Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor ...fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Anxiety and fear-related disorders are common and disabling, and they significantly increase risk for suicide and other causes of morbidity and mortality. However, there is tremendous potential for ...translational neuroscience to advance our understanding of these disorders, leading to novel and powerful interventions and even to preventing their initial development. This overview examines the general circuits and processes thought to underlie fear and anxiety, along with the promise of translational research. It then examines some of the data-driven "next-generation" approaches that are needed for discovery and understanding but that do not always fit neatly into established models. From one perspective, these disorders offer among the most tractable problems in psychiatry, with a great deal of accumulated understanding, across species, of neurocircuit, behavioral, and, increasingly, genetic mechanisms, of how dysregulation of fear and threat processes contributes to anxiety-related disorders. One example is the progressively sophisticated understanding of how extinction underlies the exposure therapy component of cognitive-behavioral therapy approaches, which are ubiquitously used across anxiety and fear-related disorders. However, it is also critical to examine gaps in our understanding between reasonably well-replicated examples of successful translation, areas of significant deficits in knowledge, and the role of large-scale data-driven approaches in future progress and discovery. Although a tremendous amount of progress is still needed, translational approaches to understanding, treating, and even preventing anxiety and fear-related disorders offer great opportunities for successfully bridging neuroscience discovery to clinical practice.
Post-traumatic stress disorder (PTSD) is a prevalent, debilitating and sometimes deadly consequence of exposure to severe psychological trauma. Although effective treatments exist for some ...individuals, they are limited. New approaches to intervention, treatment and prevention are therefore much needed. In the past few years, the field has rapidly developed a greater understanding of the dysfunctional brain circuits underlying PTSD, a shift in understanding that has been made possible by technological revolutions that have allowed the observation and perturbation of the macrocircuits and microcircuits thought to underlie PTSD-related symptoms. These advances have allowed us to gain a more translational knowledge of PTSD, have provided further insights into the mechanisms of risk and resilience and offer promising avenues for therapeutic discovery.
Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing ...experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Following sexual maturity, females disproportionately have higher rates of posttraumatic stress disorder (PTSD) and experience greater symptom severity and chronicity as compared with males. This ...observation has led many to examine sex differences in PTSD risk factors. Though relatively few, these studies reveal that the root causes of PTSD sex differences are complex, and partly represent interactions between sex-specific nonbiological and biological risk factors, which differentially shape PTSD vulnerability. Moreover, these studies suggest that sex-specific PTSD vulnerability is partly regulated by sex differences in fear systems. Fear, which represents a highly conserved adaptive response to threatening environmental stimuli, becomes pathological in trauma- and stress-based psychiatric syndromes, such as PTSD. Over the last 30 years, considerable progress has been made in understanding normal and pathological molecular and behavioral fear processes in humans and animal models. Thus, fear mechanisms represent a tractable PTSD biomarker in the study of sex differences in fear. In this review, we discuss studies that examine nonbiological and biological sex differences that contribute to normal and pathological fear behaviors in humans and animal models. This, we hope, will shed greater light on the potential mechanisms that contribute to increased PTSD vulnerability in females.
Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such ...disorders on society and the individual can be tremendous. In this article, we review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components that underlie PTSD, and the biology of fear conditioning with a particular focus on the brain-derived neurotrophic factor (BDNF)–tyrosine kinase B (TrkB), GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches might help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD.
AbstractExposure to traumatic events that produce extreme fear and horror is all too common in both military and civilian populations, but not all individuals develop posttraumatic stress disorder ...(PTSD) as a result of the exposure. What mediates risk and resilience in the development of PTSD and other stress-related psychopathology is of paramount importance to our further understanding of trauma-related psychopathology as well as the development of new treatment approaches. Biological factors, such as genotype and neurobiology, interact with environmental factors, such as childhood background and trauma load, to affect vulnerability and resilience in the aftermath of trauma exposure. One of the core symptoms of PTSD is the inability to control fear, which has led some investigators and clinicians to conceptualize PTSD as a disorder of fear or, more importantly, its inhibition. This review focuses on translational methods that have been used to examine fear conditioning and inhibition of fear in PTSD and summarizes genetic and neurobiological factors related to fear inhibition. The authors also discuss different pharmacological approaches that enhance fear inhibition and may improve treatment outcomes for patients with PTSD.
The study of inflammation in fear- and anxiety-based disorders has gained interest as growing literature indicates that pro-inflammatory markers can directly modulate affective behavior. Indeed, ...heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear- and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear- and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.
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