Glycemic State Regulates Brain-Derived Neurotrophic Factor Responsiveness of Neurons in the Paraventricular Nucleus of the Hypothalamus

Brain derived neurotrophic factor (BDNF) is a member of the family of neurotrophins and binds to the tropomyosin-related kinase B (TrkB) receptor. Like other neurotrophic factors, BDNF is involved in the development and differentiation of neurons. Recently, studies have suggested important roles for BDNF in the regulation of energy homeostasis. The paraventricular nucleus (PVN) is critical for normal energy balance contains high levels of both BDNF and TrkB mRNA. Studies have shown that microinjections of BDNF into the PVN increase energy expenditure, suggesting BDNF plays a role in energy homeostasis through direct actions in this hypothalamic nucleus. We used male Sprague-Dawley rats to perform whole-cell current-clamp experiments from PVN neurons in slice preparation. BDNF was bath applied at a concentration of 2nM and caused depolarizations in 54% of neurons (n = 25; mean change in membrane potential: 8.9 ± 1.2 mV), hyperpolarizations in 23% (n = 11; mean change in membrane potential: -6.7 ± 1.4 mV), while the remaining cells tested were unaffected. Previous studies showing effects of BDNF on γ-aminobutyric acid type A (GABAA) mediated neurotransmission in PVN led us to examine if these BDNF-mediated changes in membrane potential were maintained in the presence of tetrodotoxin (TTX) sodium channel blocker (N = 9; 56% depolarized, 22% hyperpolarized, 22% non-responders) and bicuculline (GABAA antagonist) (N = 12; 42% depolarized, 17% hyperpolarized, 41% non-responders), supporting the conclusion that these effects on membrane potential were postsynaptic. We also evaluated the effects of BDNF on these neurons across varying physiologically relevant extracellular glucose concentrations. At 10 mM 23% (n = 11; mean: -6.7 ± 1.4 mV) of PVN neurons hyperpolarized in response to BDNF treatment, whereas at 0.2 mM glucose, 71% showed hyperpolarizing effects (n = 12; mean: -6.3 ± 2.8 mV). Our findings reveal that BDNF has direct impacts on PVN neurons and that these neurons are capable of integrating multiple sources of metabolically relevant input. Our analysis regarding glucose concentrations and their effects on these neurons’ response to other metabolic signals emphasizes the importance of using physiologically relevant conditions for study of central pathways involved in the regulation of energy homeostasis.

Detection of Staphylococcus aureus by 16S rRNA directed in situ hybridisation in a patient with a brain abscess caused by small colony variants.

Kipp F, Ziebuhr W, Becker K, Krimmer V, Höbeta N, Peters G, Von Eiff C. Institute of Medical Microbiology, Hospital and Clinics, University of Münster, Germany. A 45 year old man was admitted to hospital with a right sided facial paralysis and three month history of seizures. Computed tomography showed a left temporal mass including both intracerebral and extracerebral structures. Ten years earlier the patient had undergone a neurosurgical intervention in the same anatomical region to treat a subarachnoid haemorrhage. In tissue samples and pus obtained during neurosurgery, Staphylococcus aureus was detected by a 16S rRNA-directed in situ hybridisation technique. Following long term cultivation, small colony variants (SCV) of methicillin resistant S aureus were identified. The patient was treated successfully with a combination of vancomycin and rifampin followed by prolonged treatment with teicoplanin, with no sign of infection on follow up nine months after discharge. This is the first report in which S aureus SCV have been identified as causative organisms in a patient with brain abscess and in which in situ hybridisation has been used to detect S aureus in a clinical specimen containing SCV. Antimicrobial agents such as rifampin which have intracellular activity should be included in treatment of infections caused by S aureus SCV.

Organs of the human brain, created by the human hand? The social epistemology of information technology

Purpose
– Information science has been conceptualized as a partly unreflexive response to developments in information and computer technology, and, most powerfully, as part of the gestalt of the computer. The computer was viewed as an historical accident in the original formulation of the gestalt. An alternative, and timely, approach to understanding, and then dissolving, the gestalt would be to address the motivating technology directly, fully recognizing it as a radical human construction. This paper aims to address the issues.

Design/methodology/approach
– The paper adopts a social epistemological perspective and is concerned with collective, rather than primarily individual, ways of knowing.

Findings
– Information technology tends to be received as objectively given, autonomously developing, and causing but not itself caused, by the language of discussions in information science. It has also been characterized as artificial, in the sense of unnatural, and sometimes as threatening. Attitudes to technology are implied, rather than explicit, and can appear weak when articulated, corresponding to collective repression.

Research limitations/implications
– Receiving technology as objectively given has an analogy with the Platonist view of mathematical propositions as discovered, in its exclusion of human activity, opening up the possibility of a comparable critique which insists on human agency.

Originality/value
– Apprehensions of information technology have been raised to consciousness, exposing their limitations.

Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases.

Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past twenty years that the molecular events that precipitate disease have begun to be understood. Protein aggregation is a common feature of many neurodegenerative diseases, and it is assumed that the aggregation process plays a central role in pathogenesis. In this process, one molecule (monomer) of a soluble protein interacts with other monomers of the same protein to form dimers, oligomers, and polymers. Conformation changes in three-dimensional structure of the protein, especially the formation of beta-strands, often accompany the process. Eventually, as the size of the aggregates increases, they may precipitate as insoluble amyloid fibrils, in which the structure is stabilized by the beta-strands interacting within a beta-sheet. In this review, we discuss this theme as it relates to the two most common neurodegenerative conditions-Alzheimer's and Parkinson's diseases.

Effect of angiotensin-related antihypertensives on brain neurotransmitter levels in rats.

The extensive clinical experience of angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists as antihypertensive agents provide numerous examples of anecdotal evidence of improvements in cognition and mood. This study aimed to determine the effect of chronic treatment with the angiotensin converting enzyme inhibitor, perindopril, and the angiotensin AT(1) receptor antagonist, candesartan, on central neurotransmitter levels in the rat. Perindopril (1.0mg/kg/day) or candesartan (10mg/kg/day) was administered via the drinking water at for 1 week, while controls received water alone. At the end of treatment rats were sacrificed, brains removed and discrete regions dissected and analysed for noradrenaline, dopamine and its major metabolites, and serotonin content. As shown previously we found an increase in striatal dopamine levels after perindopril treatment, though this did not extend to the mesolimbic system with neurotransmitter levels unchanged in the hippocampus, nucleus accumbens and frontal cortex. Conversely, candesartan administration produced no change in dopamine, but significant decreases in both DOPAC and HVA in the striatum. In addition chronic candesartan infusion produced a significant increase in the levels of hippocampal noradrenaline and serotonin; and frontal cortex serotonin content. These results demonstrate that while angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists act as antihypertensives by affecting the renin-angiotensin system, they have divergent actions on brain neurochemistry.

Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation

Insulin resistance and diabetes might promote neurodegenerative disease, but a molecular link between these disorders is unknown. Many factors are responsible for brain growth, patterning, and survival, including the insulin-insulin-like growth factor (IGF)-signaling cascades that are mediated by tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. Irs2 signaling mediates peripheral insulin action and pancreatic beta-cell function, and its failure causes diabetes in mice. In this study, we reveal two important roles for Irs2 signaling in the mouse brain. First, disruption of the Irs2 gene reduced neuronal proliferation during development by 50%, which dissociated brain growth from Irs1-dependent body growth. Second, neurofibrillary tangles containing phosphorylated tau accumulated in the hippocampus of old Irs2 knock-out mice, suggesting that Irs2 signaling is neuroprotective. Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease.