How does the brain decide whether you like what you eat?

When we encounter a taste, we appreciate both its chemosensory properties and its palatability—the degree to which the taste is pleasurable or aversive. Recent work suggests that the processing of this complex taste experience may involve coordination between multiple brain areas. Dissecting these interactions help understand the organization and working of the taste system.

F4.largeThe lateral hypothalamus (LH) is a region of the brain important for feeding. In a rodent, damage the LH, and the rodent may starve itself to death; stimulate it, and you get a curious mix of voracious eating and expressions of disgust over what is being eaten. Such data suggest that LH plays a complex game of balancing escape and avoidance, palatability and aversion, during the evaluation of a taste stimulus. Little is known, however, about how neurons in LH actually respond to tastes of different valences.

Brandeis postdocs Jennifer Li and Takashi Yoshida. undergraduate Kevin Monk ’13, and Associate Professor of Psychology Don Katz have recently published a study of neuronal reponses in LH in the Journal of Neuroscience. They have shown that taste-responsive neurons in LH break neatly down into two groups–one that responds preferentially to palatable tastes and one to aversive tastes. Virtually every taste neuron in LH could be identified as a palatable- or aversive-preferring neuron. In addition, even without considering the specific tastes to which a particular neuron responded, these two groups of neurons could be differentiated according to their baseline firing rate, shape of response, and tuning width. While these neurons were spatially intermingled, several pieces of data (functional connectivity analysis, relationship to responses in amygdala and cortex) suggest that they are parts of distinct neural circuits. These results offer insights into the multiple feeding-related processes that LH manages, and how the hypothalamus’ role in these processes might be related to its connection to other parts of the taste system.

Li JX, Yoshida T, Monk KJ, Katz DB. Lateral Hypothalamus Contains Two Types of Palatability-Related Taste Responses with Distinct Dynamics. J Neurosci. 2013;33(22):9462-73.

Making new synapses with Sema4D

There are two main types of synaptic connections in the mammalian brain: excitatory glutamatergic synapses and inhibitory GABAergic synapses. The balance between excitatory and inhibitory inputs a neuron receives regulates the overall activity of neuronal networks; disruptions to this balance can cause epilepsy.

A new paper in J. Neuroscience from the Paradis lab shows that treatment of cultured neurons with the extracellular domain of the protein Sema4D causes a rapid increase (i.e. within 30 minutes) in the density of functional GABAergic synapses. Further, addition of Sema4D to neurons drives GABAergic synapse formation through a previously unappreciated mechanism: the splitting of pre-existing assemblies of the Gephyrin scaffolding protein. To our knowledge this is the fastest demonstration of synapse formation reported thus far and has significant implications for our understanding of the mechanisms of GABAergic synapse formation.

Screen Shot 2013-05-26 at 5.03.05 PMWhile the underlying mechanism of epileptogenesis is largely unknown, recurrent seizures emerge when there is an increase in network activity. One possible therapeutic treatment would be to restore normal network activity by increasing network inhibition. In an in vitro model of epilepsy, acute treatment with the protein Sema4D rapidly silences neuronal hyperexcitability, suggesting a possible use of Sema4D as a disease-modifying treatment for epilepsy.

Lead authors on the paper were Marissa Kuzirian, a grad student in the Neuroscience Ph.D. program, and Anna Moore, a Brandeis Neuroscience postdoctoral fellow.

The Genetics Training Grant hosts a panel discussion and lunch focused on careers outside academia

This past Monday, April 29th, students and post-docs, eager to learn more about careers outside of academia, had the opportunity to hear from, and question, panelist who have successfully harnessed their PhD experience to excel in non-academic careers. The event, hosted by the Genetics Training Grant, brought together panelists from several different fields, including scientific publishing, pharmaceutical research, consulting, and intellectual property law. The panelists were Priya Budde, Reviews Editor, The Journal of Cell Biology; Sadanand Vodala, Research Scientist, ARIAD Pharmaceuticals; Derek Buhl, Principal Scientist, Pfizer Neuroscience; Peter Bak, Consultant, Back Bay Life Science Advisors; and John Garvey, Partner, K&L Gates LLP. Each panelist spoke about their background in academia, how they made the transition to their current position, and fielded numerous questions from the audience both during the panel and at the networking lunch that followed.

The panelists gave the audience a sense of what their specific careers entail, and how skills they had acquired during their PhDs were highly relevant to their current work. Some of the transferable skills mentioned included critical thinking and the ability to quickly synthesize information and distill what is most important and interesting about a given scientific finding. These skills enabled them to be highly effective in their jobs, whether efficiently evaluating scientific manuscripts as an editor, or determining the crux of a client’s research as a consultant or intellectual property lawyer.

Current jobs for recent Brandeis Life Science PhDs (graduates 2002 and beyond, n=200)

Current jobs for recent Brandeis Life Science PhDs (Neuro, Mol Cell Biol, Biochem, Biophys graduates, 2002 and beyond, n=200)

Having completed their transition from academia to the business world, panelists were able to highlight some of key cultural and practical differences associated with working in a profit-driven industry. While Derek described his lab at Pfizer as largely mimicking an academic environment (minus the need to perpetually write grants), he and other panelists noted that, unlike academia, business evaluations are based almost exclusively on having achieved specific pre-determined goals. On the upside, for those who exceed expectations in business, there are lots of opportunities to move up the ladder. Other differences that panelists encountered in their non-academic professions included firmer deadlines, higher dressing standards, and less flexible hours.

While the majority of the discussion was specific to the panelists’ career paths, much of the advice applied to career searches in general. The importance of good networking was emphasized. Job seekers were encouraged to make the most of their networks – and their network’s network as well. Each panelist explained how he or she had acquired their job through a combination of effective networking, being proactive, and in some cases, luck. Panelists were quick to point out, though, that time and effort invested were positively correlated with “luck.”

Panelists stressed that effective networking required quickly following through with contacts, and being prepared to impress key contacts with excellent questions that demonstrate your research on a given company. They encouraged the audience to be proactive, and if needed persistent, in reaching out to people whose work they find interesting. Several panelists also emphasized the benefits of acquiring job-related experience. They noted this was a good way to both boost your resume and get a better sense of whether a given profession is the right fit for you. For example, John Garvey recommended joining a consulting or biotech club, and/or taking a business class. Getting involved in job-related activities is also excellent ways to establish good contacts for networking.

Overall the panelist presented several attractive alternatives to a traditional academic career. By carefully analyzing his or her personality, strengths, and working style, each of them had found a rewarding career that effectively utilized their scientific background/training. Priya, the editor, described how she enjoyed being able to see where scientific fields are going and staying up to date with the latest scientific breakthroughs. Derek, the pharmaceutical researcher, explained how it was gratifying for him to be working directly to develop drugs that could benefit people. John, the lawyer, explained how his work solving business problems was important because it helped provide pharmaceutical companies with the financial resources to bring new life-saving drugs to market. The general take-home message from all of the panelists was that, using the right career strategies, one can effectively use one’s PhD as a launching point to successfully pursue many different avenues outside of academia. Those interested in getting a better sense of what career might be a good fit for them are encouraged to visit http://myidp.sciencecareers.org and fill out the survey.

What do Brandeis life science PhD students go on to do?

Deciding the fate of a stalled RNA polymerase

Ever wondered what happens when the transcription machinery runs into a DNA lesion or a protein roadblock? Alexandra M. Deaconescu, corresponding author and research associate in the Grigorieff laboratory together with HHMI Investigator and Biochemistry Professor Dr. Nikolaus Grigorieff and Dr. Irina Artsimovitch (Ohio State University) address this question in a new review “Interplay of DNA repair with transcription: from structures to mechanisms” featured in the latest issue of Trends in Biochemical Sciences. The review describes emerging mechanisms of transcription-coupled DNA repair with emphasis on the bacterial system.

It’s not all transcription! New insights on how biological rhythms are generated

Sleepy during the day? Hungry at night? You should check your biological clock!

As in every organism, humans are exposed to daily variations of their environment. There is obviously the day/night cycle, but significant variations of temperature and humidity also occur in temperate regions of the globe. To survive to these environmental changes, organisms have evolved so that their biology, biochemistry, physiology and behavior are rhythmically regulated on a 24hr-basis. Humans are no exception, and most (if not all) of our biological functions are set to function optimally at the most appropriate time of the day. For example, the physiology of muscle cells is rhythmic so that their capacity of coping with physical activity is maximal during the day.

A lot of progress has been made over the last two decades to uncover the molecular underpinnings of circadian (for circa, about and dies, day) rhythms. To keep the story short, in all eukaryotes the circadian system relies on transcriptional feedback loops that operate at the level of individual cells (see figure 1). In mammals, these loops are composed of the two transcription factors CLK and BMAL1, which act as a heterodimeric complex to activate the expression of the transcriptional repressors Period (Per1, Per2 and Per3) and Cryptochrome (Cry1 and Cry2). When expressed, these repressor proteins are post-translationally modified (e.g., phosphorylation) and feedback to inhibit the transcriptional activity of CLK:BMAL1. As a result, transcription of Per and Cry genes is shut-off. The progressive degradation of the PER and CRY proteins then leads to a new cycle of CLK:BMAL1-mediated transcription. Importantly, these transcriptional oscillations regulate the rhythmic expression of a large fraction of the transcriptome (up to 10-15% of all mRNAs). These output genes, also called “clock-controlled genes”, are rhythmically regulated in a tissue-specific manner, and are responsible for the daily oscillations of biological functions.

As in other biological systems, it is generally assumed that daily variations of mRNA levels are a direct consequence of transcription regulation. However, there is growing evidence that post-transcriptional events such as mRNA splicing, polyadenylation, nuclear export and half-life also contribute to changes in the amount of mRNA expressed by particular genes. Such post-transcriptional processes are known to have a role in other areas of cell biology but until very recently this had not been studied in detail at a genome-wide level.

This is the question addressed by Jerome Menet, Joseph Rodriguez, Katharine Abruzzi and Michael Rosbash, in a paper recently published at eLife (Menet et al., 2012). The authors directly assayed rhythmic transcription by measuring the amount of nascent RNA being produced at a given time, six times a day, across all the genes in mouse liver cells using a high-throughput sequencing approach called Nascent-Seq (see figure 2). They compared this with the amount of liver mRNA expressed at six time points of the day. Although the authors found that many genes exhibit rhythmic mRNA expression in the mouse liver, about 70% of them did not show comparable transcriptional rhythms. Post-transcriptional regulations have therefore a major role in the circadian system of mice. Interestingly, similar experiments performed by Joe Rodriguez in the Rosbash lab using Drosophila as the model system led to the same conclusions, suggesting that the contribution of post-transcriptional events to the generation of circadian rhythms is common to all animals (Rodriguez et al., in press).

To assess the contribution of the core molecular clock to genome-wide transcriptional rhythms, Menet et al. also examined how rhythmic CLK:BMAL1 DNA binding directly affects the transcription of its target genes. They found that although maximal binding occurs at an apparently uniform phase, the peak transcriptional phases of CLK:BMAL1 target genes are heterogeneous, which indicates a disconnect between CLK:BMAL1 DNA binding and its transcriptional output.

The data taken together reveal novel regulatory features of rhythmic gene expression and illustrate the potential of Nascent-Seq as a genome-wide assay technique for exploring a range of questions related to gene expression and gene regulation.

Menet JS, Rodriguez J, Abruzzi KC, Rosbash M. Nascent-Seq Reveals Novel Features of Mouse Circadian Transcriptional Regulation. elife. 2012;1:e00011. doi: 10.7554/eLife.00011.

Rodriguez J, Tang CHA, Khodor YL, Vodala S, Menet JS, Rosbash M. Post-transcriptional events regulate genome-wide rhythmic gene expression in Drosophila. Proc Natl Acad Sci U S A. (In press).

Biotech, Health & Science Forum on Nov. 14

Cary Weir Lytle from the Hiatt Career Center writes:

I am delighted to announce that registration is open for Brandeis’ premier career event of the year for science, health and research, and this year more than 25 employers from Sloan-Kettering and Health Corps to Pfizer and Boston Healthcare for the Homeless will be attending to help you.

Brandeis University’s 4th Annual
Biotech, Health and Science Forum
“Addressing unmet medical need.”

Sponsored by the Hiatt Career Center
Nov. 14, 6:00-9:00 p.m., Sherman Function Hall

Grad Students & Post Docs RSVP Here

Undergraduate Students RSVP Here

Meet the panel

This year’s program features employers in public health, research and development, medical research, clinical care, and business… all focused on new ways to improve health and patient outcomes. (see employers list below)

Thanks,
Cary

EMPLOYER LIST

Biotech, Pharma and R&D

  • Alnylam Pharmaceuticals
  • Cubist Pharmaceuticals
  • GlaxoSmithKline
  • Massachusetts Life Sciences Center
  • Merrimack Pharmaceuticals
  • Millennium
  • Novartis Institutes for BioMedical Research (NIBR)
  • Pfizer
  • Vertex Pharmaceuticals

Hospitals & Research Institutes

  • Beth Israel Deaconess Medical Center
  • Boston Medical Center
  • Brigham and Women’s Hospital
  • Children’s Hospital Boston
  • Memorial Sloan Kettering Cancer Center
  • MGH, Institute for Neurodegenerative Diseases (MIND)
  • US Environment Protection Agency

Public Health

  • Boston Health Care for the Homeless Program
  • Harvard School of Public Health
  • HealthCorps
  • Massachusetts Division of Health Care Finance and Policy
  • Physicians for Human Rights
  • Research Triangle Institute

Business & Emerging Health Solutions

  • Epic
  • Medical Information Technology, Inc. (MEDITECH)
  • Neuro Alert Monitoring Services
  • Safe Passage Neuromonitoring
  • Yesware

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