Neurobiology & Organismal Biology
Vulnerability and Resilience to early life stress (ELS)
Takao Hensch
Individual outcomes can vary widely following early adversity, but the reasons remain unclear. The Hensch lab has recently characterized a mouse model of parental neglect that reveals dramatic behavioral differences by sex. Notably, fragmented maternal care yields internalizing symptoms (cognitive rigidity) in female offspring, while producing externalizing consequences (attention deficits, social impairments) in male siblings. Here, we will focus on the circuit changes in the anterior cingulate cortex (ACC) underlying their inverse susceptibility/resilience despite sharing an identical unpredictable care during their developmental critical period. A notable structure of interest is the perineuronal net (PNN) which gradually enwraps a pivotal inhibitory cell type that drives critical period trajectory. Our pilot study will span: 1) high-resolution EM (electron microscopy) of synaptic excitatory-inhibitory (E-I) balance and nearby glial cells; 2) functional electrophysiological signatures of altered E-I balance by sex in ACC brain slices; 3) molecular correlates of these impairments that can be targeted for recovery of function. Future work will then examine how to regulate the accelerated rate of PNN maturation in ELS females and what prevents this from occurring in ELS males.
Takao Hensch, Harvard/Boston Children’s Hospital
Takao Hensch, Ph.D. is joint professor of Neurology, Harvard Medical School at Children's Hospital Boston, and professor of Molecular and Cellular Biology at Harvard’s Center for Brain Science. After undergraduate studies with Dr. J Allan Hobson at Harvard, he was a student of Dr. Masao Ito at the University Tokyo (MPH) and Fulbright fellow with Dr. Wolf Singer at the Max-Planck Institute for Brain Research, prior to receiving a Ph.D. in neuroscience working with Dr. Michael Stryker at the University of California San Francisco in 1996. He then helped to launch the RIKEN Brain Science Institute as lab head for neuronal circuit development and served as group director (and now special advisor) before returning to the United States in 2006. Dr. Hensch has received several honors, including the Society for Neuroscience Young Investigator Award both in Japan (2001 Tsukahara Prize) and the US (2005), an NIH Director's Pioneer Award (2007), and most recently the Mortimer Sackler MD Prize (2016) for Distinguished Achievement in Developmental Psychobiology; How Early Life Experiences Shape Brain Function (Columbia University Medical Center Press Release and Weill Cornell Press Release). He currently directs an NIMH Silvio O. Conte Center for Basic Mental Health Research at Harvard. He is co-chief editor of Frontiers in Neural Circuits and serves on the editorial board of various other journals, including the Journal of Neuroscience, Neural Development, Neuroscience Research, and Neuron.
Postbiotics for the Treatment of Post-Traumatic Stress Disorder
Yang-Yu Liu & Jakob Hartmann
The gut microbiome is increasingly recognized as an important player within physiological homeostasis of the body but also in pathophysiological derailments. In PTSD, previous human correlational studies and animal models suggest a brain-gut connection, whereby gut microbiota influences both amygdala development and response. Neuroimaging studies demonstrate dysregulation in brain circuits involved in learned fear, with an emphasis on the amygdala, which plays a central role in PTSD. Hence, the gut microbiome may be especially important for PTSD. Importantly, preliminary data from our recent pilot analysis of gut microbiome data of a subgroup of women (with Trauma-no-PTSD vs. PTSD) within the Nurses’ Health Study II identified multiple putative PTSD-causal species/pathways. Based on these results we identified multiple candidate probiotics, which can potentially prevent or ameliorate PTSD.
Adverse childhood experiences (ACE) including physical, emotional, or sexual abuse or trauma as well as physical or emotional neglect represent major risk factors for the development of PTSD later in life. There is growing evidence that ACEs may impact the gut microbiome in humans. Moreover, multiple studies demonstrate that early life stress (ELS) models affect the gut microbiota in rodents. Although still understudied, emerging data also suggests, particularly in rodents, that dietary interventions such as omega-3 fatty acids and pre- and pro- biotics may buffer against the effects of stress on the gut microbiome. Thus, animal models can serve as valuable tools to further explore underlying pathophysiological pathways and, in particular, the complex interaction of environmental, genetic, neuroendocrine and gut microbiome factors that may be responsible for the development of psychopathology or resilience. The limited bedding and nesting paradigm induces stress in the pups evidenced by increased plasma glucocorticoid concentrations and by the presence of hypertrophied adrenal glands at the end of this one week stress period, on postnatal day 9. The consequences of this form of ELS are profound, including a progressive loss of cognitive function and robust derangements of fear, neophobia and social behavior later in life. This project will systematically test if the administration of postbiotics (i.e., metabolic products or byproducts secreted by the candidate probiotics) can reverse an early life stress-induced susceptibility phenotype in adult mice and whether these changes are associated with transcriptional alterations in the brain. It is hypothesized that the candidate postbiotics contribute to the prevention and amelioration of specific endophenotypes relevant to PTSD.
Yang-Yu Liu, MGB/Harvard Medical School/McLean Hospital
Yang-Yu Liu, Ph.D. is currently an Associate Professor of Medicine at Harvard Medical School (HMS) and an Associate Scientist at Brigham and Women’s Hospital (BWH). He received his Ph.D. in Physics from the University of Illinois at Urbana-Champaign in 2009. After that, he held positions as Postdoctoral Research Associate and then Research Assistant Professor at the Center for Complex Network Research at Northeastern University before he joined HMS and BWH in 2013. His current research focuses on studying the human microbiome from community ecology, dynamical systems, control theory, and machine learning perspectives. His lab has published important papers in this field (including a Nature paper on the universal dynamics of the human microbiome, a Nature Methods paper on the fundamental challenges in benchmarking metagenomic profilers, a Nature Machine Intelligence paper on predicting metabolomic profiles from microbial compositions, a series of Nature Communications papers on mapping and controlling the ecological networks of microbial communities, the design of personalized probiotic cocktails, the origin of functional redundancy in the human microbiome, and the role of the human microbiome in COVID-19), as well as an invited review article "Controlling the human microbiome" published in Cell Systems. For more information, please visit: https://yangyuliu.bwh.harvard.edu.
Jakob Hartmann, MGB/Harvard Medical School/McLean Hospital
Jakob Hartmann, Ph.D., is an Assistant Professor of Psychiatry at Harvard Medical School and director of the Neurobehavioral Stress Resilience Laboratory at McLean Hospital. He earned his PhD at the Max-Planck Institute of Psychiatry in Munich, Germany in 2014. He then moved to Boston where he received his postdoctoral training under the mentorship of Kerry Ressler at McLean Hospital, before he started his own lab in 2022. Dr. Hartmann’s work is dedicated to exploring the molecular, cellular, and neurocircuit-specific changes that shape an individual’s trajectory towards susceptibility or resilience to stress-related mental disorders. His research employs a combination of mouse models, machine learning based behavioral analysis, single-cell transcriptomics, and viral vectors to gain deeper insights into the specific cell types and polygenic architecture involved in stress-related psychiatric disorders including major depression and posttraumatic stress disorder. Another crucial aspect of his lab’s research centers around the crosstalk between neuronal stress circuits and the immune system with a specific focus on the impact of chronic stress on neuroinflammation and neurodegeneration. His multidisciplinary approach encompasses primary cell cultures, genetic and transgenic techniques in mice, and analysis of human postmortem brain tissue. By integrating clinical and preclinical data, his goal is to unravel the complex interplay between stress and immune function in psychiatric and neurodegenerative disorders. Through his comprehensive investigations, he strives to advance knowledge and identify potential therapeutic interventions for stress-related psychiatric disorders and neurodegenerative diseases. Dr. Hartmann has published over 40 research articles, reviews and book chapters. He is the recipient of several honors and fellowships, including a research scholarship from the German Research Foundation and NARSAD Young Investigator Awards in 2016 and 2022.
The transcriptional encoding of trauma-relevant cortical states and their impacts on neural circuits
Daniel Hochbaum
A deep understanding of how both low and high glucocorticoid levels impact brain circuitry will be critical to deciphering trauma’s impact on behavior and the brain and will identify potential therapeutic targets. Glucocorticoid receptors are ligand-gated transcription factors that are expressed in cortex, and glucocorticoid levels are known to regulate structural plasticity in neurons among many other changes in the brain. The cell-type specific transcriptional programs driving these changes, and the link between altered physiology, circuit function and behavior remains unresolved. The work proposed below will parallel recent efforts in understanding the effects of thyroid hormone on cortical circuitry. Thyroid hormone is, like glucocorticoids, a nuclear hormone with transcription-factor receptors present in adult (both mouse and human) cortex. We demonstrated that thyroid hormone couples peripheral metabolism to cell-type specific transcriptional changes in cortex that rewire neural circuits and alter an animal’s willingness to explore and take risks. Here we propose to uncover the cell-type specific transcriptional pathways governed by cortisol levels in the frontal cortex, which comprises brain areas that are determinants of high-level cognition and mood, and therefore relevant to the symptomology of PTSD.
Daniel Hochbaum, Harvard Medical School
Daniel Hochbaum, Ph.D. earned his Ph.D. in Applied Physics from Harvard University in 2014 and his B.Sc. in Physics from Massachusetts Institute of Technology in 2009. He is currently serving as a Junior Fellow at the Harvard Society of Fellows and a Postdoctoral Fellow with Dr. Bernardo Sabatini, MD, PhD in his lab at Harvard Medical School. The Sabatini Lab focuses on the development and regulation of synapses in the brain and the relationship of these processes to behavior and disease.
An iPSC-based platform and biobank for the functional characterization of genes associated with posttraumatic stress disorder and their interplay with the environment in genetically and clinically stratified donor cohorts
Greta Pintacuda
This study proposes to develop a pipeline that tests the function of risk genes associated with PTSD. For this, the research team will use cultured human induced pluripotent stem cell (iPSC)-derived neurons (iNs) - which represent a bone fide proxy for glutamatergic neurons in the postnatal brain. In collaboration with Dr. Koenen, the research team is in the process of selecting donor cohorts for this study using the following criteria: donors must be fully genotyped, phenotypically profiled, and with varied experience of trauma. Furthermore, the number and details of target genes will be formalized based on the upcoming PGC-PTSD data freeze (all genome-wide significant, monogenic loci, associated with a protein-coding gene). Overall, this study proposes to create an iPSC biobank of cell lines from genetically and clinically stratified donors with varied experience of trauma as well as a scalable system to systematically test, evaluate, and functionally interpret PTSD-linked genes in iPSC-derived neurons. Specifically, the research team plans to leverage genetic variants identified by recent genetic studies to:
- Build a rich dataset of cellular phenotypes, associated with PTSD variants in the presence of a cellular stressor, as a proxy for trauma.
- Create PPI datasets for functionally grouping target genes and driving hypothesis generation.
- Investigate the modulation of all measured effects described above, and genetic background using iPSC lines from cohorts of donors who experienced trauma vs. controls.
Greta Pintacuda, Broad Institute
Greta Pintacuda, D.Phil, MSc earned her D.Phil. in molecular and cell biology and biochemistry from the University of Oxford. She completed postdoctoral training in the labs of Kevin Eggan and Kasper Lage at the Broad Institute and at Harvard University. She contributed to conceiving experimental plans aimed at combining human genetics, human neural cell models, and biochemistry, to investigate molecular mechanisms affected in neuropsychiatric and neurodevelopmental disorders, including autism spectrum disorders, schizophrenia, and post-traumatic stress disorders.
