June 2017

Prefrontal Neurons Encode a Solution to the Credit Assignment Problem

A fundamental aspect of learning is the ability to link causes with effects. How do we determine why we received a particular outcome, successful or otherwise? However, sometimes the causes may be ephemeral and so removed in time, or there may be multiple potential causes for any particular effect. These are the temporal and structural credit assignment problems, respectively. Our study found that neurons in the prefrontal cortex convey the information necessary to solve these problems. Specifically, the activity of prefrontal neurons reflected the environmental events responsible for outcomes when those outcomes were revealed. These data suggest that credit assignment is an important function of the prefrontal cortex.

Summary provided by Wael Asaad, MD, PhD, a former resident in the Department of Neurosurgery at Massachusetts General Hospital, and lead author of the study. Emad Eskandar, MD, Director of Stereotactic and Functional Neurosurgery at Massachusetts General Hospital, is senior author of the study

A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin

A study from the laboratory of David E. Fisher MD, PhD, Chief of Dermatology, has discovered a skin treatment approach that is able to stimulate dark pigmentation without a need for ultraviolet radiation. This approach was built upon his lab’s extensive studies of the molecular basis of pigment production. Collaborating with chemist Nathanael Gray PhD from Dana-Farber Cancer Institute, a class of agents was identified that could be applied topically to human skin and activate the pigmentation machinery. Ultraviolet radiation is damaging to skin and also strongly implicated as a cause of skin cancer. This approach, likely to be combined with existing sunscreen ingredients, could provide a novel strategy for prevention of skin cancer as well as the “photo-aging” process of sun-related injury to skin.

Summary provided by David Fisher, MD, PhD, Chief of the Department of Dermatology at Massachusetts General Hospital, and senior author of the study.

Intensive Blood Pressure Reduction and Spot Sign in Intracerebral Hemorrhage: A Secondary Analysis of a Randomized Clinical Trial

People who suffer a hemorrhagic stroke, or bleeding into the brain, are often found to have very high blood pressures when they come to the emergency department. It is important to know which patients are at risk for having more bleeding after arrival, and what to do with their blood pressure. This study examined whether a specific finding on CT scan, called the Spot Sign, predicts which patients will continue to bleed, and whether rapidly lowering their blood pressure with intravenous medication would help stop the bleeding. It found that the Spot Sign does a good job marking those patients who will keep bleeding, but that rapid blood pressure lowering did not change their outcome. It highlights the importance of better understanding the effects of blood pressure management in the first hours after stroke.

Summary provided by Joshua Goldstein, MD, PhD, Director of the Center for Neurologic Emergencies at Massachusetts General Hospital, and senior author of the study.

Fine-Mapping Inflammatory Bowel Disease Loci to Single-Variant Resolution

The inflammatory bowel diseases (IBD) are a group of chronic autoimmune disorders that affects millions worldwide. To date, hundreds of genomic loci have been discovered to be associated with IBD. But the majority of these IBD loci span large genomic regions, and it is often not clear which particular genetic factor in the region is responsible for IBD. This study applied “fine-mapping” techniques to the genome of 67,852 individuals to narrow in on genes that may be responsible for IBD. Ninety-four IBD associated loci have been fine-mapped, among which 18 could be pin-pointed to a single genetic variant with more than 95 percent certainty. The results form a basis for more effective prescription of current treatments for the disease as well as the discovery of new drug targets.

Summary provided by Hailiang Huang, PhD, from the Analytic and Translational Genetics Unit at Massachusetts General Hospital, and lead author of the study.

Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Coeruleus in Humans

Understanding the brain regions that regulate the human conscious experience is an important question in neuroscience. Song et al. studied how the locus coeruleus (LC) – a key arousal promoting nucleus located in the brainstem – regulates consciousness in humans. By administering a special type of anesthetic (dexmedetomidine) that acts on the LC to create a state of anesthesia that is similar to sleep, the authors show that the LC integrates with certain parts of the brain to regulate consciousness. This finding fundamentally advances our understanding of brain arousal mechanisms, and could guide development of site-specific anesthetics with minimal cognitive side-effects.

Summary provided by Oluwaseun Johnson-Akeju, PhD, Clinical Director of Neuroanesthesia at Massachusetts General Hospital, and senior author of the study.

The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma

Relapse and continued tumor growth are driven by a small subset of cancer cells, yet mechanisms that control their growth and expansion have not been fully defined. This is especially relevant for a pediatric cancer of the muscle called embryonal rhabdomyosarcoma. In this manuscript, Ignatius et al. define novel roles for the Notch pathway in expanding the overall number of relapse-driving cell types. Importantly, this pathway is activated in nearly 60% of patients and new drug strategies are now in development to target this pathway therapeutically in a wide array of cancers. The long term goal of the work is to identify drugs that will kill the rare cancer-sustaining cell types, curbing relapse and therapy resistance for the highest risk patients.

Summary provided by David Langenau, PhD, Director of the Molecular Pathology Unit at Massachusetts General Hospital, and senior author of the study.

High-Affinity Cooperative Ca2+ Binding by MICU1-MICU2 Serves as an On-Off Switch for the Uniporter

Mitochondria produce energy used by cells (called ATP). They also take in calcium through a channel known as the mitochondrial calcium uniporter. Calcium transport into mitochondria stimulates ATP production, which is important to replenish energy when the cell does work. We show that the mitochondrial calcium channel is regulated by two proteins--MICU1 and MICU2-- which together act as an “on-off” switch for the channel, only flipping “on” when needed to avoid wasting energy. Unregulated calcium uptake can lead to calcium overload, which is implicated in disease states, so understanding how the channel is regulated could have important disease implications down the road.

Summary provided by Vamsi Mootha, MD, from the Department of Molecular Biology and Center for Human Genetic Research, and senior author of the study.

Hierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex

Understanding why some neuronal circuits are vulnerable to tau and amyloid accumulation will help us understand the foundations of Alzheimer’s disease and design better prevention trials. In this study from the Harvard Brain Aging Study, led by Jorge Sepulcre and Keith Johnson, we used a sample of cognitively normal elderly, PET imaging, and a hierarchical clustering approach to extract cortical patterns of tau and amyloid accumulation in a high-resolution and unbiased brain-wide manner. We found that tau deposition in heteromodal areas of the cortex links both tau and amyloid beta pathology in other regions of the brain, coupling the two pathologies at axonally distant sites. This result reveals associations not seen before and sheds light on how tau and amyloid pathologies advance through different systems in the living human brain. Moreover, we believe our work will improve our ability to track potential responses to therapeutic interventions in the future.

Summary provided by Jorge Sepulcre, MD, PhD, from the Gordon Center for Medical Imaging at Massachusetts General Hospital, and lead author of the study.

Brain Circuit-Gene Expression Relationships and Neuroplasticity of Multisensory Cortices in Blind Children

How the brain is able to reorganize and form new neural connections (called neuroplasticity) after sensory deprivation remains unknown, particularly in early stages of development. In this study, we investigated brain connectivity and neural reorganization in 13 children with blindness and 15 sighted controls using novel network neuroimaging techniques. We also examined the relationship between connectivity changes and neuroplasticity-related gene expression. We observed that a specific network called the "multimodal integration network" enhanced brain connectivity in blind children and that this reorganization was spatially associated with a specific protein gene family called the CREB family. This study advances our understanding of human neuroplasticity and its genetic underpinnings following sensory deprivation.

Summary provided by Jorge Sepulcre, MD, PhD, from the Gordon Center for Medical Imaging at Massachusetts General Hospital, and senior author of the study.

Childhood Obesity Prevention in the Women, Infants, and Children Program: Outcomes of the MA-CORD Study

Researchers examined the extent to which a Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) intervention improved BMI z scores and obesity-related behaviors among children age 2 to 4 years. In two Massachusetts communities, practice changes in WIC were implemented as part of the Massachusetts Childhood Obesity Research Demonstration (MA-CORD) initiative to prevent obesity among low-income children. Among children enrolled in WIC, the MA-CORD intervention was associated with reduced prevalence of obesity risk factors in both intervention communities and a small improvement in BMI z scores in one of two intervention communities in non-Asian children.

Summary provided by Elsie Taveras, MD, MPH, Chief of the Division of General Pediatrics at Massachusetts General Hospital, and senior author of the study.

Synthesis and Preliminary PET Imaging of 11C and 18F Isotopologues of the ROS1/ALK Inhibitor Lorlatinib

The MGH Radiochemistry Program led by Dr. Neil Vasdev, in collaboration with Pfizer, has developed unique radiochemistry strategies to radiolabel the brain penetrant cancer drug Lorlatinib (PF-06463922) which is undergoing Phase I/II clinical trial investigations for treatment of non-small cell lung cancers. A major goal in cancer therapeutics is to measure the concentrations of this drug in brain metastases of lung cancer patients, and penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Their publication in Nature Communications employed a molecular imaging technique called positron emission tomography (PET) to show high permeability of radiolabeled Lorlatinib into the living brain.

Summary provided by Neil Vasdev, PhD, Director of Radiochemistry at Massachusetts General Hospital, and senior author of the study.

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