carnivores.

Social Cognition: From Brains to Culture 1. Introduction a. Approaches to Studying the Social Thinker b. Ebb & Flow of Cognition in Psychology & Neuroscience c. What is Social Cognition? d. People Are Not Things f. Brains Matter e. Cultures Matter g. Summary Basic Topics in Social Cognition 2. Dual Modes in Social Cognition a. Automatic Processes b. Controlled Processes c. Motivations Influence Which Modes Operate d. Models of Both Automatic and Controlled Processes f. Summary 3. Attention and Encoding a. Salience: A Property of Stimuli in Context b. Vividness: An Inherent Property of Stimuli c. Accessibility: A Property of Categories in Our Heads d. Direct Perception: Not Just in Our Heads e. Faces: The focus of social attention 4. Representation in Memory a. Associative Networks: Organizing Memory b. Procedural and Declarative memory: What memory Does c. Parallel Versus Serial Processing: Coordinating Memory Processes d. Embodies Memory: Including Physical Representation e. Social Memory Structures: Why Social Memory matters F. Summary Topics in Social Cognition: From Self to Society 5. Self in Social Cognition a. Mental Representations of the Self b. Self-Regulation c. Motivation and Self-Regulation d. The Self as a Reference Point e. Summary 6. Attribution Process a. What is Attribution? b. Early Contributions to Attribution Theory c. Processes Underlying Attribution d. Attributional Biases e. Summary 7. Heuristics and Shortcuts: Efficiency in Inference and Decision Making a. What Are Heuristics? b. When Are Heuristics Used, and When Do They Lead to Wrong Answers? c. Judgments Over Time d. Summary 8. Accuracy and Efficiency in Social Inference a. Errors and Biases as Consequential: impoving the Inference Process b. Errors and Biases in Social Inference: Perhaps They Don't Matter? c. Are rapid Judgments Sometimes Better Than Thoughtfully Considered Ones? d. Neuroeconomics: Back to the Future? e. Summary 9. Cognitive Structures of Attitudes a. Background b. Cognitive Features of Two Consistency Theories c. Lay Theories and Attitude Change d. Functional Dimensions of Attitudes e. Summary 10. Cognitive Processing of Attitudes a. Heuristic Versus Systemic Model b. Peripheral Versus Central Routes to Persuasion: Elaboration Liklihood Model c. Motivation and Opportunity Determine Attitude Processes: The MODE Model d. Implicit Associations e. Embodied Attitdes f. Neural Correlates of Attitudes g. Summary 11. Stereotyping: Cognition and Bias a. Blatant Stereotypes b. Subtle Stereotypes c. Effects of Bias d. Summary 12. Prejudice: Interplay of Cogntive with Affective Biases a. Intergroup Cognition and Emotion b. Racial Prejudice c. Gender Prejudice d. Age Prejudice e. Sexual Prejudice f. Summary 13. From Social Cognition to Affect a. Differentiating Among Affects, Preferences, Evaluations, Moods, and Emotions b. Early Theories c. Physiological Theories of Emotion d. Social Cognitive Foundations of Affect e. Summary 14. From Affect to Social Cognitioncognition a. Affective Influences on Cognition b. Affect Versus Cognition c. Summary 15. Behavior and Cognition a. Goal Directed Behavior b. When Are Cognitions and Behavior Related c. Using Behavior for Impression Management d. Using Behavior as a Test Hypotheses About Others d. Summary References Cited Author Index Subject Index

The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinson's disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)-binding, protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.

Dysfunction of the central nervous system (CNS) is a prominent feature of the acquired immune deficiency syndrome (AIDS). Many of these patients have a subacute encephalitis consistent with a viral infection of the CNS. We studied the brains of 12 AIDS patients using in situ hybridization to identify human immunodeficiency virus [HIV, referred to by others as human T-cell lymphotropic virus type III (HTLV-III), lymphadenopathy-associated virus (LAV), AIDS-associated retrovirus (ARV)] nucleic acid sequences and immunocytochemistry to identify viral and cellular proteins. Nine patients had significant HIV infection in the CNS. In all examined brains, the white matter was more severely involved than the grey matter. In most cases the infection was restricted to capillary endothelial cells, mononuclear inflammatory cells, and giant cells. In a single case with severe CNS involvement, a low-level infection was seen in some astrocytes and neurons. These results suggest that CNS dysfunction is due to indirect effects rather than neuronal or glial infection.

The best-selling author of The Big Switch returns with an explosive look at technologys effect on the mind. Is Google making us stupid? When Nicholas Carr posed that question, in a celebrated Atlantic Monthly cover story, he tapped into a well of anxiety about how the Internet is changing us. He also crystallized one of the most important debates of our time: As we enjoy the Nets bounties, are we sacrificing our ability to read and think deeply? Now, Carr expands his argument into the most compelling exploration of the Internets intellectual and cultural consequences yet published. As he describes how human thought has been shaped through the centuries by tools of the mindfrom the alphabet to maps, to the printing press, the clock, and the computerCarr interweaves a fascinating account of recent discoveries in neuroscience by such pioneers as Michael Merzenich and Eric Kandel. Our brains, the historical and scientific evidence reveals, change in response to our experiences. The technologies we use to find, store, and share information can literally reroute our neural pathways. Building on the insights of thinkers from Plato to McLuhan, Carr makes a convincing case that every information technology carries an intellectual ethica set of assumptions about the nature of knowledge and intelligence. He explains how the printed book served to focus our attention, promoting deep and creative thought. In stark contrast, the Internet encourages the rapid, distracted sampling of small bits of information from many sources. Its ethic is that of the industrialist, an ethic of speed and efficiency, of optimized production and consumptionand now the Net is remaking us in its own image. We are becoming ever more adept at scanning and skimming, but what we are losing is our capacity for concentration, contemplation, and reflection. Part intellectual history, part popular science, and part cultural criticism, The Shallows sparkles with memorable vignettesFriedrich Nietzsche wrestling with a typewriter, Sigmund Freud dissecting the brains of sea creatures, Nathaniel Hawthorne contemplating the thunderous approach of a steam locomotiveeven as it plumbs profound questions about the state of our modern psyche. This is a book that will forever alter the way we think about media and our minds.

Brains, it has recently been argued, are essentially prediction machines. They are bundles of cells that support perception and action by constantly attempting to match incoming sensory inputs with top-down expectations or predictions. This is achieved using a hierarchical generative model that aims to minimize prediction error within a bidirectional cascade of cortical processing. Such accounts offer a unifying model of perception and action, illuminate the functional role of attention, and may neatly capture the special contribution of cortical processing to adaptive success. This target article critically examines this "hierarchical prediction machine" approach, concluding that it offers the best clue yet to the shape of a unified science of mind and action. Sections 1 and 2 lay out the key elements and implications of the approach. Section 3 explores a variety of pitfalls and challenges, spanning the evidential, the methodological, and the more properly conceptual. The paper ends (sections 4 and 5) by asking how such approaches might impact our more general vision of mind, experience, and agency.

Unexplained debilitating dementia or encephalopathy occurs frequently in adults and children with the acquired immune deficiency syndrome (AIDS). Brains from 15 individuals with AIDS and encephalopathy were examined by Southern analysis and in situ hybridization for the presence of human T-cell leukemia (lymphotropic) virus type III (HTLV-III), the virus believed to be the causative agent of AIDS. HTLV-III DNA was detected in the brains of five patients, and viral-specific RNA was detected in four of these. In view of these findings and the recent demonstration of morphologic and genetic relatedness between HTLV-III and visna virus, a lentivirus that causes a chronic degenerative neurologic disease in sheep, HTLV-III should be evaluated further as a possible cause of AIDS encephalopathy.

Comparisons of gene expression between human and non-human primate brains have identified hundreds of differentially expressed genes, yet translating these lists into key functional distinctions between species has proved difficult. Here we provide a more integrated view of human brain evolution by examining the large-scale organization of gene coexpression networks in human and chimpanzee brains. We identify modules of coexpressed genes that correspond to discrete brain regions and quantify their conservation between the species. Module conservation in cerebral cortex is significantly weaker than module conservation in subcortical brain regions, revealing a striking gradient that parallels known evolutionary hierarchies. We introduce a method for identifying species-specific network connections and demonstrate how differential network connectivity can be used to identify key drivers of evolutionary change. By integrating our results with comparative genomic sequence data and estimates of protein sequence divergence rates, we confirm a number of network predictions and validate these findings. Our results provide insights into the molecular bases of primate brain organization and demonstrate the general utility of weighted gene coexpression network analysis.

We studied the frequency, severity, and clinical correlations of cerebral amyloid angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions than those of subjects with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2) High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia. Our findings suggest that factors contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may play a role in amyloid deposition in cerebral vessels in AD.

OBJECTIVE: To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD). DESIGN: Postmortem observational study. SETTING: University Department of Clinical Neuroscience, Institute of Neurology, University College London. SUBJECTS: Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains. MAIN OUTCOME MEASURE: Lysosomal-associated membrane protein 2A (LAMP2A) and heat shock cognate 70 (hsc70) protein levels were compared in the substantia nigra pars compacta and amygdala of PD, AD, and control brain samples. To provide insight into the turnover of α-synuclein, degradation pathways for this protein were studied in a dopaminergic cell line. RESULTS: The expression levels of the chaperone-mediated autophagy proteins LAMP2A and hsc70 were significantly reduced in the substantia nigra pars compacta and amygdala of PD brains compared with age-matched AD and control brain samples. Lewy bodies in these regions contained autophagy-related proteins. We demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of α-synuclein. CONCLUSIONS: These findings suggest that there is reduced chaperone-mediated autophagy activity in the PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation, and suggest that this pathway may be a suitable therapeutic target in PD.