Epigenetic effects of stress and corticosteroids in the brain

Stress is a common life event with potentially long lasting effects on health and behavior. Stress, and the corticosteroid hormones that mediate many of its effects, are well known for their ability to alter brain function and plasticity. While genetic susceptibility may influence the impact of stress on the brain, it does not provide us with a complete understanding of the capacity of stress to produce long lasting perturbations on the brain and behavior. The growing science of epigenetics, however, shows great promise of deepening our understanding of the persistent impacts of stress and corticosteroids on health and disease. Epigenetics, broadly defined, refers to influences on phenotype operating above the level of the genetic code itself. At the molecular level, epigenetic events belong to three major classes: DNA methylation, covalent histone modification and non-coding RNA. This review will examine the bi-directional interactions between stress and corticosteroids and epigenetic mechanisms in the brain and how the novel insights, gleaned from recent research in neuro-epigenetics, change our understanding of mammalian brain function and human disease states

Cortex

Objective:Childhood physical and sexual abuse are stressful experiences that may alter the emotional response to future stressors. Stress-related emotional function is supported by brain regions that include the prefrontal cortex (PFC), hippocampus, and amygdala. The present study investigated whether childhood physical and sexual abuse are associated with stress-elicited brain activity in young adulthood.Methods:Participants (N=300; Mage=20.0; 151 female) completed a psychosocial stress task during functional magnetic resonance imaging (fMRI). Measures of physical and sexual abuse were included in a linear mixed effects model to estimate the unique relationship each type of childhood abuse had with stress-elicited brain activity.Results:Stress-elicited dorsolateral PFC, ventromedial PFC, and hippocampal activity decreased as the frequency of childhood sexual abuse increased. There were no regions in which stress-elicited activation varied with physical abuse.Conclusions:The present findings suggest there is a unique relationship between childhood sexual abuse and the stress-elicited PFC and hippocampal activity of young adults that is not observed following childhood physical abuse.Significance:These findings may have important implications for understanding the mechanisms by which childhood sexual abuse impacts the development of future psychopathology.U19 DP002664/DP/NCCDPHP CDC HHSUnited States/U48 DP000046/DP/NCCDPHP CDC HHSUnited States/U48 DP000057/DP/NCCDPHP CDC HHSUnited States/U19 DP002663/DP/NCCDPHP CDC HHSUnited States/U48 DP000056/DP/NCCDPHP CDC HHSUnited States/R01 MH098348/MH/NIMH NIH HHSUnited States/U19 DP002665/DP/NCCDPHP CDC HHSUnited States/F31 AA027137/AA/NIAAA NIH HHSUnited States/2022-04-01T00:00:00Z33609897PMC804401811163vault:3694

Spin-Mediated Consciousness Theory: Possible Roles of Neural Membrane Nuclear Spin Ensembles and Paramagnetic Oxygen

A novel theory of consciousness is proposed in this paper. We postulate that consciousness is intrinsically connected to quantum spin since the latter is the origin of quantum effects in both Bohm and Hestenes quantum formulism and a fundamental quantum process associated with the structure of space-time. That is, spin is the “mind-pixel.” The unity of mind is achieved by entanglement of the mind-pixels. Applying these ideas to the particular structures and dynamics of the brain, we theorize that human brain works as follows: Through action potential modulated nuclear spin interactions and paramagnetic O2/NO driven activations, the nuclear spins inside neural membranes and proteins form various entangled quantum states some of which survive decoherence through quantum Zeno effects or in decoherence-free subspaces and then collapse contextually via irreversible and non-computable means producing consciousness and, in turn, the collective spin dynamics associated with said collapses have effects through spin chemistry on classical neural activities thus influencing the neural networks of the brain. Our proposal calls for extension of associative encoding of neural memories to the dynamical structures of neural membranes and proteins. Thus, according our theory, the nuclear spin ensembles are the “mind-screen” with nuclear spins as its pixels, the neural membranes and proteins are the mind-screen and memory matrices, and the biologically available paramagnetic species such as O2 and NO are pixel-activating agents. Together, they form the neural substrates of consciousness. We also present supporting evidence and make important predictions. We stress that our theory is experimentally verifiable with present technologies. Further, experimental realizations of intra-/inter-molecular nuclear spin coherence and entanglement, macroscopic entanglement of spin ensembles and NMR quantum computation, all in room temperatures, strongly suggest the possibility of a spin-mediated mind

Spin-Mediated Consciousness Theory: An Approach Based On Pan-Protopsychism

As an alternative to our original dualistic approach, we present here our spin-mediated consciousness theory based on pan-protopsychism. We postulate that consciousness is intrinsically connected to quantum mechanical spin since said spin is embedded in the microscopic structure of spacetime and may be more fundamental than spacetime itself. Thus, we theorize that consciousness emerges quantum mechanically from the collective dynamics of "protopsychic" spins under the influence of spacetime dynamics. That is, spin is the "pixel" of mind. The unity of mind is achieved by quantum entanglement of the mind-pixels. Applying these ideas to the particular structures and dynamics of the brain, we postulate that the human mind works as follows: The nuclear spin ensembles ("NSE") in both neural membranes and proteins quantum mechanically process consciousness-related information such that conscious experience emerges from the collapses of entangled quantum states of NSE under the influence of the underlying spacetime dynamics. Said information is communicated to NSE through strong spin-spin couplings by biologically available unpaired electronic spins such as those carried by rapidly diffusing oxygen molecules and neural transmitter nitric oxides that extract information from their diffusing pathways in the brain. In turn, the dynamics of NSE has effects through spin chemistry on the classical neural activities such as action potentials and receptor functions thus influencing the classical neural networks of said brain. We also present supporting evidence and make important predictions. We stress that our theory is experimentally verifiable with present technologies

Brain structure across the lifespan : the influence of stress and mood

Normal brain aging is an inevitable and heterogeneous process characterized by a selective pattern of structural changes. Such heterogeneity arises as a consequence of cumulative effects over the lifespan, including stress and mood effects, which drive different micro- and macro-structural alterations in the brain. Investigating these differences in healthy age-related changes is a major challenge for the comprehension of the cognitive status. Herein we addressed the impact of normal aging, stress, mood, and their interplay in the brain gray and white matter (WM) structure. We showed the critical impact of age in the WM volume and how stress and mood influence brain volumetry across the lifespan. Moreover, we found a more profound effect of the interaction of aging/stress/mood on structures located in the left hemisphere. These findings help to clarify some divergent results associated with the aging decline and to enlighten the association between abnormal volumetric alterations and several states that may lead to psychiatric disorders.We are thankful to all study participants. This work was funded by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772) and co-financed by the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). Jose M. Soares, Paulo Marques, and Nadine C. Santos are supported by fellowships of the project "SwitchBox"; Ricardo Magalhaes is supported by a fellowship from the project FCTANR/NEU-OSD/0258/2012 funded by FCT/MEC (www.fct.pt) and by ON.2 - ONOVONORTE - North - Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/2013, through FEDER

Allostatic load and disordered white matter microstructure in overweight adults

Overweight and stress are both related to brain structural abnormalities. The allostatic load model states that frequent disruption of homeostasis is inherently linked to oxidative stress and inflammatory responses that in turn can damage the brain. However, the effects of the allostatic load on the central nervous system remain largely unknown. The current study aimed to assess the relationship between the allostatic load and the composition of whole-brain white matter tracts in overweight subjects. Additionally, we have also tested for grey matter changes regarding allostatic load increase. Thirty-one overweight-to-obese adults and 21 lean controls participated in the study. Our results showed that overweight participants presented higher allostatic load indexes. Such increases correlated with lower fractional anisotropy in the inferior fronto-occipital fasciculi and the right anterior corona radiata, as well as with grey matter reductions in the left precentral gyrus, the left lateral occipital gyrus, and the right pars opercularis. These results suggest that an otherwise healthy overweight status is linked to long-term biological changes potentially harmful to the brain

Optogenetic elevation of endogenous glucocorticoid level in larval zebrafish

The stress response is a suite of physiological and behavioral processes that help to maintain or reestablish homeostasis. Central to the stress response is the hypothalamic-pituitary-adrenal (HPA) axis, as it releases crucial hormones in response to stress. Glucocorticoids (GCs) are the final effector hormones of the HPA axis, and exert a variety of actions under both basal and stress conditions. Despite their far-reaching importance for health, specific GC effects have been difficult to pin-down due to a lack of methods for selectively manipulating endogenous GC levels. Hence, in order to study stress-induced GC effects, we developed a novel optogenetic approach to selectively manipulate the rise of GCs triggered by stress. Using this approach, we could induce both transient hypercortisolic states and persistent forms of hypercortisolaemia in freely behaving larval zebrafish. Our results also established that transient hypercortisolism leads to enhanced locomotion shortly after stressor exposure. Altogether, we present a highly specific method for manipulating the gain of the stress axis with high temporal accuracy, altering endocrine and behavioral responses to stress as well as basal GC levels. Our study offers a powerful tool for the analysis of rapid (non-genomic) and delayed (genomic) GC effects on brain function and behavior, feedbacks within the stress axis and developmental programming by GCs

An Introduction: Quantification of the Hippocampal BDNF Content of Maternally Separated Rats Using a Western Blot Protocol

Among industrialized nations, the United States has the worst incidence of child maltreatment with 3 million cases per year (U.S. Department of Health and Human Services, 2012). Studies have shown that individuals who were maltreated when they were young are more susceptible to drug abuse such as alcohol, cocaine, and nicotine (Maddahian, Newcomb, & Bentle, 1988). Early life stress (ELS) causes hyperactivation of the Hypothalamic-Pituitary- Adrenal (HPA) Axis (Heim et al., 2000; Plotsky et al., 2005). The dysregulation of the HPA axis causes the secretion of glucocorticoid stress hormones by large amounts, which in return attenuates hippocampal Brain-derived neurotrophic factor (BDNF) (Smith, Makino, Kvetnansky, & Post, 1995). BDNF is a neurotrophin that helps the growth, maintenance, and survival of neurons and is also involved in neuronal plasticity. To mimic ELS, maternal separation is used as an animal model. Studies have shown that adult maternally separated rats have decreased hippocampal mature BDNF (Lippman et al., 2007). Exercise alters some of the effects of ELS by protecting hippocampal BDNF from the down-regulation caused by the hyperactivation of HPA axis (Maniam & Morris, 2010; Neeper et al., 1996). The purpose of this research is to investigate the effects of ELS and exercise on behaviors related to substance abuse and hippocampal BDNF content. When we attempted to measure hippocampal BDNF by the enzyme-linked immunosorbent assay (ELISA), we did not observe the previously-published down-regulation of BDNF in the hippocampi of maternally separated animals (Dold, 2013). Thus, a western blot protocol was developed for the quantification of BDNF in the same protein samples that were previously quantified using ELISA. Western blot is more specific in targeting protein due to SDS-page capability to separate protein components in accordance to their size. BDNF undergoes post-translational processing, such that both pro- BDNF (the 32 kD precursor) and mature BDNF (14 kD) are present and biologically active in rat brain tissue. Thus, western blot will allow us to distinguish between these BDNF proteins, which is important in our study since we are primarily interested in mature BDNF. We expect maternal separation (MS) to attenuate the hippocampal mature BDNF content. Furthermore, we expect that the mature BDNF content will positively correlate with the total running activity

Mindfulness Research Update: 2008.

OBJECTIVE: To briefly review the effects of mindfulness on the mind, the brain, the body, and behavior. METHODS: Selective review of MEDLINE, PsycINFO, and Google Scholar databases (2003-2008) using the terms mindfulness , meditation , mental health , physical health , quality of life , and stress reduction. A total of 52 exemplars of empirical and theoretical work were selected for review. RESULTS: Both basic and clinical research indicate that cultivating a more mindful way of being is associated with less emotional distress, more positive states of mind, and better quality of life. In addition, mindfulness practice can influence the brain, the autonomic nervous system, stress hormones, the immune system, and health behaviors, including eating, sleeping and substance use, in salutary ways. CONCLUSION: The application of cutting-edge technology toward understanding mindfulness - an inner technology - is elucidating new ways in which attention, awareness, acceptance, and compassion may promote optimal health - in mind, body, relationships, and spirit

The (un)conscious mouse as a model for human brain functions: key principles of anesthesia and their impact on translational neuroimaging

In recent years, technical and procedural advances have brought functional magnetic resonance imaging (fMRI) to the field of murine neuroscience. Due to its unique capacity to measure functional activity non-invasively, across the entire brain, fMRI allows for the direct comparison of large-scale murine and human brain functions. This opens an avenue for bidirectional translational strategies to address fundamental questions ranging from neurological disorders to the nature of consciousness. The key challenges of murine fMRI are: (1) to generate and maintain functional brain states that approximate those of calm and relaxed human volunteers, while (2) preserving neurovascular coupling and physiological baseline conditions. Low-dose anesthetic protocols are commonly applied in murine functional brain studies to prevent stress and facilitate a calm and relaxed condition among animals. Yet, current mono-anesthesia has been shown to impair neural transmission and hemodynamic integrity. By linking the current state of murine electrophysiology, Ca(2+) imaging and fMRI of anesthetic effects to findings from human studies, this systematic review proposes general principles to design, apply and monitor anesthetic protocols in a more sophisticated way. The further development of balanced multimodal anesthesia, combining two or more drugs with complementary modes of action helps to shape and maintain specific brain states and relevant aspects of murine physiology. Functional connectivity and its dynamic repertoire as assessed by fMRI can be used to make inferences about cortical states and provide additional information about whole-brain functional dynamics. Based on this, a simple and comprehensive functional neurosignature pattern can be determined for use in defining brain states and anesthetic depth in rest and in response to stimuli. Such a signature can be evaluated and shared between labs to indicate the brain state of a mouse during experiments, an important step toward translating findings across species