in fields of inquiry as diverse as neuroscience, molecular biology, genomics, developmental psychology, epidemiology, sociology, and economics are catalyzing an important paradigm shift in our un- derstanding of health and disease across the lifespan. This converging, multidisciplinary science of human development has profound impli- cations for our ability to enhance the life prospects of children and to strengthen the social and economic fabric of society. Drawing on these multiple streams of investigation, this report presents an ecobiodeve- lopmental framework that illustrates how early experiences and envi- ronmental influences can leave a lasting signature on the genetic predispositions that affect emerging brain architecture and long-term health. The report also examines extensive evidence of the disruptive impacts of toxic stress, offering intriguing insights into causal mech- anisms that link early adversity to later impairments in learning, be- havior, and both physical and mental well-being. The implications of this framework for the practice of medicine, in general, and pediatrics, specifically, are potentially transformational. They suggest that many adultdiseasesshouldbeviewedasdevelopmentaldisordersthatbegin early in life and that persistent health disparities associated with pov- erty, discrimination, or maltreatment could be reduced by the allevi- ation of toxic stress in childhood. An ecobiodevelopmental framework alsounderscoresthe needfornewthinking aboutthe focus andbound- aries of pediatric practice. It calls for pediatricians to serve as both front-line guardians of healthy child development and strategically po- sitioned, community leaders to inform new science-based strategies that build strong foundations for educational achievement, economic productivity, responsible citizenship, and lifelong health. Pediatrics

/pdf/the-lifelong-effects-of-early-childhood-adversity-and-toxic-49ejk1ikxi.pdf

The Lifelong Effects of Early Childhood Adversity and Toxic Stress

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)00234-2.pdf

Suicide and suicidal behaviour

Socioeconomic status (SES) influences brain development. Farah and colleagues discuss evidence that prenatal factors, parent–child interactions and cognitive stimulation mediate this effect, and consider implications for alleviating SES-related disparities in mental health and academic achievement. Human brain development occurs within a socioeconomic context and childhood socioeconomic status (SES) influences neural development — particularly of the systems that subserve language and executive function. Research in humans and in animal models has implicated prenatal factors, parent–child interactions and cognitive stimulation in the home environment in the effects of SES on neural development. These findings provide a unique opportunity for understanding how environmental factors can lead to individual differences in brain development, and for improving the programmes and policies that are designed to alleviate SES-related disparities in mental health and academic achievement.

/pdf/socioeconomic-status-and-the-brain-mechanistic-insights-from-2bocwkx5yq.pdf

Socioeconomic status and the brain: mechanistic insights from human and animal research

Variations in phenotype reflect the influence of environmental conditions during development on cellular functions, including that of the genome. The recent integration of epigenetics into developmental psychobiology illustrates the processes by which environmental conditions in early life structurally alter DNA, providing a physical basis for the influence of the perinatal environmental signals on phenotype over the life of the individual. This review focuses on the enduring effects of naturally occurring variations in maternal care on gene expression and phenotype to provide an example of environmentally driven plasticity at the level of the DNA, revealing the interdependence of gene and environmental in the regulation of phenotype.

Epigenetics and the biological definition of gene x environment interactions.

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.

/pdf/parental-olfactory-experience-influences-behavior-and-neural-2vpk7mtbsp.pdf

Parental olfactory experience influences behavior and neural structure in subsequent generations

Background
The human brain is comprised of billions of neurons that form networks of connections within and between brain regions. These connections facilitate neuroplastic events that underlie learning and memory, critical aspects of cognitive function often perturbed in neuropsychiatric illnesses. Neuronal signaling is mediated by fast and slow transmission events, encompassing receptors, ligands, ions, enzymes, and other substrates. These elements are spatially arranged in subcellular microdomains, facilitating juxtaposition of proteins that coordinate various biological processes. For example, synaptic transmission is modulated via release of neurotransmitter into the synaptic cleft, where receptors are activated and the postsynaptic cell modulated via electrical and chemical signals. The pre- and postsynaptic compartments include highly specialized protein clusters, with elegant and complex regulatory mechanisms that traffic proteins to and from these zones. In particular, postsynaptic densities are microdomains comprised of about 1000 unique proteins that are interacting with one another via specialized multipotent scaffolding molecule. Postsynaptic density-95 (PSD-95) is a multipotent scaffolding, trafficking, and clustering protein that links glutamate receptors, signaling molecules, and other structural proteins at postsynaptic sites. More than 95% of PSD-95 expression is localized to excitatory synapses, and it is the most abundant scaffolding protein within the postsynaptic density. Mounting genetic, proteomic, and pharmacological evidence converges on alterations in the postsynaptic density of excitatory synapses in subjects with schizophrenia. Cognitive and negative symptoms associated with dysfunction of limbic circuitry, including working memory and motivation, are particularly implicated by this mechanism. To investigate excitatory postsynaptic protein hubs in schizophrenia, we assessed the PSD-95 protein interactome from brain tissue of subjects with schizophrenia and controls.

32.2 abnormalities of synaptic proteomes in schizophrenia

Abstract Background Several imaging and postmortem studies provide evidence that, in the brains of people with schizophrenia, there are alterations in glucose metabolism and energy utilization. However, it is difficult to determine whether altered excitatory transmission alters bioenergetics that then contributes to symptoms of the disorder. We have used a mouse model to begin to address these questions. GluN1 knockdown mice have a mutation that reduces NMDA receptor levels throughout development and maturity. Methods We affinity purified PSD95 protein complexes from GluN1KD and WT brains (n=3 per group) and ran each sample through our liquid chromatography tandem mass spectrometry (LC-MS/MS) protocol in singlicate. We performed pathway analysis with the EnRICHr suite of bioinformatic tools and compared WT to GluN1KD PSD95 interactomes using the top 20 differentially expressed proteins. We also studied how NMDA receptor hypofunction changes the expression of genes related to glucose metabolism and bioenergetics by quantitative PCR of brain cDNA from WT and GluN1 knockdown mice. Results Pathway analysis revealed that WT mice showed pathways relevant for synaptic plasticity (as expected), while GluN1KD analyses yielded proteins related to glucose metabolism and utilization. Gene expression analysis revealed that GluN1 knockdown mice have significant decreases in the expression of Slc16a3, Slc2a1, and Slc2a3, which are the genes for the monocarboxylate transporter (MCT4), and glucose transporters 1 and 3 (GLUT1 and GLUT3). Discussion Our results show that NMDA receptor dysfunction leads to expression changes that would reduce glucose and lactate transport into neurons. The synaptic proteome of NMDAR deficient mice shows an increase in glycolytic enzymes located at the synapse. These data suggest a profound shift in the composition of the cortical excitatory synaptic proteome in GluN1KD mice, with apparent increases in neuroenergetic substrates in neurons. At the same time, there were significant decreases in the levels of transporters that bring glucose and the primary energy substrate, lactate, into neurons. The MCT4 shuttles lactate from astrocytes to neurons, which can then be used for oxidative respiration in neurons. GLUT1 is responsible for transport of glucose across the blood-brain-barrier, and GLUT3 is expressed on neurons and is responsible for glucose uptake in those cells. Notably, we have identified that these transporter gene transcripts are reduced in postmortem brains of people with schizophrenia. Thus, this mouse may be a useful tool to model bioenergetic changes that are observed in schizophrenia, and study functional outcomes when glucose metabolism is improved.

12.2 metabolic consequences of developmental nmda receptor hypofunction

Schizophrenia (SCZ) is a severe and debilitating mental illness. Antipsychotic drugs (APDs) are used to treat both positive and negative SCZ symptoms, by influencing the cellular, subcellular-synaptic, and molecular processes. We posit that these effects influence our understanding of SCZ. To address this, we analyzed postmortem dorsolateral prefrontal cortex grey matter samples from control and SCZ subjects (n=10/group) using liquid-chromatography mass-spectrometry-based proteomics. We retrieved SCZ-altered and APD-influenced proteome-sets using linear and mixed linear models, respectively, and validated them experimentally using independent cohorts and insilico using published datasets. Functional analysis of proteome-sets was contrasted at the biological pathway, cell-type, subcellular-synaptic, and drug-target levels. The SCZ-altered proteome was conserved across several studies from DLPFC and other brain areas and was dependent on drug effect. At the pathway level, we observed an aberrant extracellular event and, except for homeostasis, signal-transduction, cytoskeleton, and dendrites associated downregulated changes, the APDs compensated for the majority of the SCZ-altered pathways. At the cell-type level, the up-and down-regulated SCZ-altered events were associated with two different subsets of striatum projecting layer-5 pyramidal-neurons regulating dopaminergic secretion. At the subcellular synaptic level, compensatory pre- and post-synaptic events were observed. At the drug target level, dopaminergic processes influence the SCZ-altered up-regulated proteome, whereas non-dopaminergic and a diverse array of non-neuromodulatory mechanisms influence the SCZ-altered down-regulated proteome. While these findings are dependent on pharmacological effects, they are also consistent with previous SCZ studies, implying the need to re-evaluate previous results. We discuss our findings in the context of cortico-striatal influence in SCZ-pathology.

https://www.biorxiv.org/content/biorxiv/early/2021/10/28/2021.10.26.465949.full.pdf

Adam J. Funk

Papers

32.2 abnormalities of synaptic proteomes in schizophrenia

12.2 metabolic consequences of developmental nmda receptor hypofunction

Pharmacological impacts on schizophrenia functional analysis: a postmortem proteome study