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Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging

October 14, 2022 By

More than 6 million people in the U.S. are living with Alzheimer’s disease in 2022. The prevalence of this neurodegenerative disease has prompted scientists to study the factors that may increase someone’s risk for developing Alzheimer’s disease. Higher neuroticism is a well-known dementia risk factor, which is associated with disordered stress responses. The locus coeruleus, a small catecholamine-producing nucleus in the brainstem, is activated during stressful experiences. The locus coeruleus is a centerpiece of developing models of the pathophysiology of Alzheimer’s disease as it is the first brain region to develop abnormal tau protein, a hallmark feature of the disease. Chronic activation of stress pathways involving the locus coeruleus and amygdala may promote tau spread, even in cognitively normal older adults. This leads to the question of whether high-neuroticism individuals show non-optimal affective function, altered locus coeruleus neurotransmitter function, and greater tau accumulation.  Researchers in the Neurochemistry and Cognition Lab, led by Dr. Anne Berry set out to answer this question.LC blog post figurePhD candidate Jourdan Parent examined relationships among personality traits, locus coeruleus catecholamine neurotransmitter function, and tau burden using positron emission tomography imaging in cognitively normal older adults. She found that lower locus coeruleus catecholamine function was associated with higher neuroticism, more depressive symptoms, and higher tau burden in the amygdala, a brain region implicated in stress and emotional responses. Exploratory analyses revealed similar associations with low trait conscientiousness, a personality trait that is also considered a risk factor for dementia. Path analyses revealed that high neuroticism and low conscientiousness were linked to greater amygdala tau burden through their mutual association with low locus coeruleus catecholamine function. Together, these findings reveal locus coeruleus catecholamine function is a promising marker of affective health and pathology burden in aging, and that this may be a candidate neurobiological mechanism for the effect of personality on increased vulnerability to dementia.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging. Jourdan H.Parent, Claire J.Ciampa, Theresa M. Harrison, Jenna N. Adams, Kailin Zhuang, Matthew J.Betts, Anne Maass, Joseph R. Winer, William J. Jagust, Anne S. Berry. NeuroImage, 30 September 2022, 119658.

 

Filed Under: Biology, division of science, division of science, division of science, General, labs, Neuroscience, Psychology Tagged With: , , , , ,

Natasha Baas-Thomas & Don Katz Receive 2022 Gilliam Fellowship

August 17, 2022 By

Natasha Baas-Thomas and her thesis adviser, Donald Katz, Professor of Neuroscience have received the 2022 HHMI Gilliam Fellowship. The Gilliam Fellowship is awarded to both the graduate student and the student’s adviser with each pair receiving an annual award of $53,000 for up to three years.

The Gilliam Program goal is to assist graduate students from populations historically excluded and underrepresented in science. Recipients are chosen based upon their scientific and leadership potential, the quality of and commitment to mentorship and to the development of a more inclusive environment in the sciences.

Natasha noted “I am honored to be selected as a 2022 Gilliam Fellow. I hope to use the award to advance my leadership abilities as I work towards a professorship position. I am also excited by the mentorship focus of this award, which I can implement to improve diversity and inclusivity at Brandeis.”

Donald Katz said “I’m thrilled that the HHMI has recognized Natasha to be both a stellar scientist and a vital force for change in the field — a future leader. And I’m excited to learn from the expert mentorship training team that HHMI has put together. The Gilliam program is quite unlike anything that has come before, in the multi-pronged approach that it takes to promoting diversity and opportunity in science.”

When discussing her research plans, Natasha said “during my PhD in the Katz lab, I will be studying the gustatory system in rats. Specifically, I will be investigating the signal sent from the gustatory cortex to the motor circuit. Focusing on how the gustatory cortex guides the decision to either consume or expel a taste stimulus.”

 

Filed Under: awards, division of science, division of science, labs, Neuroscience Tagged With: , , , ,

Blanchette and Scalera et al., discover new insights into an intercellular communication method in neurons

May 5, 2022 By

Fruit fly neuron (magenta) with extracellular vesicle cargoes (green). Cargoes are packaged inside the neuron and, then released outside of the neuron in extracellular vesicles.

Research scientist Cassie Blanchette and Neuroscience Ph.D. student Amy Scalera, working in the Rodal lab, discovered a new mechanism of regulation of extracellular vesicles (EVs). EVs are small, membrane-bound compartments that can transfer cargoes such as DNA and proteins between cells for communication. EVs are important for normal cell-cell signaling, but they are also hijacked in neurodegenerative disease to spread toxic disease proteins to other cells. Therefore, it is crucial to understand how and where EVs are formed. Blanchette and Scalera discovered a novel method of regulation of EVs specifically at the synapses (the region of the neuron that contacts adjacent cells), using the fruit fly nervous system as an experimental model.

EVs are derived from endosomes, a network of intracellular sorting compartments that cells use to separate cargoes into different ‘packages’ with distinct inter and intracellular destinations. Blanchette and Scalera found a surprising function for the proteins that regulate endocytosis, a process in which the cell membrane buds inward, thus forming a compartment to bring cargoes to endosomes. The authors found that mutants lacking endocytic proteins lose the local pool of EV cargoes that are available for release from synapses, and instead send these cargoes for disposal elsewhere in the neuron. They hypothesized that the normal function of endocytosis  is akin to a plane circling in a holding pattern at an airport – while it waits for its time to land, it is better for the passengers to circle (between the cell membrane and endosomes), nearby their destination (release in EVs), rather than being sent to an entirely different city (a different region of the neuron). They also found that disrupting this holding pattern had consequences for the physiological functions of EV cargoes; in endocytic mutants, loss of Synaptotagmin-4, an EV cargo important for neuronal adaptability, was associated with failure of the neuron to grow in response to firing. Endocytic mutants also caused synaptic depletion of the Alzheimer’s disease associated EV cargo Amyloid Precursor Protein (APP), thus suppressing its toxicity and increasing the survival of APP-expressing flies. These discoveries raise the possibility that proteins regulating EV traffic may be targets for neurodegenerative disease therapies.

Filed Under: Biology, division of science, division of science, division of science, General, grad students, labs, Neuroscience Tagged With: , , , , , ,

SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

April 25, 2022 By

SARS-CoV-2 is the pathogen causing the COVID-19 pandemic, that as of early February 2022 has caused 5.7 million deaths worldwide.

When a virus infects a cell, it transforms it, so it can become a “virus factory”. To do so, it needs to suspend it from doing the normal functions, but not to a point that the immune system will detect those changes and “decide” to kill the infected cell. Understanding how viruses accomplish that is very important for virology and medicine as, for example, it could be used to help the immune system identify these cells and stop the virus from spreading through the body.

Graphical abstract for Zaffagni post

To tackle this issue, researchers identify genes that get activated or repressed when a virus infects a cell. One way to monitor the genes that are “on” or “off” during the infection is to measure RNAs abundance by RNA sequencing (RNA-seq). Through this approach, recent studies showed that SARS-CoV-2 infection induces big changes on the cells that it infects. Generally, scientists believe changes induced by viral infection are the consequence of the concerned action of the virus proteins acting within the host cell. For example, the SARS-CoV-2 genome encodes 29 proteins. The effect of the virus is so strong that it changes more than 5000 genes in just 48hs, this is almost ¼ of our genes.

How do individual viral proteins contribute to these changes? To answer this question, the Kadener lab in the Department of Biology introduced singular viral SARS-CoV-2 proteins into human cells and monitored gene expression changes through RNA-seq. Between the 26 tested proteins, non-structural protein 14 (Nsp14) was the one inducing the most dramatic effect, altering the expression of ≈4000 genes. Importantly, these changes overlap well with previously published RNA-seq data from human cells infected with SARS-CoV-2. This suggests that transient expression of Nsp14 partially recapitulates the molecular events downstream to SARS-CoV-2 infection. They also showed that a cellular enzyme (IMPDH2) mediates these changes, and that treatment with IMPDH2 inhibitors partially rescues the changes induced by Nsp14.

This research contributes to understanding the function of viral proteins on the host cell and on the molecular mechanisms that control the progression of viral infection. The Kadener lab showed that Nsp14 also modulates gene expression of the host cell by activating a cellular enzyme. These events may be conserved in other coronaviruses infections and the discovery of these molecular mechanisms may be important for designing new therapeutic approaches.

Publication:

SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome. Michela Zaffagni, Jenna M Harris, Ines L Patop, Nagarjuna Reddy Pamudurti, Sinead Nguyen, Sebastian Kadener.  eLife 2022;11:e71945 DOI: 10.7554/eLife.71945.

Filed Under: Biology, division of science, division of science, division of science, General, grad students, labs Tagged With: , , , , ,

Divisional Prize Instructors design & teach new classes

December 7, 2021 By

The University Prize Instructorships have been a great opportunity for our graduate students to gain experience designing and teaching their own class, and a great opportunity for our undergraduates to engage in learning new areas with a great instructor. When the UPIs were put on hiatus during the pandemic, the Division of Science stepped in to keep this opportunity going for our community. We are really excited for the new courses that will be taught by Xin Yao Lin and Narges Iraji in the Spring 2022 semester- “Science versus Science Fiction” by Narges Iraji, and “Technology Use and Well-Being: Multidisciplinary Perspectives”.

Xin Yao Lin

Xin Yao LinI am very honored and delighted to receive the Divisional Prize Instructorship. I am currently a 5th-year psychology PhD student and I will be teaching a psychology course entitled “PSYC 55B: Technology Use and Well-Being: Multidisciplinary Perspectives” in the spring of 2022. The increase in technology use is changing how we connect, feel, and act. We are relying on technology more than ever, but whether the increased usage of technology is beneficial or detrimental to well-being has been controversial. Drawing on perspectives from psychology, neuroscience, computer-human interaction, and public health, this course explores the positive and negative impact of technology usage on our well-being across the lifespan. We will examine technology use in computer-mediated communication (e.g., smartphone, social media, internet, social apps), mHealth and telehealth, gaming, and other technology trends (e.g., Artificial intelligence, robots, virtual reality), and will explore how these technologies influence social life, adult development and aging, and health/health behavior (e.g., physical activity, diet, sleep).

I am very thankful for this opportunity provided by the Division of Science, and for my mentors and peers who have provided feedback and supported me along the way. I look forward to teaching this course and engaging students with how technology influences our social life, how we develop and age, and our health/health behavior.

Narges Iraji

Narges IrajiThe course Science and Science Fiction, designed for students with little to no science or math background, encourages conversations around science within the context of culture. Reading the works of science fiction by a diverse group of authors and discussing the science and imagination in them illuminates the inseparability of science from its human nature. I hope that this approach not only bridges the materials taught in class and the outside world but also sparks a curiosity that goes beyond the classroom.

Our inner urge to observe, decode patterns, and predict has existed well past the modern times and so has our passing of knowledge to the future in the form of storytelling. The combination of imagination and science is nothing new but the access to both, who can imagine and who can be a scientist, has changed throughout history. During the course, the students will read, discuss, and write about science fiction stories that inspire questions and problems which call for mathematical modeling. After becoming more familiar with some well-known mathematical models in areas such as population modeling and epidemiology, the students start working on a final project. They will formulate a question related to what they are passionate or curious about and pursue the answer using the tools that they have gained from the course. The goal is not to solve the problem, but to gain some insight into the steps required in doing so.

Teaching a University Prize Instructorship course has been a dream of mine since I heard about this opportunity in my first or second year. I am grateful for this, and thankful to all those who are helping me along the way. Numerous challenges follow developing a course, and while being one of the greatest projects that I have taken on, it has tested my patience a few times. I hope that after serving as a University Prize Instructorship instructor, I can help other graduate students who are interested in this opportunity by sharing some resources, such as information on inviting speakers or reserving classrooms with computers. My experience as a graduate student in physics and my research in the field of mathematical biology have truly led me to a new perspective. I now look around and find questions in all that I observe knowing someone else might have already started working on the answer. The course, Science and Science Fiction, encapsulates one of my attempts to pass this curiosity about the universe and life forward.

Filed Under: awards, division of science, grad students, labs, Neuroscience, Physics, Psychology Tagged With: , , , , ,

Brandeis Receives Grant to Further Collaboration with Hampton University

December 6, 2021 By

Irving EpsteinIn collaboration with Hampton University, an historically Black institution in Hampton, VA, Brandeis has received a $250,000 grant from the Alfred P. Sloan Foundation’s Equity-Minded Pathways to STEM Graduate Education program to create a route for Hampton students to enroll in masters degree programs at Brandeis. The program will comprise summer research internships at Brandeis for Hampton juniors and a senior-year course at Hampton jointly developed and taught by Brandeis and Hampton faculty, as well as cohort-based mentoring during the students’ masters study.  It extends the existing Brandeis-Hampton collaboration associated with our Materials Research Science and Engineering Center (MRSEC) and will be led by Profs. Irving Epstein at Brandeis and Demetris Geddis at Hampton.

Filed Under: awards, chemistry, division of science, division of science, General, grad students, outreach, Uncategorized Tagged With: , ,

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