Computational modeling of excitatory/inhibitory balance impairments in schizophrenia.

Deficits in glutamatergic function are well established in schizophrenia (SZ) as reflected in "input" dysfunction across sensory systems. By contrast, less is known about contributions of the GABAergic system to impairments in excitatory/inhibitory balance. We investigated this issue by measuring contrast thresholds for orientation detection, orientation discriminability, and orientation-tilt-aftereffect curves in schizophrenia subjects and matched controls. These measures depend on the amplitude and width of underlying orientation tuning curves, which, in turn, depend on excitatory and inhibitory interactions. By simulating a well-established V1 orientation selectivity model and its link to perception, we demonstrate that reduced cortical excitation and inhibition are both necessary to explain our psychophysical data. Reductions in GABAergic feedback may represent a compensatory response to impaired glutamatergic input in SZ, or a separate pathophysiological event. We also found evidence for the widely accepted, but rarely tested, inverse relationship between orientation discriminability and tuning width.

Transmembrane Pore Structures of ß-Hairpin Antimicrobial Peptides by All-Atom Simulations.

Protegrin-1 is an 18-residue ß-hairpin antimicrobial peptide (AMP) that has been suggested to form transmembrane ß-barrels in biological membranes. However, alternative structures have also been proposed. Here, we performed multimicrosecond, all-atom molecular dynamics simulations of various protegrin-1 oligomers on the membrane surface and in transmembrane topologies. The membrane surface simulations indicated that protegrin dimers are stable, whereas trimers and tetramers break down. Tetrameric arcs remained stably inserted in lipid membranes, but the pore water was displaced by lipid molecules. Unsheared protegrin ß-barrels opened into ß-sheets that surrounded stable aqueous pores, whereas tilted barrels with sheared hydrogen bonding patterns were stable in most topologies. A third type of observed pore consisted of multiple small oligomers surrounding a small, partially lipidic pore. We also considered the ß-hairpin AMP tachyplesin, which showed less tendency to oligomerize than protegrin: the octameric bundle resulted in small pores surrounded by six peptides as monomers and dimers, with some peptides returning to the membrane surface. The results imply that multiple configurations of protegrin oligomers may produce aqueous pores and illustrate the relationship between topology and putative steps in protegrin-1's pore formation. However, the long-term stability of these structures needs to be assessed further.

Computational studies of peptide-induced membrane pore formation.

A variety of peptides induce pores in biological membranes; the most common ones are naturally produced antimicrobial peptides (AMPs), which are small, usually cationic, and defend diverse organisms against biological threats. Because it is not possible to observe these pores directly on a molecular scale, the structure of AMP-induced pores and the exact sequence of steps leading to their formation remain uncertain. Hence, these questions have been investigated via molecular modelling. In this article, we review computational studies of AMP pore formation using all-atom, coarse-grained, and implicit solvent models; evaluate the results obtained and suggest future research directions to further elucidate the pore formation mechanism of AMPs.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.

Computational prediction of the optimal oligomeric state for membrane-inserted ß-barrels of protegrin-1 and related mutants.

Protegrin-1 is a widely studied 18-residue ß-hairpin antimicrobial peptide. Evidence suggests that it acts via a ß-barrel pore formation mechanism, but the exact number of peptides comprising the pore state is unknown. In this study, we performed molecular dynamics simulations of ß-barrels of protegrin and three related mutants (v14v16l, v14v16a, and r4n) in NCNC parallel topology in implicit membrane pores of varying radius and curvature for oligomeric numbers 6-14. We then identified the optimal pore radius and curvature values for all constructs and determined the total effective energy and the translational and rotational entropic losses. These, along with an estimate of membrane deformation free energy from experimental line tension values, provided an estimate of the overall energetics of formation of each pore state. The results indicated that oligomeric numbers 7-13 are generally stable, allowing the possibility of a heterogeneous pore state. The optimal oligomeric state for protegrin is the nonamer, shifting to higher numbers for the mutants. Protegrin, v14v16l, and r4n are stable as membrane-inserted ß-barrels, but v14v16a seems much less so because of its decreased hydrophobicity. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Implicit Membrane Investigation of the Stability of Antimicrobial Peptide ß-Barrels and Arcs.

Previous simulations showed that the ß-hairpin antimicrobial peptide (AMP) protegrin-1 can form stable octameric ß-barrels and tetrameric arcs (half barrels) in both implicit and explicit membranes. Here, we extend this investigation to several AMPs of similar structure: tachyplesin, androctonin, polyphemusin, gomesin, and the retrocyclin θ-defensin. These peptides form short ß-hairpins stabilized by 2-3 disulfide bonds. We also examine synthetic ß-sheet peptides selected from a combinatorial library for their ability or inability to form pores in lipid membranes. When heptameric, octameric, and decameric ß-barrels and tetrameric arcs of these peptides were embedded in pre-formed neutral or anionic lipid pores (i.e., pores in neutral or anionic membranes, respectively), a variety of behaviors and membrane binding energies were observed. Due to the cationic charge of the peptides, more favorable transfer energies and more stable binding were observed in anionic than neutral pores. The synthetic peptides bound very strongly and formed stable barrels and arcs in both neutral and anionic pores. The natural AMPs exhibited unfavorable or marginally favorable binding energy and kinetic stability in neutral pores, consistent with the lower hemolytic activity of some of them compared with protegrin-1. Binding to anionic pores was more favorable, but significant distortions of the barrel or arc structures were sometimes noted. These results are discussed in light of the available experimental data. The diversity of behaviors obtained makes it unlikely that the barrel and arc mechanisms are valid for the entire family of ß-hairpin AMPs.

Reliable and durable Golgi staining of brain tissue from human autopsies and experimental animals.

BACKGROUND: Golgi stains are notoriously capricious, particularly when applied to human brain. The well-known difficulties, which include complete failure of impregnation, patchy staining, unstable staining, and extensive crystalline deposits in superficial sections, have discouraged many from attempting to use these techniques. A reliable method that produces uniform impregnation in tissue from human autopsies and experimental animals is needed. NEW METHOD: The method described, "NeoGolgi", modifies previous Golgi-Cox protocols (Glaser and Van der Loos, 1981). Changes include: much longer time (>10 weeks) in Golgi solution, agitation on a slowly rocking platform, more gradual infiltration with Parlodion, more thorough removal of excess staining solution during embedding, and shorter exposure to ammonia after infiltration. RESULTS: The procedure has successfully stained over 220 consecutive frontal or hippocampal blocks from more than 175 consecutive human autopsy cases. Dendritic spines are easily recognized, and background is clear, allowing examination of very thick (200 µm) sections. Stained neurons are evenly distributed within cortical regions. The stain is stable for at least eight years. Most importantly, all stained neurons are apparently well-impregnated, eliminating ambiguity between pathology and poor impregnation that is inherent to other methods. COMPARISON WITH EXISTING METHODS: Most methods of Golgi staining are poorly predictable. They often fail completely, staining is patchy, and abnormal morphology is often indistinguishable from poor impregnation. "NeoGolgi" overcomes these problems. CONCLUSION: Starting with unfixed tissue, it is possible to obtain Golgi staining of predictably high quality in brains from human autopsies and experimental animals.

A learning-style theory for understanding autistic behaviors.

Understanding autism's ever-expanding array of behaviors, from sensation to cognition, is a major challenge. We posit that autistic and typically developing brains implement different algorithms that are better suited to learn, represent, and process different tasks; consequently, they develop different interests and behaviors. Computationally, a continuum of algorithms exists, from lookup table (LUT) learning, which aims to store experiences precisely, to interpolation (INT) learning, which focuses on extracting underlying statistical structure (regularities) from experiences. We hypothesize that autistic and typical brains, respectively, are biased toward LUT and INT learning, in low- and high-dimensional feature spaces, possibly because of their narrow and broad tuning functions. The LUT style is good at learning relationships that are local, precise, rigid, and contain little regularity for generalization (e.g., the name-number association in a phonebook). However, it is poor at learning relationships that are context dependent, noisy, flexible, and do contain regularities for generalization (e.g., associations between gaze direction and intention, language and meaning, sensory input and interpretation, motor-control signal and movement, and social situation and proper response). The LUT style poorly compresses information, resulting in inefficiency, sensory overload (overwhelm), restricted interests, and resistance to change. It also leads to poor prediction and anticipation, frequent surprises and over-reaction (hyper-sensitivity), impaired attentional selection and switching, concreteness, strong local focus, weak adaptation, and superior and inferior performances on simple and complex tasks. The spectrum nature of autism can be explained by different degrees of LUT learning among different individuals, and in different systems of the same individual. Our theory suggests that therapy should focus on training autistic LUT algorithm to learn regularities.

Regional cerebral blood flow and metabolic rate in persistent Lyme encephalopathy.

CONTEXT: There is controversy regarding whether objective neurobiological abnormalities exist after intensive antibiotic treatment for Lyme disease. OBJECTIVES: To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR). DESIGN: Case-controlled study. SETTING: A university medical center. PARTICIPANTS: A total of 35 patients and 17 healthy volunteers (controls). Patients had well-documented prior Lyme disease, a currently reactive IgG Western blot, prior treatment with at least 3 weeks of intravenous cephalosporin, and objective memory impairment. MAIN OUTCOME MEASURES: Patients with persistent Lyme encephalopathy were compared with age-, sex-, and education-matched controls. Fully quantified assessments of rCBF and rCMR for glucose were obtained while subjects were medication-free using positron emission tomography. The CBF was assessed in 2 resting room air conditions (without snorkel and with snorkel) and 1 challenge condition (room air enhanced with carbon dioxide, ie, hypercapnia). RESULTS: Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (P < .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements. CONCLUSIONS: Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.

Adaptation across the cortical hierarchy: low-level curve adaptation affects high-level facial-expression judgments.

Adaptation is ubiquitous in sensory processing. Although sensory processing is hierarchical, with neurons at higher levels exhibiting greater degrees of tuning complexity and invariance than those at lower levels, few experimental or theoretical studies address how adaptation at one hierarchical level affects processing at others. Nevertheless, this issue is critical for understanding cortical coding and computation. Therefore, we examined whether perception of high-level facial expressions can be affected by adaptation to low-level curves (i.e., the shape of a mouth). After adapting to a concave curve, subjects more frequently perceived faces as happy, and after adapting to a convex curve, subjects more frequently perceived faces as sad. We observed this multilevel aftereffect with both cartoon and real test faces when the adapting curve and the mouths of the test faces had the same location. However, when we placed the adapting curve 0.2 degrees below the test faces, the effect disappeared. Surprisingly, this positional specificity held even when real faces, instead of curves, were the adapting stimuli, suggesting that it is a general property for facial-expression aftereffects. We also studied the converse question of whether face adaptation affects curvature judgments, and found such effects after adapting to a cartoon face, but not a real face. Our results suggest that there is a local component in facial-expression representation, in addition to holistic representations emphasized in previous studies. By showing that adaptation can propagate up the cortical hierarchy, our findings also challenge existing functional accounts of adaptation.