Adversity-induced relapse of fear: neural mechanisms and implications for relapse prevention from a study on experimentally induced return-of-fear following fear conditioning and extinction.

The efficacy of current treatments for anxiety disorders is limited by high relapse rates. Relapse of anxiety disorders and addiction can be triggered by exposure to life adversity, but the underlying mechanisms remain unexplored. Seventy-six healthy adults were a priori selected for the presence or absence of adverse experiences during childhood (CA) and recent past (RA; that is, past 12 months). Participants underwent fear conditioning (day 1) and fear extinction and experimental return-of-fear (ROF) induction through reinstatement (a model for adversity-induced relapse; day 2). Ratings, autonomic (skin conductance response) and neuronal activation measures (functional magnetic resonance imaging (fMRI)) were acquired. Individuals exposed to RA showed a generalized (that is, not CS- specific) fear recall and ROF, whereas unexposed individuals showed differential (that is, CS+ specific) fear recall and ROF on an autonomic level despite no group differences during fear acquisition and extinction learning. These group differences in ROF were accompanied by corresponding activation differences in brain areas known to be involved in fear processing and differentiability/generalization of ROF (that is, hippocampus). In addition, dimensional measures of RA, CA and lifetime adversity were negatively correlated with differential skin conductance responses (SCRs) during ROF and hippocampal activation. As discriminating signals of danger and safety, as well as a tendency for overgeneralization, are core features in clinically anxious populations, these deficits may specifically contribute to relapse risk following exposure to adversity, in particular to recent adversity. Hence, our results may provide first and novel insights into the possible mechanisms mediating enhanced relapse risk following exposure to (recent) adversity, which may guide the development of effective pre- and intervention programs.

Deficient inhibitory processing in trait anxiety: Evidence from context-dependent fear learning, extinction recall and renewal.

BACKGROUND: Impaired fear inhibition has been described as a hallmark of pathological anxiety. We aimed at further characterizing the relation between fear inhibition and anxiety by extending previous work to contextual safety stimuli as well as to dimensional scores of trait anxiety in a large sample. METHODS: We employed a validated paradigm for context-dependent fear acquisition/extinction (day 1) and retrieval/expression (day 2) in 377 healthy individuals. This large sample size allowed the employment of a dimensional rather than binary approach with respect to individual differences in trait anxiety. RESULTS: We observed a positive correlation on day 1 between trait anxiety with all CSs that possess an inherent inhibitory component, conveyed either by reliable non-reinforcement of a specific CS in a dangerous context (safe cue) or by the context itself (i.e., safe context). No correlation however was observed for a CS that possesses excitatory (threatening) properties only. These results were observed during fear learning (day 1) for US expectancy and fear ratings but not for SCRs. No such pattern was evident during fear and extinction retrieval/expression (day 2). CONCLUSION: We provide further evidence that high trait anxiety is associated with the inability to take immediate advantage of environmental safety cues (cued and contextual), which might represent a promising trans-diagnostic marker for different anxiety disorders. Consequently, the incorporation of methods to optimize inhibitory learning in current cognitive behavioral therapy (CBT) treatments might open up a promising avenue for precision medicine in anxiety disorders. LIMITATIONS: We did not include patients diagnosed with anxiety disorders.

The role of sleep and sleep deprivation in consolidating fear memories.

Sleep, in particular REM sleep, has been shown to improve the consolidation of emotional memories. Here, we investigated the role of sleep and sleep deprivation on the consolidation of fear memories and underlying neuronal mechanisms. We employed a Pavlovian fear conditioning paradigm either followed by a night of polysomnographically monitored sleep, or wakefulness in forty healthy participants. Recall of learned fear was better after sleep, as indicated by stronger explicitly perceived anxiety and autonomous nervous responses. These effects were positively correlated with the preceding time spent in REM sleep and paralleled by activation of the basolateral amygdala. These findings suggest REM sleep-associated consolidation of fear memory in the human amygdala. In view of the critical participation of fear learning mechanisms in the etiology of anxiety and post-traumatic stress disorder, deprivation of REM sleep after exposure to distressing events is an interesting target for further investigation.

Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents.

Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder).

Parietal modules for reaching.

Optic ataxia (OA) is classically defined as a deficit of visually guided movements that follows lesions of the posterior part of the posterior parietal cortex (PPC). Since the formalisation of the double stream of visual information processing [Milner, A. D., & Goodale, M. A. (1995). The visual brain in action. Oxford: Oxford University Press] and the use of OA as an argument in favour of the involvement of the posterior parietal cortex (dorsal stream) in visually guided movements, many studies have looked at the visuomotor deficits of these patients. In parallel, the development of neuroimaging methods have led to increasing information about the role of the posterior parietal cortex in visually guided actions. In this article, we discuss the similarities and differences in the results that emerged from these two complementary viewpoints by combining a meta-analysis of neuroimaging data on reaching with lesion studies from OA patients and results of our own fMRI study on reaching in the ipsi- and contra-lateral visual field. We identified four bilateral parietal foci from the meta-analysis and found that the more posterior foci showed greater lateralisation for contralateral visual stimulation than more anterior ones Additionally, the more anterior foci showed greater lateralisation for the use of the contralateral hand than the more posterior ones. Therefore, we can demonstrate that they are organised along a postero-anterior gradient of visual-to-somatic information integration. Furthermore, from the combination of imaging and lesion data it can be inferred that a lesion of the three most posterior foci responsible for the target-hand integration could explain the hand and field effect revealed in OA reaching behaviour.

Qualitative and quantitative trait loci conditioning resistance to Puccinia coronata pathotypes NQMG and LGCG in the oat (Avena sativa L.) cultivars Ogle and TAM O-301.

Mapping disease resistance loci relies on the type and precision of phenotypic measurements. For crown rust of oat, disease severity is commonly assessed based on visual ratings of infection types (IT) and/or diseased leaf area (DLA) of infected plants in the greenhouse or field. These data can be affected by several variables including; (i) non-uniform disease development in the field; (ii) atypical symptom development in the greenhouse; (iii) the presence of multiple pathogenic races or pathotypes in the field, and (iv) rating bias. To overcome these limitations, we mapped crown rust resistance to single isolates in the Ogle/TAM O-301 (OT) recombinant inbred line (RIL) population using detailed measurements of IT, uredinia length (UL) and relative fungal DNA (FDNA) estimates determined by q-PCR. Measurements were taken on OT parents and recombinant inbred lines (RIL) inoculated with Puccinia coronata pathotypes NQMG and LGCG in separate greenhouse and field tests. Qualitative mapping identified an allele conferred by TAM O-301 on linkage group (LG) OT-11, which produced a bleached fleck phenotype to both NQMG and LGCG. Quantitative mapping identified two major quantitative trait loci (QTL) originating from TAM O-301 on LGs OT-11 and OT-32 which reduced UL and FDNA of both isolates in all experiments. Additionally, minor QTLs that reduced UL and FDNA were detected on LGs OT-15 and OT-8, originating from TAM O-301, and on LG OT-27, originating from Ogle. Detailed assessments of the OT population using two pathotypes in both the greenhouse and field provided comprehensive information to effectively map the genes responsible for crown rust resistance in Ogle and TAM O-301 to NQMG and LGCG.

Characterization and mapping of oat crown rust resistance genes using three assessment methods.

ABSTRACT Resistance is the primary means of control for crown rust of oat (Avena sativa L.), caused by Puccinia coronata f. sp. avenae, and better knowledge of the genetics of resistance will enhance resistance breeding. Disease data were generated in the field and greenhouse for parents and recombinant inbred lines of the Ogle/TAM O-301 (OT) oat mapping population using (i) a new quantitative assay that employs quantitative real-time polymerase chain reaction (q-PCR) to estimate fungal growth in the host, (ii) digital image analysis, and (iii) visual ratings. The objectives of this study were to evaluate each assessment method's ability to map a major gene from cv. Ogle and potential quantitative trait loci (QTL) contributed by Ogle and TAM O-301. All three assessment methods identified the major gene in Ogle, which was mapped to linkage group OT6. The resolution produced by q-PCR, however, enabled more precise mapping of the major gene. Quantitative analysis indicated that 64% of the phenotypic variation was accounted for using q-PCR, whereas 41 and 52% were accounted for using visual and digital assessments, respectively. Data generated by q-PCR permitted identification of QTL on linkage groups OT32, accounting for 6% of the phenotypic variation, and OT2, accounting for 4% of the variation. QTL on both OT32 and OT2 were conferred by TAM O-301, one of which (OT2) was indiscernible using data from the visual and digital assessments. The new method of precisely phenotyping crown rust resistance provided a more accurate and thorough means of dissecting resistance in the OT mapping population. Similar methods could be developed and applied to other important cereal rust diseases.

Identification and molecular tagging of a gene from PI 289824 conferring resistance to leaf rust (Puccinia triticina) in wheat.

Host-plant resistance is the most economically viable and environmentally responsible method of control for Puccinia triticina, the causal agent of leaf rust in wheat (Triticum aestivum L.). The identification and utilization of new resistance sources is critical to the continued development of improved cultivars as shifts in pathogen races cause the effectiveness of widely deployed genes to be short lived. The objectives of this research were to identify and tag new leaf rust resistance genes. Forty landraces from Afghanistan and Iran were obtained from the National Plant Germplasm System and evaluated under field conditions at two locations in Texas. PI 289824, a landrace from Iran, was highly resistant under field infection. Further evaluation revealed that PI 289824 is highly resistant to a broad spectrum of leaf rust races, including the currently prevalent races of leaf rust in the Great Plains area of the USA. Eight F1 plants, 176 F2 individuals and 139 F2:3 families of a cross between PI 289824 and T112 (susceptible) were evaluated for resistance to leaf rust at the seedling stage. Genetic analysis indicated resistance in PI 289824 is controlled by a single dominant gene. The AFLP analyses resulted in the identification of a marker (P39 M48-367) linked to resistance. The diagnostic AFLP band was sequenced and that sequence information was used to develop an STS marker (TXW200) linked to the gene at a distance of 2.3 cM. The addition of microsatellite markers allowed the gene to be mapped to the short arm of Chromosome 5B. The only resistance gene to be assigned to Chr 5BS is Lr52. The Lr52 gene was reported to be 16.5 cM distal to Xgwm443 while the gene in PI 289824 mapped 16.7 cM proximal to Xgwm443. Allelism tests are needed to determine the relationship between the gene in PI 289824 and Lr52. If the reported map positions are correct, the gene in PI 289824 is unique.

QTL analysis of genotype x environment interactions affecting cotton fiber quality.

Cotton is unusual among major crops in that large acreages are grown under both irrigated and rainfed conditions, making genotype x environment interactions of even greater importance than usual in designing crop-improvement strategies. We describe the impact of well-watered versus water-limited growth conditions on the genetic control of fiber quality, a complex suite of traits that collectively determine the utility of cotton. Fiber length, length uniformity, elongation, strength, fineness, and color (yellowness) were influenced by 6, 7, 9, 21, 25 and 11 QTLs (respectively) that could be detected in one or more treatments. The genetic control of cotton fiber quality was markedly affected both by general differences between growing seasons ("years") and by specific differences in water management regimes. Seventeen QTLs were detected only in the water-limited treatment while only two were specific to the well-watered treatment, suggesting that improvement of fiber quality under water stress may be even more complicated than improvement of this already complex trait under well-watered conditions. In crops such as cotton with widespread use of both irrigated and rainfed production systems, the need to manipulate larger numbers of genes to confer adequate quality under both sets of conditions will reduce the expected rate of genetic gain. These difficulties may be partly ameliorated by efficiencies gained through identification and use of diagnostic DNA markers, including those identified herein.

A high-density genetic map of Sorghum bicolor (L.) Moench based on 2926 AFLP, RFLP and SSR markers.

Using AFLP technology and a recombinant inbred line population derived from the sorghum cross of BTx623 x IS3620C, a high-density genetic map of the sorghum genome was constructed. The 1713 cM map encompassed 2926 loci distributed on ten linkage groups; 2454 of those loci are AFLP products generated from either the EcoRI/MseI or PstI/MseI enzyme combinations. Among the non-AFLP markers, 136 are SSRs previously mapped in sorghum, and 203 are cDNA and genomic clones from rice, barley, oat, and maize. This latter group of markers has been mapped in various grass species and, as such, can serve as reference markers in comparative mapping. Of the nearly 3000 markers mapped, 692 comprised a LOD >3.0 framework map on which the remaining markers were placed with lower resolution (LOD <3.0). By comparing the map positions of the common grass markers in all sorghum maps reported to date, it was determined that these reference markers were essentially collinear in all published maps. Some clustering of the EcoRI/MseI AFLP markers was observed, possibly in centromeric regions. In general, however, the AFLP markers filled most of the gaps left by the RFLP/SSR markers demonstrating that AFLP technology is effective in providing excellent genome coverage. A web site, http://SorghumGenome.tamu.edu, has been created to provide all the necessary information to facilitate the use of this map and the 2590 PCR-based markers. Finally, we discuss how the information contained in this map is being integrated into a sorghum physical map for map-based gene isolation, comparative genome analysis, and as a source of sequence-ready clones for genome sequencing projects.

A molecular cytogenetic map of sorghum chromosome 1. Fluorescence in situ hybridization analysis with mapped bacterial artificial chromosomes.

We used structural genomic resources for Sorghum bicolor (L.) Moench to target and develop multiple molecular cytogenetic probes that would provide extensive coverage for a specific chromosome of sorghum. Bacterial artificial chromosome (BAC) clones containing molecular markers mapped across sorghum linkage group A were labeled as probes for fluorescence in situ hybridization (FISH). Signals from single-, dual-, and multiprobe BAC-FISH to spreads of mitotic chromosomes and pachytene bivalents were associated with the largest sorghum chromosome, which bears the nucleolus organizing region (NOR). The order of individual BAC-FISH loci along the chromosome was fully concordant to that of marker loci along the linkage map. In addition, the order of several tightly linked molecular markers was clarified by FISH analysis. The FISH results indicate that markers from the linkage map positions 0.0-81.8 cM reside in the short arm of chromosome 1 whereas markers from 81.8-242.9 cM are located in the long arm of chromosome 1. The centromere and NOR were located in a large heterochromatic region that spans approximately 60% of chromosome 1. In contrast, this region represents only 0.7% of the total genetic map distance of this chromosome. Variation in recombination frequency among euchromatic chromosomal regions also was apparent. The integrated data underscore the value of cytological data, because minor errors and uncertainties in linkage maps can involve huge physical regions. The successful development of multiprobe FISH cocktails suggests that it is feasible to develop chromosome-specific "paints" from genomic resources rather than flow sorting or microdissection and that when applied to pachytene chromatin, such cocktails provide an especially powerful framework for mapping. Such a molecular cytogenetic infrastructure would be inherently cross-linked with other genomic tools and thereby establish a cytogenomics system with extensive utility in development and application of genomic resources, cloning, transgene localization, development of plant "chromonomics," germplasm introgression, and marker-assisted breeding. In combination with previously reported work, the results indicate that a sorghum cytogenomics system would be partially applicable to other gramineous genera.

Genomic dissection of genotype x environment interactions conferring adaptation of cotton to arid conditions.

The interaction of genotype with environment is of primary importance in many aspects of genomic research and is a special priority in the study of major crops grown in a wide range of environments. Water deficit, the major factor limiting plant growth and crop productivity worldwide, is expected to increase with the spread of arid lands. In genetically equivalent cotton populations grown under well-watered and water-limited conditions (the latter is responsible for yield reduction of approximately 50% relative to well-watered conditions), productivity and quality were shown to be partly accounted for by different quantitative trait loci (QTLs), indicating that adaptation to both arid and favorable conditions can be combined in the same genotype. QTL mapping was also used to test the association between productivity and quality under water deficit with a suite of traits often found to differ between genotypes adapted to arid versus well-watered conditions. In this study, only reduced plant osmotic potential was clearly implicated in improved cotton productivity under arid conditions. Genomic tools and approaches may expedite breeding of genotypes that respond favorably to specific environments, help test roles of additional physiological factors, and guide the isolation of genes that protect crop performance under arid conditions toward improved adaptation of crops to arid cultivation.

Characterization of rhodopsin mis-sorting and constitutive activation in a transgenic rat model of retinitis pigmentosa.

PURPOSE: To determine the extent to which rhodopsin mis-sorting and constitutive activation of the phototransduction cascade contribute to retinal degeneration in a transgenic rat model of retinitis pigmentosa. METHODS: Retinas from transgenic rats expressing truncated rhodopsin (Ser334ter) were examined by light and electron microscopic immunocytochemistry at several time points. Retinal degeneration in transgenic rats raised in darkness was evaluated by quantification of outer nuclear layer thickness and by electroretinography. RESULTS: Mutant rhodopsin was found at inappropriately high levels in the plasma membrane and cytoplasm of Ser334ter rat photoreceptors. When the cell death rate was high this mis-sorting was severe, but mis-sorting attenuated greatly at later stages of degeneration, as the cell death rate decreased. The distributions of two other outer segment proteins (the cGMP-gated channel and peripherin) were examined and found to be sorted normally within the photoreceptors of these rats. Raising Ser334ter transgenic rats in darkness resulted in minimal rescue from retinal degeneration. CONCLUSIONS: Because dark rearing Ser334ter rats results in little rescue, it is concluded that constitutive activation of the phototransduction cascade does not contribute significantly to photoreceptor cell death in this rat model. The nature of the rhodopsin sorting defect and the correlation between the severity of mis-sorting and rate of cell death indicate that truncated rhodopsin may cause apoptosis by interfering with normal cellular machinery in the post-Golgi transport pathway or in the plasma membrane.

The frequency of occurrence of anti-cardiac receptor autoantibodies and their correlation with clinical manifestation in patients with hypertrophic cardiomyopathy.

The purpose of this study was to investigate the frequency of occurrence of autoantibodies against G-protein coupled cardiovascular receptors and their relation to the clinical manifestation of hypertrophic cardiomyopathy (HCM). Autoantibodies against beta1-receptors, Muscarin-2-receptors, Angiotensin-II-receptor subtype 1 and alpha1-receptors were determined with ELISA in 52 patients with HCM (37 male, 15 female, mean age 55 +/- 15 years) and 40 healthy, age and sex matched controls. The clinical characterization of the HCM-patients included ECG, 24-h Holter, and echocardiography. The results showed that there is no significant difference in the frequency of a single autoantibody between HCM-patients and controls. However, if the number of patients who have autoantibodies against beta1-receptors and/or Muscarin-2-receptors were counted together, there are significantly more autoantibodies in HCM compared to controls (11 vs. 2, p = 0.035). Analysis of clinical data from this pooled group of patients showed that in patients with autoantibodies, heart rate variability (HRV), ultra low frequency (ULF) and very low frequency (VLF) were decreased (HRV by 20%, ULF by 50%, and VLF by 46%, p < 0.008) whereas the QTc-interval was increased by 8% (p < 0.02 each). The ratio of septal to posterior wall thickness was increased by 23% (p = 0.05), and the preejection period was prolonged by 46% in patients with autoantibodies (p < 0.001). These results suggest that the existence of these autoantibodies could be associated with an advanced stage or a severe manifestation of HCM.

Chymase gene locus is not associated with myocardial infarction and is not linked to heart size or blood pressure.

The chymase gene is said to be important for the generation of angiotensin II in the heart and therefore is a candidate gene for heart disease. However, we were unable to find an association between allelic variants of the chymase gene and acute myocardial infarction or linkage between the chymase gene locus and heart size.

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms, plasma levels, cardiac dimensions. A twin study.

We tested the hypotheses that angiotensin-converting enzyme insertion/deletion (I/D) and angiotensinogen 235 methionine/threonine (M/T) substitution gene polymorphisms influence angiotensin-converting enzyme and angiotensiongen serum concentrations and cardiac dimensions in 91 monozygotic and 41 dizygotic twin pairs. Cardiac dimensions were determined echocardiographically. Angiotensin-converting enzyme levels were 24 +/- 11, 43 +/- 18, and 58 +/- 24 U/L for the II, ID, and DD genotypes, respectively (P < .01). Posterior wall thickness was 8.1 +/- 1.3, 8.6 +/- 1.7, and 8.9 +/- 1.9 mm for these genotypes (P < .05). Angiotensin-converting enzyme levels were correlated with posterior wall thickness (r = .15, P < .05). The intrapair differences in angiotensin converting enzyme levels for monozygotic, concordant dizygotic, and discordant dizygotic twins were 1.36 +/- 1.6, 1.86 +/- 1.6, and 17.25 +/- 4.3 U/L, respectively. The angiotensinogen M/T genotypes exerted no influence on cardiac dimensions or on angiotensinogen concentrations. The additive genetic effect on angiotensin-converting enzyme levels (0.49), on posterior wall thickness (0.26), and on septum thickness (0.37) was significant (P < .01), although shared and nonshared environmental effects were also identified. Our data confirm the impressive effect that the angiotensin-converting enzyme D allele exerts on angiotensin-converting enzyme plasma levels. Furthermore, our data also suggest that the angiotensin-converting enzyme gene locus is primarily responsible for angiotensin-converting enzyme plasma levels. Our twin study also indicates that the angiotensin-converting enzyme gene locus is genetically linked to posterior wall thickness. The correlation between angiotensin-converting enzyme levels and posterior wall thickness suggests that this effect is exerted by angiotensin-converting enzyme. We were unable to demonstrate genetic linkage between the angiotensinogen gene locus and cardiac dimensions in this study.

Nitrendipine treatment in so-called therapy-resistant arterial hypertension; effect as monotherapy and in combination with propranolol on blood pressure, heart rate, other hemodynamic parameters, plasma renin activity, and catecholamines.

Twenty-three patients [mean age 49.7 +/- 5.6 years (WHO II-III)] with severe hypertension and not responding to previous drug treatment were included in the study to evaluate the effect of nitrendipine (NTP) as monotherapy and also in combination with propranolol (PRO). After a control period of 10 days, NTP was started with 20 mg twice a day and titrated to the maximal dosage of 2 X 40 mg/day. After 1 week of NTP treatment, PRO was added in increasing dosage to a maximal 2 X 100 mg/day. NTP lowered systolic and diastolic blood pressure (BP) significantly (supine BP from 182/119 +/- 19/9 to 157/98 +/- 16/9 mm Hg). After combination with PRO, systolic BP was decreased additionally (supine BP from 157/98 +/- 16/9 to 150/97 +/- 19/9 mm Hg). Plasma norepinephrine (NE) was increased by NTP (from 1.82 +/- 0.78 to 2.38 +/- 1.08 nmol/l, p less than 0.01) and remained elevated during PRO treatment (2.76 +/- 1.10 nmol/l). Plasma renin activity (PRA) showed no significant changes by NTP. Additional effect of PRO on BP correlated significantly with NE and PRA after the NTP period. Plasma epinephrine and dopamine beta-hydroxylase remained unchanged. NTP decreased systemic resistance, calculated from isotope dilution technique (p less than 0.05); after combination with PRO no additional significant changes were registered. Nitrendipine is an effective alternative in so-called therapy-resistant hypertension.

[Diagnosis of heart tumors--contribution of 2-dimensional and Doppler echocardiography]. / Zur Diagnostik von Herztumoren--Beitrag der zweidimensionalen und Doppler-Echokardiographie.

The advantages of the modern two-dimensional echocardiography in comparison to the M-mode one are investigated on the basis of findings in 7 patients with heart tumors. Also the possibilities of Doppler echocardiography for comprehensive information about the cardiac situation in these patients are demonstrated. It will be shown that in some patients operation can be performed entirely on the basis of echocardiographic findings.