Learning ability and longevity: a symmetrical evolutionary trade-off in Drosophila.

Learning ability can be substantially improved by artificial selection in animals ranging from Drosophila to rats. Thus these species have not used their evolutionary potential with respect to learning ability, despite intuitively expected and experimentally demonstrated adaptive advantages of learning. This suggests that learning is costly, but this notion has rarely been tested. Here we report correlated responses of life-history traits to selection for improved learning in Drosophila melanogaster. Replicate populations selected for improved learning lived on average 15% shorter than the corresponding unselected control populations. They also showed a minor reduction in fecundity late in life and possibly a minor increase in dry adult mass. Selection for improved learning had no effect on egg-to-adult viability, development rate, or desiccation resistance. Because shortened longevity was the strongest correlated response to selection for improved learning, we also measured learning ability in another set of replicate populations that had been selected for extended longevity. In a classical olfactory conditioning assay, these long-lived flies showed an almost 40% reduction in learning ability early in life. This effect disappeared with age. Our results suggest a symmetrical evolutionary trade-off between learning ability and longevity in Drosophila.

Unconditioned responses and functional fear networks in human classical conditioning.

Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced inter-regional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network.

Aversive Stimuli and Functional Networks of Fear Learning in PTSD : 734

Background: One characteristic of post traumatic stress disorder is an inability to adapt to a safe environment i.e. to change behavior when predictions of adverse outcomes are not met. Recent studies have also indicated that PTSD patients have altered pain processing, with hyperactivation of the putamen and insula to aversive stimuli (Geuze et al, 2007). The present study examined neuronal responses to aversive and predicted aversive events. Methods: Twenty-four trauma exposed non-PTSD controls and nineteen subjects with PTSD underwent fMRI imaging during a partial reinforcement fear conditioning paradigm, with a mild electric shock as the unconditioned stimuli (UCS). Three conditions were analyzed: actual presentations of the UCS, events when a UCS was expected, but omitted (CS+), and events when the UCS was neither expected nor delivered (CS-). Results: The UCS evoked significant alterations in the pain matrix consisting of the brainstem, the midbrain, the thalamus, the insula, the anterior and middle cingulate and the contralateral somatosensory cortex. PTSD subjects displayed bilaterally elevated putamen activity to the electric shock, as compared to controls. In trials when USC was expected, but omitted, significant activations were observed in the brainstem, the midbrain, the anterior insula and the anterior cingulate. PTSD subjects displayed similar activations, but also elevated activations in the amygdala and the posterior insula. Conclusions: These results indicate altered fear and safety learning in PTSD, and neuronal activations are further explored in terms of functional connectivity using psychophysiological interaction analyses.

Effects of inbreeding on aversive learning in Drosophila.

Inbreeding adversely affects life history traits as well as various other fitness-related traits, but its effect on cognitive traits remains largely unexplored, despite their importance to fitness of many animals under natural conditions. We studied the effects of inbreeding on aversive learning (avoidance of an odour previously associated with mechanical shock) in multiple inbred lines of Drosophila melanogaster derived from a natural population through up to 12 generations of sib mating. Whereas the strongly inbred lines after 12 generations of inbreeding (0.75<F<0.93) consistently showed reduced egg-to-adult viability (on average by 28%), the reduction in learning performance varied among assays (average=18% reduction), being most pronounced for intermediate conditioning intensity. Furthermore, moderately inbred lines (F=0.38) showed no detectable decline in learning performance, but still had reduced egg-to-adult viability, which indicates that overall inbreeding effects on learning are mild. Learning performance varied among strongly inbred lines, indicating the presence of segregating variance for learning in the base population. However, the learning performance of some inbred lines matched that of outbred flies, supporting the dominance rather than the overdominance model of inbreeding depression for this trait. Across the inbred lines, learning performance was positively correlated with the egg-to-adult viability. This positive genetic correlation contradicts a trade-off observed in previous selection experiments and suggests that much of the genetic variation for learning is owing to pleiotropic effects of genes affecting functions related to survival. These results suggest that genetic variation that affects learning specifically (rather than pleiotropically through general physiological condition) is either low or mostly due to alleles with additive (semi-dominant) effects.

Virulent bacterial infection improves aversive learning performance in Drosophila melanogaster.

Virulent infections are expected to impair learning ability, either as a direct consequence of stressed physiological state or as an adaptive response that minimizes diversion of energy from immune defense. This prediction has been well supported for mammals and bees. Here, we report an opposite result in Drosophila melanogaster. Using an odor-mechanical shock conditioning paradigm, we found that intestinal infection with bacterial pathogens Pseudomonas entomophila or Erwinia c. carotovora improved flies' learning performance after a 1h retention interval. Infection with P. entomophila (but not E. c. carotovora) also improved learning performance after 5 min retention. No effect on learning performance was detected for intestinal infections with an avirulent GacA mutant of P. entomophila or for virulent systemic (hemocoel) infection with E. c. carotovora. Assays of unconditioned responses to odorants and shock do not support a major role for changes in general responsiveness to stimuli in explaining the changes in learning performance, although differences in their specific salience for learning cannot be excluded. Our results demonstrate that the effects of pathogens on learning performance in insects are less predictable than suggested by previous studies, and support the notion that immune stress can sometimes boost cognitive abilities.

Conditioning of multiple-point statistics facies simulations to tomographic images

Geophysical tomography captures the spatial distribution of the underlying geophysical property at a relatively high resolution, but the tomographic images tend to be blurred representations of reality and generally fail to reproduce sharp interfaces. Such models may cause significant bias when taken as a basis for predictive flow and transport modeling and are unsuitable for uncertainty assessment. We present a methodology in which tomograms are used to condition multiple-point statistics (MPS) simulations. A large set of geologically reasonable facies realizations and their corresponding synthetically calculated cross-hole radar tomograms are used as a training image. The training image is scanned with a direct sampling algorithm for patterns in the conditioning tomogram, while accounting for the spatially varying resolution of the tomograms. In a post-processing step, only those conditional simulations that predicted the radar traveltimes within the expected data error levels are accepted. The methodology is demonstrated on a two-facies example featuring channels and an aquifer analog of alluvial sedimentary structures with five facies. For both cases, MPS simulations exhibit the sharp interfaces and the geological patterns found in the training image. Compared to unconditioned MPS simulations, the uncertainty in transport predictions is markedly decreased for simulations conditioned to tomograms. As an improvement to other approaches relying on classical smoothness-constrained geophysical tomography, the proposed method allows for: (1) reproduction of sharp interfaces, (2) incorporation of realistic geological constraints and (3) generation of multiple realizations that enables uncertainty assessment.

BORN AT 27 WEEKS OF GESTATION WITH CLASSICAL PKU: CHALLENGES OF DIETETIC MANAGEMENT IN A VERY PRETERM INFANT

Only few cases of classical phenylketonuria (PKU) in premature infants have been reported. Treatment of these patients is challenging due to the lack of a phenylalanine-free amino acid solution for parenteral infusion. The boy was born at 27 weeks of gestation with a weight of 1000 g (P10). He received parenteral nutrition with a protein intake of 3 g/kg/day. On day 7 he was diagnosed with classical PKU (genotype IVS10-11G>A/IVS12+ 1G>A) due to highly elevated phenylalanine (Phe) level in newborn screening (2800 micromol/L). His maximum plasma Phe level reached 3696 micromol/L. Phe intake was stopped for 4 days. During this time the boy received intravenous glucose and lipids as well as little amounts of Phe-free formula by a nasogastric tube. Due to a deficit of essential amino acids and insufficient growth, a parenteral nutrition rich in branched-chain amino-acids and relatively poor in Phe was added, in order to promote protein synthesis without overloading in Phe. Under this regimen, Phe plasma levels normalized on day 19 when intake of natural protein was started. The boy has now a corrected age of 2 years. He shows normal growth parameters and psychomotor development. Despite a long period of highly elevated Phe levels in the postnatal period our patient shows good psychomotor development. The management of premature infants with PKU depends on the child's tolerance to enteral nutrition. It demands an intensive follow-up by an experienced team and dedicated dietician. Appropriate Phe-free parenteral nutrition would be necessary especially in case of gastro-intestinal complications of prematurity.

Cellular schwannomas of the intracranial and intraspinal compartment: morphological and immunological characteristics compared with classical benign schwannomas.

The concept of cellular schwannoma as an unusual benign tumor is well established for peripheral nerves but has never been tested in neurosurgical series. In order to test the validity of this concept in cranial nerves and spinal roots we performed an analysis of the clinical and morphological characteristics of 12 cellular and 166 classical benign schwannomas. Immunohistochemical detection of antigen expression in Schwann cells including proliferating cell nuclear antigen (PCNA) was also performed. This study shows that cellular schwannomas in neurosurgical series manifest at a lower age than the classical benign variant and occur mainly in the spinal roots. Mitotic activity and sinusoidal vessels appear more frequently in cellular schwannomas and constitute with high cellularity, the most valuable criteria separating both entities. The postoperative course in both types of tumors was free of metastases or sarcomatous changes. Immunoexpression of S-100 protein, vimentin, epithelial membrane antigen and glial fibrillary acidic protein is not statistically different between the two variants. In contrast, PCNA is more highly expressed in cellular schwannomas. These These results confirm the concept that cellular schwannomas are a clinico-pathological variant of benign schwannomas and provide significant support for the introduction of this entity in neurosurgical oncology.

Gamma Knife radiosurgery after previous microvascular decompression decreases the chances of pain free in classical trigeminal neuralgia

Purpose: To evaluate the safety-efficacy of Gamma Knife surgery (GKS) as a second treatment for classical trigeminal neuralgia (CTN), and the influence of prior microvascular decompression (MVD). Methods: Between July 1992 and November 2010, 737 patients have been operated with GKRS for ITN and prospectively evaluated in Timone University Hospital in Marseille, France. Among these, 54 patients had a previous history of MVD. Radiosurgery using a Gamma Knife (model B or C or Perfexion) was performed on the basis of on both MR and CT targeting. A single 4 mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.6 mm (range 3.9-11.9) anteriorly to the emergence of the nerve (retrogasserian target). A median maximum dose of 85 Gy (range 70-90) was delivered. Here, the 45 patients with previous MVD and a follow-up longer than one year are evaluated (the patients with megadolichobasilar artery compression and multiple sclerosis were excluded). Results: The median age in this series was 56.75 years (range 28.09-82.39). The median follow-up period was 39.48 months (range 14.10-144.65). All the patients had a past history of surgery, with at least one previous failed MVD, but also radiofrequency lesion (RFL) in 16 patients (35.6%), balloon microcompression in 7 (15.6%) and glycerol rhizotomy in 1 (2.2%). Thirty-five patients (77.8%) were initially pain free after GKS within a median time of 14 days (range 0, 180). Patients from this group had less probability of being pain free compared to our global population of essential trigeminal neuralgia without previous MVD history (p=0.010, hazard ratio of 0.64). Their probability of remaining pain free at 3, 5, 7 and 10 years was 66.5%, 59.1%, 59.1% and 44.3%, respectively. Twelve patients (34.3%) initially pain free experienced a recurrence with a median delay of 31.21 months (range 3.40-89.93). The hypoesthesia actuarial rate at 1 year was 9.1% and remained stable till 12 years with a median delay of onset of 8 months (range 8-8). Conclusions: Retrogasserian GKS proofed to be safe and effective on the long-term basis even after failed previous MVD. Even if the initial result of pain free was only 77.8%, the toxicity was low with only 9.1% hypoesthesia. No patient reported a bothersome hypoesthesia. The probability of maintaining pain relief in the long-term was of 44.3% at 10 years.

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

BACKGROUND: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. METHODS AND RESULTS: We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. CONCLUSIONS: We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning.

Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-beta induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach.

The philosophical foundations of classical "rDzogs chen" in Tibet : investigating the distinction between dualistic mind (sems) and primordial knowing (ye shes)

While the syncretistic Tibetan tradition known as rDzogs chen ("Great Perfection") has attracted considerable attention over the past few decades, its philosophical foundations remain largely unknown to those unacquainted with its primary sources. This thesis looks at the essentials of rDzogs chen philosophy through the lens of two principal distinctions that the tradition has considered indispensable for understanding its distinctive views and practices: dualistic mind (sems) versus primordial knowing (ye shes) and dharmakâya versus the 'ground of all' (kun gzhi) conditioned experience. Arguing that the distinctions provided classical rDzogs chen scholars with a crucial framework for (a) articulating the necessary conditions of nondual primordial knowing, the conditio sine qua non of rNying ma soteriology, and (b) schematizing the relationship between the exoteric and esoteric vehicles of Indian Buddhism within a unifying conception of the Buddhist path as the progressive disclosure of primordial knowing, the thesis shows how the rDzogs chen philosophy of mind has been integral to the tradition's complex soteriology. The thesis consists of two parts: (1) a detailed philosophical investigation of the distinctions and (2) an anthology of previously untranslated Tibetan materials on the distinctions accompanied by critical editions and introductions. The first part systematically invesigates the nature and scope of the distinctions and traces their evolution and complex relationships with Indian Buddhist Cittamâtra, Madhyamaka, Pramàriavàda, and Vajrayâna views. It concludes with an exploration of some soteriological implications of the mind/primordial knowing distinction that became central to rDzogs chen path hermeneutics in the classical period as authors of rDzogs chen path summaries used this distinction to reconcile progressivist sutric and non-progressivist tantric models of the Buddhist path. The translations and texts included in part two of the thesis consist of (a) a short treatise from Klong chen pa's Miscellaneous Writings entitled Sems dang ye shes kyi dris lan (Reply to Questions Concerning Mind and Primordial Knowing), (b) selected passages on the distinctions from this author's monumental summary of the rDzogs chen snying thig system, the Theg mchog mdzod (Treasury of the Supreme Vehicle), and (c) an excerpt on rDzogs chen distinctions taken from 'Jigs med gling pa's (1729-1798) 18th century Klong chen sNying thig path summary entitled Treasury of Qualities (Yon tan mdzod) along with a word-by- word commentary by Yon tan rgya mtsho (b. 19th c.).