An MRI study of pituitary volume and parasuicidal behavior in teenagers with first-presentation borderline personality disorder

This structural magnetic resonance imaging study examined the relationship between pituitary gland volume (PGV) and lifetime number of parasuicidal behaviors in a first-presentation, teenage borderline personality disorder (BPD) sample with minimal exposure to treatment. Hierarchical regression analysis revealed that age and number of parasuicidal behaviors were significant predictors of PGV. These findings indicate that parasuicidal behavior in BPD might be associated with greater activation of the hypothalamic-pituitary-adrenal (HPA) axis. Further studies are required using direct neuroendocrine measures and exploring other parameters of self-injurious behavior, such as recency of self-injurious behavior, intent to die and medical threat.

Pituitary volume in teenagers with first-presentation borderline personality disorder

This study used magnetic resonance imaging to examine pituitary gland volume (PGV) in teenage patients with a first presentation of borderline personality disorder (BPD). No difference in PGV was observed between healthy controls (n=20) and the total BPD cohort (n=20). However, within the BPD cohort, those exposed to childhood trauma (n=9) tended to have smaller pituitaries (-18%) than those with no history of childhood trauma (n=10). These preliminary findings suggest that exposure to childhood trauma, rather than BPD, per se, might be associated with reduced PGV, possibly reflecting hypothalamic-pituitary-adrenal axis dysfunction.

Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis

Background We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. Methods Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. Results Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (−6%; p = .032). Conclusions The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis.

Stress, the hippocampus and the HPA axis: Implications for the development of psychotic disorders

The experience of stress is commonly implicated in models of the onset of psychotic disorders. However, prospective studies investigating associations between biological markers of stress and the emergence of psychotic disorders are limited and inconclusive. One biological system proposed as the link between the psychological experience of stress and the development of psychosis is the Hypothalamic-Pituitary-Adrenal (HPA) axis. This paper summarizes and discusses evidence supporting a role for HPA-axis dysfunction in the early phase of schizophrenia and related disorders. METHOD A selective review of psychiatric and psychological research on stress, coping, HPA-axis, the hippocampus and psychotic disorders was performed, with a particular focus on the relationship between HPA-axis dysfunction and the onset of psychotic disorders. RESULTS Individual strands of past research have suggested that the HPA-axis is dysfunctional in at least some individuals with established psychotic disorders; that the hippocampus is an area of the brain that appears to be implicated in the onset and maintenance of psychotic disorders; and that an increase in the experience of stress precedes the onset of a psychotic episode in some individuals. Models of the onset and maintenance of psychotic disorders that link these individual strands of research and strategies for examining these models are proposed in this paper. CONCLUSIONS The current literature provides some evidence that the onset of psychotic disorders may be associated with a higher rate of stress and changes to the hippocampus. It is suggested that future research should investigate whether a relationship exists between psychological stress, HPA-axis functioning and the hippocampus in the onset of these disorders. Longitudinal assessment of these factors in young people at 'ultra' high risk of psychosis and first-episode psychosis cohorts may enhance understanding of the possible interaction between them in the early phases of illness.

Common genetic variants influence human subcortical brain structures

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08×10 -33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Genetic architecture of subcortical brain regions: Common and region-specific genetic contributions

Understanding the aetiology of patterns of variation within and covariation across brain regions is key to advancing our understanding of the functional, anatomical and developmental networks of the brain. Here we applied multivariate twin modelling and principal component analysis (PCA) to investigate the genetic architecture of the size of seven subcortical regions (caudate nucleus, thalamus, putamen, pallidum, hippocampus, amygdala and nucleus accumbens) in a genetically informative sample of adolescents and young adults (N=1038; mean age=21.6±3.2years; including 148 monozygotic and 202 dizygotic twin pairs) from the Queensland Twin IMaging (QTIM) study. Our multivariate twin modelling identified a common genetic factor that accounts for all the heritability of intracranial volume (0.88) and a substantial proportion of the heritability of all subcortical structures, particularly those of the thalamus (0.71 out of 0.88), pallidum (0.52 out of 0.75) and putamen (0.43 out of 0.89). In addition, we also found substantial region-specific genetic contributions to the heritability of the hippocampus (0.39 out of 0.79), caudate nucleus (0.46 out of 0.78), amygdala (0.25 out of 0.45) and nucleus accumbens (0.28 out of 0.52). This provides further insight into the extent and organization of subcortical genetic architecture, which includes developmental and general growth pathways, as well as the functional specialization and maturation trajectories that influence each subcortical region. This multivariate twin study identifies a common genetic factor that accounts for all the heritability of intracranial volume (0.88) and a substantial proportion of the heritability of all subcortical structures, particularly those of the thalamus (0.71 out of 0.88), pallidum (0.52 out of 0.75) and putamen (0.43 out of 0.89). In parallel, it also describes substantial region-specific genetic contributions to the heritability of the hippocampus (0.39 out of 0.79), caudate nucleus (0.46 out of 0.78), amygdala (0.25 out of 0.45) and nucleus accumbens (0.28 out of 0.52).

On the biomechanical significance of inter-lamellar interfaces in the intervertebral disc

The intervertebral disc (IVD) is a unique soft tissue structure which provides structural support and flexibility in the axial skeleton of vertebrates. From a structural perspective, the disc behaves somewhat like a thick walled pressure vessel, where the walls are comprised of a series of composite annular rings (lamellae). However, a prior study (Marchand and Ahmed, 1990) found a high proportion of circumferentially discontinuous lamellae in human lumbar IVDs. The presence of these discontinuities raises important structural questions, because discontinuous lamellae cannot withstand high nucleus pressures via the generation of circumferential (hoop) stress. A possible alternative mechanism may be that inter-lamellar cohesion allows shear stress transfer between adjacent annular layers. The aim of the present study was therefore to investigate the importance of inter-lamellar shear resistance in the intervertebral disc. This work found that inter-lamellar shear resistance has a strong influence on the compressive stiffness of the intervertebral disc, with a change in interface condition from tied (no slip) to frictionless (no shear resistance) reducing disc compressive stiffness by 40%. However, it appears that substantial inter-lamellar shear resistance is present in the bovine tail disc. Decreases in inter-lamellar shear resistance due to degradation of bridging collagenous or elastic fibre structures could therefore be an important part of the process of disc degeneration.

Multimodal imaging of the collagen and elastic fibre networks in the bovine intervertebral disc

INTRODUCTION. The intervertebral disc is the largest avascular structure in the human body, withstanding transient loads of up to nine times body weight during rigorous physical activity. The key structural elements of the disc are a gel-like nucleus pulposus surrounded by concentric lamellar rings containing criss-crossed collagen fibres. The disc also contains an elastic fiber network which has been suggested to play a structural role, but to date the relationship between the collagen and elastic fiber networks is unclear. CONCLUSION. The multimodal transmitted and reflected polarized light microscopy technique developed here allows clear differentiation between the collagen and elastic fiber networks of the intervertebral disc. The ability to image unstained specimens avoids concerns with uneven stain penetration or specificity of staining. In bovine tail discs, the elastic fiber network is intimately associated with the collagen network.

Single-cell-precision microplasma-induced cancer cell apoptosis

The issue of single-cell control has recently attracted enormous interest. However, in spite of the presently achievable intracellular-level physiological probing through bio-photonics, nano-probe-based, and some other techniques, the issue of inducing selective, single-cell-precision apoptosis, without affecting neighbouring cells remains essentially open. Here we resolve this issue and report on the effective single-cell-precision cancer cell treatment using the reactive chemistry of the localized corona-type plasma discharge around a needle-like electrode with the spot size ∼1 µm. When the electrode is positioned with the micrometer precision against a selected cell, a focused and highly-localized micro-plasma discharge induces apoptosis in the selected individual HepG2 and HeLa cancer cells only, without affecting any surrounding cells, even in small cell clusters. This is confirmed by the real-time monitoring of the morphological and structural changes at the cellular and cell nucleus levels after the plasma exposure.

Targeting glucocorticoid receptors that promote resilience in the treatment of addiction

There is strong evidence to suggest that the combination of alcohol and chronic repetitive stress leads to long-lasting effects on brain function, specifically areas associated with stress, motivation and decision-making such as the amygdala, nucleus accumbens and prefrontal cortex. Alcohol and stress together facilitate the imprinting of long-lasting memories. The molecular mechanisms and circuits involved are being studied but are not fully understood. Current evidence suggests that corticosterone (animals) or cortisol (humans), in addition to direct transcriptional effects on the genome, can directly regulate pre- and postsynaptic synaptic transmission through membrane bound glucocorticoid receptors (GR). Indeed, corticosterone-sensitive synaptic receptors may be critical sites for stress regulation of synaptic responses. Direct modulation of synaptic transmission by corticosterone may contribute to the regulation of synaptic plasticity and memory during stress (Johnson et al., 2005; Prager et al., 2010). Specifically, previous data has shown that long term alcohol (1) increases the expression of NR2Bcontaining NMDA receptors at glutamate synapses, (2) changes receptor density, and (3) changes morphology of dendritic spines (Prendergast and Mulholland; 2012). During alcohol withdrawal these changes are associated with increased glucocorticoid signalling and increased neuronal excitability. It has therefore been proposed that these synapse changes lead to the anxiety and alcohol craving associated with withdrawal (Prendergast and Mulholland; 2012). My lab is targeting this receptor system and the amygdala in order to understand the effect of combining alcohol and stress on these pathways. Lastly, we are testing GR specific compounds as potential new medications to promote the development of resilience to developing addiction.

Telomere structure, replication and length maintenance

Telomeres are the termini of linear eukaryotic chromosomes consisting of tandem repeats of DNA and proteins that bind to these repeat sequences. Telomeres ensure the complete replication of chromosome ends, impart protection to ends from nucleolytic degradation, end-to-end fusion, and guide the localization of chromosomes within the nucleus. In addition, a combination of genetic, biochemical, and molecular biological approaches have implicated key roles for telomeres in diverse cellular processes such as regulation of gene expression, cell division, cell senescence, and cancer. This review focuses on recent advances in our understanding of the organization of telomeres, telomere replication, proteins that bind telomeric DNA, and the establishment of telomere length equilibrium.

Early life stress, nicotinic acetylcholine receptors and alcohol use disorders

Stress is a major driving force in alcohol use disorders (AUDs). It influences how much one consumes, craving intensity and whether an abstinent individual will return to harmful alcohol consumption. We are most vulnerable to the effects of stress during early development, and exposure to multiple traumatic early life events dramatically increases the risk for AUDs. However, not everyone exposed to early life stress will develop an AUD. The mechanisms determining whether an individual’s brain adapts and becomes resilient to the effects of stress or succumbs and is unable to cope with stress remain elusive. Emerging evidence suggests that neuroplastic changes in the nucleus accumbens (NAc) following early life stress underlie the development of AUDs. This review discusses the impact of early life stress on NAc structure and function, how these changes affect cholinergic signaling within the mesolimbic reward pathway and the role nicotinic acetylcholine receptors (nAChRs) play in this process. Understanding the neural pathways and mechanism determining stress resilience or susceptibility will improve our ability to identify individuals susceptible to developing AUDs, formulate cognitive interventions to prevent AUDs in susceptible individuals and to elucidate and enhance potential therapeutic targets, such as the nAChRs, for those struggling to overcome an AUD.

Roles of forced nicotine exposure and Comt gene disruption in the development of addiction-related behavioural and neurochemical changes in mice

Activation of midbrain dopamine systems is thought to be critically involved in the addictive properties of abused substances. Drugs of abuse increase dopamine release in the nucleus accumbens and dorsal striatum, which are the target areas of mesolimbic and nigrostriatal dopamine pathways, respectively. Dopamine release in the nucleus accumbens is thought to mediate the attribution of incentive salience to rewards, and dorsal striatal dopamine release is involved in habit formation. In addition, changes in the function of prefrontal cortex (PFC), the target area of mesocortical dopamine pathway, may skew information processing and memory formation such that the addict pays an abnormal amount of attention to drug-related cues. In this study, we wanted to explore how long-term forced oral nicotine exposure or the lack of catechol-O-methyltransferase (COMT), one of the dopamine metabolizing enzymes, would affect the functioning of these pathways. We also wanted to find out how the forced nicotine exposure or the lack of COMT would affect the consumption of nicotine, alcohol, or cocaine. First, we studied the effect of forced chronic nicotine exposure on the sensitivity of dopamine D2-like autoreceptors in microdialysis and locomotor activity experiments. We found that the sensitivity of these receptors was unchanged after forced oral nicotine exposure, although an increase in the sensitivity was observed in mice treated with intermittent nicotine injections twice daily for 10 days. Thus, the effect of nicotine treatment on dopamine autoreceptor sensitivity depends on the route, frequency, and time course of drug administration. Second, we investigated whether the forced oral nicotine exposure would affect the reinforcing properties of nicotine injections. The chronic nicotine exposure did not significantly affect the development of conditioned place preference to nicotine. In the intravenous self-administration paradigm, however, the nicotine-exposed animals self-administered nicotine at a lower unit dose than the control animals, indicating that their sensitivity to the reinforcing effects of nicotine was enhanced. Next, we wanted to study whether the Comt gene knock-out animals would be a suitable model to study alcohol and cocaine consumption or addiction. Although previous work had shown male Comt knock-out mice to be less sensitive to the locomotor-activating effects of cocaine, the present study found that the lack of COMT did not affect the consumption of cocaine solutions or the development of cocaine-induced place preference. However, the present work did find that male Comt knock-out mice, but not female knock-out mice, consumed ethanol more avidly than their wild-type littermates. This finding suggests that COMT may be one of the factors, albeit not a primary one, contributing to the risk of alcoholism. Last, we explored the effect of COMT deficiency on dorsal striatal, accumbal, and prefrontal cortical dopamine metabolism under no-net-flux conditions and under levodopa load in freely-moving mice. The lack of COMT did not affect the extracellular dopamine concentrations under baseline conditions in any of the brain areas studied. In the prefrontal cortex, the dopamine levels remained high for a prolonged time after levodopa treatment in male, but not female, Comt knock-out mice. COMT deficiency induced accumulation of 3,4-dihydroxyphenylacetic acid, which increased further under levodopa load. Homovanillic acid was not detectable in Comt knock-out animals either under baseline conditions or after levodopa treatment. Taken together, the present results show that although forced chronic oral nicotine exposure affects the reinforcing properties of self-administered nicotine, it is not an addiction model itself. COMT seems to play a minor role in dopamine metabolism and in the development of addiction under baseline conditions, indicating that dopamine function in the brain is well-protected from perturbation. However, the role of COMT becomes more important when the dopaminergic system is challenged, such as by pharmacological manipulation.

The Effects of Nicotine on the Regulation of Neuronal Alpha7 Nicotinic Acetylcholine Receptors and Intracellular Signalling Pathways

Nicotine, the addictive compound of tobacco products, exerts its effects in the brain by binding to neuronal acetylcholine nicotinic receptors (nAChRs). The aim of the present study was to increase the knowledge of nicotine s complex effects, the focus being on homomeric alpha7-nAChRs that are widely expressed in the brain. Nicotinic regulation of differential signalling molecules including transcriptional regulators was also studied. We found that the number of alpha7-nAChRs is increased in specific brain regions in mice, in a time-dependent manner after chronic oral nicotine administration. Our results suggest that in addition to alpha4beta2-nAChRs, the other major nAChR subtype expressed in the brain, the number of alpha7-nAChRs is affected by chronic presence of nicotine. We suggest that when studying the long-term effects of nicotine, the duration on administration is of great importance. Next, we observed that nicotine exposure induces accumulation of cAMP in cell cultures expressing nAChRs. Furthermore, nicotine-induced alpha7-nAChR upregulation was potentiated by treatments enhancing cAMP-signalling, suggesting a role for cAMP in the upregulation process. Protein kinase C (PKC) was found essential for the basal regulation of alpha7-nAChR number. The nicotine-evoked alpha7-nAChR upregulation could be further increased by PKC overexpression. Thirdly, the effects of nicotine on dopamine and cAMP regulated phosphoprotein (DARPP-32) were characterised in rat brain. The results show that DARPP-32 is regulated by both acute and long-term nicotine treatment in the striatal subdivisions. The effect of acute nicotine is dose-dependent and the three striatal regions display differential sensitivities to nicotine. Chronic nicotine is also able to regulate DARPP-32 signalling with prominent effect seen in the nucleus accumbens (NAc), suggesting a role for DARPP-32 in the mediation of long-term effects of nicotine. Finally, the regulation of transcription factors Elk-1 and FosB/deltaFosB by nicotine was investigated. We found that Elk-1 is activated by acute nicotine selectively in the NAc core and hippocampal area CA1, whereas acute nicotine does not affect FosB/deltaFosB. Long-term intermittent or continuous nicotine increases the level of total Elk-1 in the same brain regions as acute nicotine. FosB/deltaFosB is also affected by chronic nicotine. Thus, similarly to other drugs of abuse, nicotine regulates transcriptional regulators Elk-1 and FosB/deltaFosB. These results bring further support for a common mechanism underlying the development of addiction. Nicotine s positive effects on learning and memory might involve the transcription factor Elk-1 based on the changes seen in the hippocampus, the key area in cognitive functions.

Neuro- and immunotoxic effects of fumonisin B1 in cells

Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species can also be found in moisture-damaged buildings, and therefore there may also be human exposure to Fusarium mycotoxins, including FB1. FB1 affects the metabolism of sphingolipids by inhibiting the enzyme ceramide synthase. It is neuro-, hepato- and nephrotoxic, and it is classified as possibly carcinogenic to humans. This study aimed to clarify the mechanisms behind FB1-induced neuro- and immunotoxicity. Four neural and glial cell lines of human, rat and mouse origin were exposed to graded doses of FB1 and the effects on the production of reactive oxygen species, lipid peroxidation, intracellular glutathione levels, cell viability and apoptosis were investigated. Furthermore, the effects of FB1, alone or together with lipopolysaccharide (LPS), on the mRNA and protein expression levels of different cytokines and chemokines were studied in human dendritic cells (DC). FB1 induced oxidative stress and cell death in all cell lines studied. Generally, the effects were only seen after prolonged exposure at 10 and 100 µM of FB1. Signs of apoptosis were also seen in all four cell lines. The sensitivities of the cell lines used in this study towards FB1 may be classified as human U-118MG glioblastoma > mouse GT1-7 hypothalamic > rat C6 glioblastoma > human SH-SY5Y neuroblastoma cells. When comparing cell lines of human origin, it can be concluded that glial cells seem to be more sensitive towards FB1 toxicity than those of neural origin. After exposure to FB1, significantly increased levels of the cytokine interferon-γ (IFNγ) were detected in human DC. This observation was further confirmed by FB1-induced levels of the chemokine CXCL9, which is known to be regulated by IFNγ. During co-exposure of DC to both LPS and FB1, significant inhibitions of the LPS-induced levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1β, and their regulatory chemokines CCL3 and CCL5 were observed. FB1 can thus affect immune responses in DC, and therefore, it is rather likely that it also affects other types of cells participating in the immune defence system. When evaluating the toxicity potential of FB1, it is important to consider the effects on different cell types and cell-cell interactions. The results of this study represent new information, especially about the mechanisms behind FB1-induced oxidative stress, apoptosis and immunotoxicity, as well as the varying sensitivities of different cell types towards FB1.