Progress towards understanding the genetics of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene–environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.

Phosphorylation of caveolin-1 is anti-apoptotic and promotes cell attachment during oxidative stress of kidney cells

Aims: Caveolin-1 (cav1) is reported to have both cell survival and pro-apoptotic characteristics. This may be explained by its localisation or phosphorylation in injured cells. This study investigated the role of cav1 in kidney cells of different nephron origin and developmental state after oxidative stress. Methods: Renal MCDK distal tubular, HK2 proximal tubular epithelial cells and HEK293T renal embryonic cells were treated with 1mM hydrogen peroxide. Apoptosis, loss of cell adhesion, and cell survival were compared with expression of cav1 in its non-phosphorylated and phosphorylated (p-cav1) forms. Cav1 was transfected into the HEK293T cells, or caveolae were disrupted with filipin or nystatin in HK2 cells, to investigate functions of cav1 and p-cav1. Results: Oxidative stress induced more apoptosis in HK2s than MDCKs (p<0.05). HK2s had lower endogenous cav1 and p-cav1 than MDCKs (p<0.05). Both cell lines had increased p-cav1, but not cav1, with oxidative stress. This increase was greatest in MDCKs (p<0.01). Cav1 was located mainly in the plasma membrane of untreated cells and translocated to the cytoplasm with oxidative stress in both cell lines, more so in MDCKs. Disruption of caveolae caused cytoplasmic translocation of cav1 in HK2s, but did not alter high levels of oxidative stress-induced apoptosis. When HEK293Ts lacking endogenous cav1 were transfected with cav1, oxidant-induced apoptosis and loss of cell adhesion was decreased (p<0.01), and p-cav1 was induced by treatment. Conclusion: Cav1 expression and localisation in kidney cells is not anti-apoptotic, but increased expression of p-cav1 may promote cell survival after oxidative stress. © 2008 Royal College of Pathologists of Australasia.

When size matters: exploring perceptions and justifications of deviant consumer behavior

Deterrence strategies for deviant consumer behavior are criticised for their ‘one size fits all’ approach. In two studies, this paper examines how the size of harm and size of victim influences consumer perceptions of deviant consumer behavior. Deterrence strategies are recommended that overcome the differences in consumer perceptions of deviance.

Regulatory focus moderates the relationship between task control and physiological and psychological markers of stress : a work simulation study

This experiment examined whether trait regulatory focus moderates the effects of task control on stress reactions during a demanding work simulation. Regulatory focus describes two ways in which individuals self-regulate toward desired goals: promotion and prevention. As highly promotion-focused individuals are oriented toward growth and challenge, it was expected that they would show better adaptation to demanding work under high task control. In contrast, as highly prevention-focused individuals are oriented toward safety and responsibility they were expected to show better adaptation under low task control. Participants (N = 110) completed a measure of trait regulatory focus and then three trials of a demanding inbox activity under either low, neutral, or high task control. Heart rate variability (HRV), affective reactions (anxiety & task dissatisfaction), and task performance were measured at each trial. As predicted, highly promotion-focused individuals found high (compared to neutral) task control stress-buffering for performance. Moreover, highly prevention-focused individuals found high (compared to low) task control stress-exacerbating for dissatisfaction. In addition, highly prevention-focused individuals found low task control stress-buffering for dissatisfaction, performance, and HRV. However, these effects of low task control for highly prevention-focused individuals depended on their promotion focus.

Heartbeat and economic decisions : observing mental stress among proposers and responders in the ultimatum bargaining game

The ultimatum bargaining game (UBG), a widely used method in experimental economics, clearly demonstrates that motives other than pure monetary reward play a role in human economic decision making. In this study, we explore the behaviour and physiological reactions of both responders and proposers in an ultimatum bargaining game using heart rate variability (HRV), a small and nonintrusive technology that allows observation of both sides of an interaction in a normal experimental economics laboratory environment. We find that low offers by a proposer cause signs of mental stress in both the proposer and the responder; that is, both exhibit high ratios of low to high frequency activity in the HRV spectrum.

Examining the neural correlates of choice behavior in a gambling task using steady state topography

The present study investigated the behavioral and neuropsychological characteristics of decision-making behavior during a gambling task as well as how these characteristics may relate to the Somatic Marker Hypothesis and the Frequency of Gain model. The applicability to intertemporal choice was also discussed. Patterns of card selection during a computerized interpretation of the Iowa Gambling Task were assessed for 10 men and 10 women. Steady State Topography was employed to assess cortical processing throughout this task. Results supported the hypothesis that patterns of card selection were in line with both theories. As hypothesized, these 2 patterns of card selection were also associated with distinct patterns of cortical activity, suggesting that intertemporal choice may involve the recruitment of right dorsolateral prefrontal cortex for somatic labeling, left fusiform gyrus for object representations, and the left dorsolateral prefrontal cortex for an analysis of the associated frequency of gain or loss. It is suggested that processes contributing to intertemporal choice may include inhibition of negatively valenced options, guiding decisions away from those options, as well as computations favoring frequently rewarded options.

Differential effects of tissue culture coating substrates on prostate cancer cell adherence, morphology and behavior

Weak cell-surface adhesion of cell lines to tissue culture surfaces is a common problem and presents technical limitations to the design of experiments. To overcome this problem, various surface coating protocols have been developed. However, a comparative and precise real-time measurement of their impact on cell behavior has not been conducted. The prostate cancer cell line LNCaP, derived from a patient lymph node metastasis, is a commonly used model system in prostate cancer research. However, the cells’ characteristically weak attachment to the surface of tissue culture vessels and cover slips has impeded their manipulation and analysis and use in high throughput screening. To improve the adherence of LNCaP cells to the culture surface, we compared different coating reagents (poly-L-lysine, poly-L-ornithine, collagen type IV, fibronectin, and laminin) and culturing conditions and analyzed their impact on cell proliferation, adhesion, morphology, mobility and gene expression using real-time technologies. The results showed that fibronectin, poly-L-lysine and poly-L-ornithine improved LNCaP cells adherence and provoked cell morphology alterations, such as increase of nuclear and cellular area. These coating reagents also induced a higher expression of F-actin and reduced cell mobility. In contrast, laminin and collagen type IV did not improve adherence but promoted cell aggregation and affected cell morphology. Cells cultured in the presence of laminin displayed higher mobility than control cells. All the coating conditions significantly affected cell viability; however, they did not affect the expression of androgen receptor-regulated genes. Our comparative findings provide important insight for the selection of the ideal coating reagent and culture conditions for the cancer cell lines with respect to their effect on proliferation rate, attachment, morphology, migration, transcriptional response and cellular cytoskeleton arrangement.

Retinal anatomy of the New Zealand kiwi: Structural traits consistent with their nocturnal behavior

Kiwi (Apteryx spp.) have a visual system unlike that of other nocturnal birds, and have specializations to their auditory, olfactory and tactile systems. Eye size, binocular visual fields and visual brain centers in kiwi are proportionally the smallest yet recorded among birds. Given the many unique features of the kiwi visual system, we examined the laminar organization of the kiwi retina to determine if they evolved increased light sensitivity with a shift to a nocturnal niche or if they retained features of their diurnal ancestor. The laminar organization of the kiwi retina was consistent with an ability to detect low light levels similar to that of other nocturnal species. In particular, the retina appeared to have a high proportion of rod photoreceptors compared to diurnal species, as evidenced by a thick outer nuclear layer, and also numerous thin photoreceptor segments intercalated among the conical shaped cone photoreceptor inner segments. Therefore, the retinal structure of kiwi was consistent with increased light sensitivity, although other features of the visual system, such as eye size, suggest a reduced reliance on vision. The unique combination of a nocturnal retina and smaller than expected eye size, binocular visual fields and brain regions make the kiwi visual system unlike that of any bird examined to date. Whether these features of their visual system are an evolutionary design that meets their specific visual needs or are a remnant of a kiwi ancestor that relied more heavily on vision is yet to be determined.

Female greater wax moths reduce sexual display behavior in relation to the potential risk of predation by echolocating bats

Female greater wax moths Galleria mellonella display by wing fanning in response to bursts of ultrasonic calls produced by males. The temporal and spectral characteristics of these calls show some similarities with the echolocation calls of bats that emit frequency-modulated (FM) signals. Female G. mellonella therefore need to distinguish between the attractive signals of male conspecifics, which may lead to mating opportunities, and similar sounds made by predatory bats. We therefore predicted that (1) females would display in response to playbacks of male calls; (2) females would not display in response to playbacks of the calls of echolocating bats (we used the calls of Daubenton's bat Myotis daubentonii as representative of a typical FM echolocating bat); and (3) when presented with male calls and bat calls during the same time block, females would display more when perceived predation risk was lower. We manipulated predation risk in two ways. First, we varied the intensity of bat calls to represent a nearby (high risk) or distant (low risk) bat. Second, we played back calls of bats searching for prey (low risk) and attacking prey (high risk). All predictions were supported, suggesting that female G. mellonella are able to distinguish conspecific male mating calls from bat calls, and that they modify display rate in relation to predation risk. The mechanism (s) by which the moths separate the calls of bat and moth must involve temporal cues. Bat and moth signals differ considerably in duration, and differences in duration could be encoded by the moth's nervous system and used in discrimination.

Stress at the synapse : signal transduction mechanisms of adrenal steroids at neuronal membranes

As the key neuron-to-neuron interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. However, the signal transduction mechanisms by which stress mediates its lasting effects on synapse transmission and on memory are not fully understood. A key component of the stress response is the increased secretion of adrenal steroids. Adrenal steroids (e.g., cortisol) bind to genomic mineralocorticoid and glucocorticoid receptors (gMRs and gGRs) in the cytosol. In addition, they may act through membrane receptors (mMRs and mGRs), and signal transduction through these receptors may allow for rapid modulation of synaptic transmission as well as modulation of membrane ion currents. mMRs increase synaptic and neuronal excitability; mechanisms include the facilitation of glutamate release through extracellular signal-regulated kinase signal transduction. In contrast, mGRs decrease synaptic and neuronal excitability by reducing calcium currents through N-methyl-D-aspartate receptors and voltage-gated calcium channels by way of protein kinase A- and G protein-dependent mechanisms. This body of functional data complements anatomical evidence localizing GRs to the postsynaptic membrane. Finally, accumulating data also suggest the possibility that mMRs and mGRs may show an inverted U-shaped dose response, whereby glutamatergic synaptic transmission is increased by low doses of corticosterone acting at mMRs and decreased by higher doses acting at mGRs. Thus, synaptic transmission is regulated by mMRs and mGRs, and part of the stress signaling response is a direct and bidirectional modulation of the synapse itself by adrenal steroids.

High and low fear phenotypes show differences in phosphorylated (p44/42 ERK) MAPK-expressing neurons in the lateral amygdala

Post traumatic stress disorder (PTSD) is a serious medical condition effecting both military and civilian populations. While its etiology remains poorly understood it is characterized by high and prolonged levels of fear responding. One biological unknown is whether individuals expressing high or low conditioned fear memory encode the memory differently and if that difference underlies fear response. In this study we examined cellular mechanisms that underlie high and low conditioned fear behavior by using an advanced intercrossed mouse line (B6D2F1) selected for high and low Pavlovian fear response. A known requirement for consolidation of fear memory, phosphorylated mitogen activated protein kinase (p44/42 (ERK) MAPK (pMAPK)) in the lateral amygdala (LA) is a reliable marker of fear learning-related plasticity. In this study, we asked whether high and low conditioned fear behavior is associated with differential pMAPK expression in the LA and if so, is it due to an increase in neurons expressing pMAPK or increased pMAPK per neuron. To examine this, we quantified pMAPK-expressing neurons in the LA at baseline and following Pavlovian fear conditioning. Results indicate that high fear phenotype mice have more pMAPK-expressing neurons in the LA. This finding suggests that increased endogenous plasticity in the LA may be a component of higher conditioned fear responses and begins to explain at the cellular level how different fear responders encode fear memories. Understanding how high and low fear responders encode fear memory will help identify novel ways in which fear-related illness risk can be better predicted and treated.

Mice behaviorally selected for high Pavlovian fear memory exhibit fear generalization, HPA-axis alterations and increased basal activity in cortico-limbic circuits

Biological factors underlying individual variability in fearfulness and anxiety have important implications for stress-related psychiatric illness including PTSD and major depression. Using an advanced intercross line (AIL) derived from C57BL/6 and DBA/2J mouse strains and behavioral selection over 3 generations, we established two lines exhibiting High or Low fear behavior after fear conditioning. Across the selection generations, the two lines showed clear differences in training and tests for contextual and conditioned fear. Before fear conditioning training, there were no differences between lines in baseline freezing to a novel context. However, after fear conditioning High line mice demonstrated pronounced freezing in a new context suggestive of poor context discrimination. Fear generalization was not restricted to contextual fear. High fear mice froze to a novel acoustic stimulus while freezing in the Low line did not increase over baseline. Enhanced fear learning and generalization are consistent with transgenic and pharmacological disruption of the hypothalamic-pituitary-adrenal axis (HPA-axis) (Brinks, 2009, Thompson, 2004, Kaouane, 2012). To determine whether there were differences in HPA-axis regulation between the lines, morning urine samples were collected to measure basal corticosterone. Levels of secreted corticosterone in the circadian trough were analyzed by corticosterone ELISA. High fear mice were found to have higher basal corticosterone levels than low line animals. Examination of hormonal stress response components by qPCR revealed increased expression of CRH mRNA and decreased mRNA for MR and CRHR1 in hypothalamus of high fear mice. These alterations may contribute to both the behavioral phenotype and higher basal corticosterone in High fear mice. To determine basal brain activity in vivo in High and Low fear mice we used manganese-enhanced magnetic resonance imaging (MEMRI). Analysis revealed a pattern of basal brain activity made up of amygdala, cortical and hippocampal circuits that was elevated in the High line. Ongoing studies also seek to determine the relative balance of excitatory and inhibitory tone in the amygdala and hippocampus and the neuronal structure of its neurons. While these heterogeneous lines are selected on fear memory expression, HPA-axis alterations and differences in hippocampal activity segregate with the behavioral phenotypes. These differences are detectable in a basal state strongly suggesting these are biological traits underlying the behavioral phenotype (Johnson et al, 2011).