Yohimbine-Induced Reactivity of Heart Rate Variability in Unmedicated Depressed Patients With and Without Adverse Childhood Experience

Stressful life events play a role in the pathogenesis of major depressive disorder (MDD) and many patients with MDD were exposed to developmental stress due to adverse childhood experiences (ACE). Furthermore, dysregulation of the autonomic nervous system and higher incidence of cardiovascular disease are found in MDD. In MDD, and independently in individuals with ACE, abnormalities in heart rate variability (HRV) have been reported. While these are often confounded, we systematically investigated them with a study which included MDD patients with/without ACE as well as healthy individuals with/without ACE. With this study, we investigated the influence of noradrenergic stimulation on HRV reactivity in unmedicated participants in a randomized, double-blind, repeated measures design. Our sample consisted of men and women with MDD and ACE (n = 25), MDD without ACE (n = 24), healthy participants with ACE (n = 27), and without ACE (n = 48). Participants received a 10 mg single dose of the alpha-2 antagonist yohimbine that increases noradrenergic activity or placebo on 2 separate days, with ECG recordings before and after drug administration at defined intervals. We found lower basal HRV in MDD and ACE: patients with MDD had reduced RMSSD whereas participants with ACE had lower LF-HRV. Contrary to our hypothesis, there was no effect of yohimbine. With this study, we were able to replicate previous findings on HRV differences in MDD and ACE. From the null effect of yohimbine, we conclude that the yohimbine-induced sympathetic activation is not a significant driver of HRV in MDD and ACE.

A Limpet’s Legacy: Carry-Over Effects across Life Stages and Generations Caused by Global Change Stressors

<p>Global change is increasingly impacting coastal marine systems. Organisms inhabiting the intertidal zone may be especially vulnerable to additional anthropogenic influences, which augment the naturally stressful, highly variable conditions to which they are already subjected and may lead to the manifestation of artificially severe carry-over effects (COEs). In marine invertebrates with complex life histories, COEs can occur between life stages, when the conditions experienced by one stage influence the characteristics or performance of the next, as well as trans-generationally, in which case the environment experienced by a parental generation affects offspring. Most of the existing literature surrounding COEs focuses only on those between life stages or generations, seldom both simultaneously, and do so with the implementation of only a single stressor. In nature however, organisms may be affected by both forms of COE, since the presence of one does not preclude the other, and are invariably subjected to multiple co-occurring stressors that can interact in complex ways. Consequently, how trans-generational COEs might impact the propagation of stress through offspring life stages remains unclear, and how these processes operate in a global change context is little understood. It was here aimed to elucidate the role of COEs under ongoing global change by addressing these common literature imitations and taking the novel approach of examining how the effects of multiple, global change-associated stressors carry-over from a parental generation through their offspring’s life stages in order to provide a more realistic representation of the conditions under which COEs manifest in the field. This was done using Siphonaria australis, an intertidal pulmonate limpet that deposits benthic egg masses, from which hatch planktonic veliger larvae. Adult S. australis were subjected to one of four treatments for 4h/day over four weeks to induce trans-generational COEs: a no-stress control, a pollution treatment with added copper (5.0μg/L), a “climate change” treatment with elevated temperature (25°C) and UVR (1.7W/m2), and a full global change treatment incorporating all three stressors. At the end of this period, the egg masses laid under each of these adult treatments were subjected to further experimentation for two weeks by being redistributed among the same four treatments again, so as to produce 16 unique treatment histories of adult-to-egg mass stress. Of these, 11 provided successfully hatching larvae, which were reared and observed for COEs between life stages (from egg to larva) under ambient conditions (ie. no added stressors) for 27 days. In adult S. australis survivor size, the size of egg masses laid and the size of individual eggs varied in complex ways over time and across treatments, while the number of survivors was unaffected by stress. Egg masses were unaffected in terms of hatching time but displayed strong responses to parental and developmental stress exposure through hatching success, and the percentage of viable eggs per egg mass, with the latter clearly declining according to adult treatment severity and both showing trans-generational COEs. Larval characteristics were extremely varied across treatment histories and highly context-dependent as hatching size, size reached by 27 days, growth rate, and size at death all showed evidence of COEs between generations and life stages, as well as interaction between both types of COE, with the number of survivors again being the only unaffected response variable. Overall, trans-generational COEs were slightly more common than those between life stages. These results show that both forms of COE, each triggered by exposure to multiple stressors in progenitors and developmental stages, interact to form highly context-dependent legacies of mostly impaired performance in S. australis larvae. This implies that COEs may become more prominent with worsening stressors in the future and suggests that the role of COEs in the persistence of marine invertebrates under ongoing global change may so far have been underestimated by the existing literature.</p>

A Limpet’s Legacy: Carry-Over Effects across Life Stages and Generations Caused by Global Change Stressors

<p>Global change is increasingly impacting coastal marine systems. Organisms inhabiting the intertidal zone may be especially vulnerable to additional anthropogenic influences, which augment the naturally stressful, highly variable conditions to which they are already subjected and may lead to the manifestation of artificially severe carry-over effects (COEs). In marine invertebrates with complex life histories, COEs can occur between life stages, when the conditions experienced by one stage influence the characteristics or performance of the next, as well as trans-generationally, in which case the environment experienced by a parental generation affects offspring. Most of the existing literature surrounding COEs focuses only on those between life stages or generations, seldom both simultaneously, and do so with the implementation of only a single stressor. In nature however, organisms may be affected by both forms of COE, since the presence of one does not preclude the other, and are invariably subjected to multiple co-occurring stressors that can interact in complex ways. Consequently, how trans-generational COEs might impact the propagation of stress through offspring life stages remains unclear, and how these processes operate in a global change context is little understood. It was here aimed to elucidate the role of COEs under ongoing global change by addressing these common literature imitations and taking the novel approach of examining how the effects of multiple, global change-associated stressors carry-over from a parental generation through their offspring’s life stages in order to provide a more realistic representation of the conditions under which COEs manifest in the field. This was done using Siphonaria australis, an intertidal pulmonate limpet that deposits benthic egg masses, from which hatch planktonic veliger larvae. Adult S. australis were subjected to one of four treatments for 4h/day over four weeks to induce trans-generational COEs: a no-stress control, a pollution treatment with added copper (5.0μg/L), a “climate change” treatment with elevated temperature (25°C) and UVR (1.7W/m2), and a full global change treatment incorporating all three stressors. At the end of this period, the egg masses laid under each of these adult treatments were subjected to further experimentation for two weeks by being redistributed among the same four treatments again, so as to produce 16 unique treatment histories of adult-to-egg mass stress. Of these, 11 provided successfully hatching larvae, which were reared and observed for COEs between life stages (from egg to larva) under ambient conditions (ie. no added stressors) for 27 days. In adult S. australis survivor size, the size of egg masses laid and the size of individual eggs varied in complex ways over time and across treatments, while the number of survivors was unaffected by stress. Egg masses were unaffected in terms of hatching time but displayed strong responses to parental and developmental stress exposure through hatching success, and the percentage of viable eggs per egg mass, with the latter clearly declining according to adult treatment severity and both showing trans-generational COEs. Larval characteristics were extremely varied across treatment histories and highly context-dependent as hatching size, size reached by 27 days, growth rate, and size at death all showed evidence of COEs between generations and life stages, as well as interaction between both types of COE, with the number of survivors again being the only unaffected response variable. Overall, trans-generational COEs were slightly more common than those between life stages. These results show that both forms of COE, each triggered by exposure to multiple stressors in progenitors and developmental stages, interact to form highly context-dependent legacies of mostly impaired performance in S. australis larvae. This implies that COEs may become more prominent with worsening stressors in the future and suggests that the role of COEs in the persistence of marine invertebrates under ongoing global change may so far have been underestimated by the existing literature.</p>

Detrimental or beneficial? Untangling the literature on developmental stress studies in birds

ABSTRACT Developing animals display a tremendous ability to change the course of their developmental path in response to the environment they experience, a concept referred to as developmental plasticity. This change in behavior, physiology or cellular processes is primarily thought to allow animals to better accommodate themselves to the surrounding environment. However, existing data on developmental stress and whether it brings about beneficial or detrimental outcomes show conflicting results. There are several well-referred hypotheses related to developmental stress in the current literature, such as the environmental matching, silver spoon and thrifty phenotype hypotheses. These hypotheses speculate that the early-life environment defines the capacity of the physiological functions and behavioral tendencies and that this change is permanent and impacts the fitness of the individual. These hypotheses also postulate there is a trade-off among organ systems and physiological functions when resources are insufficient. Published data on avian taxa show that some effects of developmental nutritional and thermal stressors are long lasting, such as the effects on body mass and birdsong. Although hypotheses on developmental stress are based on fitness components, data on reproduction and survival are scarce, making it difficult to determine which hypothesis these data support. Furthermore, most physiological and performance measures are collected only once; thus, the physiological mechanisms remain undertested. Here, we offer potential avenues of research to identify reasons behind the contrasting results in developmental stress research and possible ways to determine whether developmental programming due to stressors is beneficial or detrimental, including quantifying reproduction and survival in multiple environments, measuring temporal changes in physiological variables and testing for stress resistance later in life.

Morphological Stability of Rural Populations Confirms Their Use As Controls in Urban Ecology Studies

The expansion of urban environments and how animals may be affected by them are being increasingly investigated, leading to a surge in urban ecology studies. Many urban ecology studies involve a direct comparison between rural and urban populations, or the use of urban gradients along a continuum from rural to urban areas. The implicit, although not properly investigated, assumption in these rural vs urban comparisons is that the rural populations offer a control that represents a lack of the anthropogenic stressors affecting the urban populations. Here we used museum skulls from 14 rodent species to conduct two separate studies, measuring fluctuating asymmetry (FA) as a proxy of developmental stress to assess the effect of anthropogenic disturbance. First, we compared urban and rural specimens of house mice (Mus musculus) to validate our methodological approach. Second, we compared rural specimens from 14 rodent species collected during the last two centuries across Austria. We hypothesised that FA in rural populations has not increased over the last two centuries, which would support the use of rural populations as a proper control in rural vs urban comparisons. We found higher morphological asymmetry in urban populations of Mus musculus compared to rural populations, which is consistent with similar studies in other species. However, we did not find any significant increase in FA over time in rural populations for any of the studied species. This supports the common practice of using rural populations as a control in rural vs urban comparisons when assessing the effects of urbanisation.

ANALYTICAL METHODS OF DENTAL ANTHROPOLOGY & FORENSIC ODONTOLOGY –AN OVERVIEW

Dental Anthropology is a scientic discipline, which deals with studies of sexual dimorphism, paleodemography, oral evolutionary trends, paleodiet, biodistance and paleopathology through the analysis & comparison of the dentition of extinct and modern human populations by the study of Non-metric morphological variations (dental morphological features) and metric morphological trends of the dentition of human populations over time (prehistoric and modern) and space impact (ie.ethnic inuences) on them along-with their relation to the processes of adaptation and diet changes that contributed to the evolution of the current dental system and thereby the human race.(1,3,5) Teeth exhibit a wide array of variables, ranging from those largely controlled by genes to those largely dictated by environment. Anthropological questions focusing on teeth therefore, include issues of population origins and population relationships using information on (tooth morphology, size, number), diet and behavior (attrition, crown chipping, tooth-tool use), health (caries, abscesses, periodontal disease, calculus), and developmental stress (hypoplasia, asymmetry).Traits showing a wider distribution and higher frequency suggest a more ancient origin. (7) Apart from classical methods in this eld, many innovative techniques such as extraction of ancient DNA (aDNA), trace element and stable isotope analyses methods are used . Also, the analysis of development of microwear and confocal analyses of occlusal surfaces of teeth is done for documenting tooth use and masticatory function. Dental anthropologists and forensic odontologists can thus, together decipher problems associated with craniofacial identication & can also collaborate in museum model reconstructions out of skull bones for Forensic Facial Approximation.

DNA damage in embryonic neural stem cell determines FTLDs’ fate via early-stage neuronal necrosis

The early-stage pathologies of frontotemporal lobal degeneration (FTLD) remain largely unknown. In VCPT262A-KI mice carrying VCP gene mutation linked to FTLD, insufficient DNA damage repair in neural stem/progenitor cells (NSCs) activated DNA-PK and CDK1 that disabled MCM3 essential for the G1/S cell cycle transition. Abnormal neural exit produced neurons carrying over unrepaired DNA damage and induced early-stage transcriptional repression-induced atypical cell death (TRIAD) necrosis accompanied by the specific markers pSer46-MARCKS and YAP. In utero gene therapy expressing normal VCP or non-phosphorylated mutant MCM3 rescued DNA damage, neuronal necrosis, cognitive function, and TDP43 aggregation in adult neurons of VCPT262A-KI mice, whereas similar therapy in adulthood was less effective. The similar early-stage neuronal necrosis was detected in PGRNR504X-KI, CHMP2BQ165X-KI, and TDPN267S-KI mice, and blocked by embryonic treatment with AAV–non-phospho-MCM3. Moreover, YAP-dependent necrosis occurred in neurons of human FTLD patients, and consistently pSer46-MARCKS was increased in cerebrospinal fluid (CSF) and serum of these patients. Collectively, developmental stress followed by early-stage neuronal necrosis is a potential target for therapeutics and one of the earliest general biomarkers for FTLD.

Adolescent Stress Confers Resilience to Traumatic Stress Later in Life: Role of the Prefrontal Cortex

Background: Stress during adolescence is usually associated with psychopathology later in life. However, under certain circumstances, developmental stress can promote an adaptive phenotype, allowing individuals to cope better with adverse situations in adulthood, thereby contributing to resilience. Methods: Sprague Dawley rats (50 males, 48 females) were subjected to adolescent chronic variable stress (adol CVS) for 2-weeks at PND45. At PND 85, a group was subjected to single prolonged stress (SPS). After a week, animals were evaluated in an auditory-cued fear conditioning paradigm and neuronal recruitment during reinstatement was assessed by Fos expression. Patch clamp electrophysiology (17-35 cells/group) was performed in male rats to examine physiological changes associated with resilience. Results: Adol CVS blocked fear potentiation evoked by SPS. We observed that SPS impaired extinction (males) and enhanced reinstatement (both sexes) of the conditioned freezing response. Prior adol CVS prevented both effects. SPS effects were associated with a reduction of infralimbic (IL) cortex neuronal recruitment after reinstatement in males and increased engagement of the central amygdala in females, both also prevented by adol CVS, suggesting different neurocircuits involved in generating resilience between sexes. We explored the mechanism behind reduced IL recruitment by studying the intrinsic excitability of IL pyramidal neurons. SPS reduced excitability of IL neurons and prior adol CVS prevented this effect. Conclusion: Our data indicate that adolescent stress can impart resilience to the effects of traumatic stress on neuroplasticity and behavior. Our data provide a mechanistic link behind developmental stress induced behavioral resilience and prefrontal (IL) cortical excitability.

A bioecocultural approach to supporting adolescent mothers and their young children in conflict-affected contexts

An estimated 12 million girls aged 15–19 years, and 777,000 girls younger than 15 give birth globally each year. Contexts of war and displacement increase the likelihood of early marriage and childbearing. Given the developmentally sensitive periods of early childhood and adolescence, adolescent motherhood in conflict-affected contexts may put a family at risk intergenerationally. We propose that the specifics of normative neuroendocrine development during adolescence, including increased sensitivity to stress, pose additional risks to adolescent girls and their young children in the face of war and displacement, with potential lifelong consequences for health and development. This paper proposes a developmental, dual-generational framework for research and policies to better understand and address the needs of adolescent mothers and their small children. We draw from the literature on developmental stress physiology, adolescent parenthood in contexts of war and displacement internationally, and developmental cultural neurobiology. We also identify culturally meaningful sources of resilience and provide a review of the existing literature on interventions supporting adolescent mothers and their offspring. We aim to honor Edward Zigler's groundbreaking life and career by integrating basic developmental science with applied intervention and policy.