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Spontaneity and Precision in the Drosophila Central Nervous System
Get PDFMany organisms that can locomote change their navigational strategies depending upon behavioral context. During foraging or exploration, for instance, many animals navigate by interspersing straight runs with turns whose direction and frequency may originate, at least at times, from largely stochastic processes. Conversely, during goal-directed navigation, animals may use stored heading and distance signals to travel efficiently to a desired location. This thesis explores the circuitry underlying these disparate navigational strategies in Drosophila. I first show that normal synaptic transmission in a genetically specified population of neurons is necessary for one to observe an appreciable rate of spontaneous flight turns in Drosophila, but synaptic transmission in these same neurons is dispensable for the execution of two types of visually evoked turns. I then describe experiments on a population of neurons whose coordinated activity is thought to represent the fly\u27s heading angle during walking. Specifically, I show that angular resolution of the heading estimate carried by this population of neurons is at most 5.625°, and may be even finer. Furthermore, it is known that the neurons that carry this heading signal can update their heading estimate either in reference to a visual landmark or, when such a landmark is absent, in reference to the animal\u27s rotational body movements. I end the thesis by demonstrating that, when a fly stands still, the visual and non-visual estimates of the fly\u27s heading angle are not always aligned and can in fact deviate by many tens of degrees. The functional purpose of this discrepancy remains unclear, but this difference might provide insight into how a heading system can store an angular memory in complete darkness, without significant drift, for many minutes
Sensory Coding and Olfactory Integration in Caenorhabditis Elegans
Get PDFAnimals must sense their external environments to guide meaningful behavior. The nematode Caenorhabditis elegans, for example, uses volatile cues to navigate toward food from a distance. How does an animal integrate the olfactory information from its environment? Here, I ask how multiple sensory neurons drive and shape one interneuron\u27s activity. C. elegans senses several odors, including the bacterial metabolite diacetyl, using the AWA sensory neurons. AWA forms chemical and electrical synapses onto several interconnected interneurons, which contribute to chemotaxis toward attractive odors like diacetyl. One AWA target is the interneuron AIA, which is connected to AWA via a putative electrical synapse. Both AWA and AIA are robustly activated by diacetyl, but the reliability of their responses decreases at low concentrations. AIA relies on AWA for its reliable response to diacetyl. However, directly activating AWA is not sufficient to evoke reliable AIA responses. Instead, AIA responses to optogenetic AWA stimulation had high and variable latencies and low probabilities. AIA responses, when they did occur, had stereotyped on-dynamics to all concentrations of diacetyl tested, to AWA optogenetic stimulation, and to several additional attractive odors, suggesting all-or-none AIA activation to sensory input. In animals lacking chemical synaptic transmission, AIA responses to direct AWA optogenetic stimulation were fast and reliable, resembling those evoked by diacetyl. AWA-to-AIA communication is thus regulated by inhibitory synaptic input from surrounding neurons. This inhibition comes from a small set of glutamatergic sensory neurons that work together to gate AIA responses to AWA activation. Consistently, two of these glutamatergic sensory neurons directly sense and are inhibited by diacetyl. Their responses are less reliable, or even non-existent, at low concentrations of diacetyl. The difference in the reliability of AIA responses to different diacetyl concentrations may be explained by differences in the composition of the upstream sensory responses. Reliable AIA responses appear to require both activation from AWA through an electrical synapse and the release of inhibition from glutamatergic sensory neurons through chemical synapses. AIA acts as a coincidence detector, and its activity represents a readout of global sensory state, providing insight into how AIA represents food signals that are sensed by multiple sensory neurons
The Sebastians
No full textThe Sebastians, baroque ensemble: Soprano, trumpet, violins, viola, cello, contrabass, theorbo, organ performing Sammartini: Concerto Grosso op. 5, no. 6; Schütz: Mein Herz ist bereit, SWV 341a; J.S. Bach: Trio Sonata in G Major, BWV 1039; Graupner: Trio Sonata in D Major, GWV 204; J. S. Bach: Cantata, BWV 51 “Jauchzet Gott in allen Landen”https://digitalcommons.rockefeller.edu/tri-institutional-noon-recitals/1014/thumbnail.jp
Alcohol burner
No full textAlcohol burner. Used to melt tablets for making parenteral injection liquids
Photograph by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/the-evolving-campus/1015/thumbnail.jp
In Vitro, In Vivo, and In Silico Studies of Reticulospinal Circuits and Generalized Arousal
Get PDFGeneralized arousal (GA) is a fundamental force in the nervous system that alerts an individual to abrupt changes in its environment. A state of high GA is operationally defined by increases in an animal\u27s a.) locomotor output, b.) responsiveness to sensory stimuli, and c.) emotional reactivity. Previous studies have identified the nucleus gigantocellularis (NGC), a small group of large-bodied neurons in the hindbrain reticular formation, as a potential neuronal substrate for GA. These neurons are responsive to a wide range of sensory modalities and have diverse projections that target both forebrain areas and motor effectors directly within the spinal cord, thereby facilitating rapid responses to sensory stimulation. Here, we used three different approaches to study the role of GA in driving and modulating mammalian motor activity: in silico modeling of GA circuits, in vitro culture of a reticulospinal circuit, and in vivo behavioral assays of circadian transitions in GA. In our in silico study, we constructed a variety of computational models of the generalized arousal circuit and asked how modifying specific aspects of the NGC and its connectivity would influence the responsiveness of motor effectors in the circuit to arousing sensory stimuli. These models reveal that an NGC with a homogeneous microstructure that integrates all inputs equally and bifurcating projections that simultaneously target limbic and spinal areas is most effective at transducing an arousing sensory signal. We then chose to focus specifically on hindbrain Chx10+ neurons, a population of spinally projecting neurons localized to the NGC, and developed an in vitro system to culture these neurons both as an isolated population and together with spinal motor neurons. Under these conditions, Chx10+ neurons develop a cell-type specific pattern of robust network bursts that they can impose on otherwise irregularly spiking motor neurons, thereby generating a functional reticulospinal connection. The activity of Chx10+ neurons was inhibited AMPAR blockers, indicating that their bursts are generated by a synaptic mechanism. Furthermore, we identified a subset of Chx10+ neurons that respond to the arousal neuromodulators orexin and norepinephrine, highlighting these neurons\u27 role in communicating arousal signals to the spinal cord. As these two studies have demonstrated the intimate link between GA and motor output, we then used an in vivo behavioral assay of voluntary motor activity to study the dynamics of circadian transition in arousal levels in mice. We found that despite the intrinsic noisiness and variability of mouse behavior, these transitions follow a remarkably lawful sigmoidal curve that could be robustly fit to a logistic equation with only three parameters and shows time reversibility between the low-to-high and high-to-low arousal transitions. In addition to demonstrating how complex behavior can be reduced to a relatively simple mathematical form, this new curve fitting paradigm allowed us to quantify how different behavioral conditions affect arousal transitions in greater detail than ever before
Hospital addition construction, 1950
No full textHospital addition construction, 1950
Courtesy of The Rockefeller Archive Center
In 1951, a new wing was added to the hospital and the original building was fully modernized. The rebuilt hospital at that time was home to five research groups investigating respiratory diseases, rheumatic fever, cardiovascular disease, endocrine disorders, and acute and chronic diseases of the liver. But the physicians did not limit their attack to particular illnesses; instead the contemplation of disease as general biological problem led them to look ever more deeply into organic structure and function, and to build a body of knowledge upon which the scientific medicine of the future can be firmly based.https://digitalcommons.rockefeller.edu/the-evolving-campus/1035/thumbnail.jp
Saul Steinberg. East River Arch Bridge
No full textSaul Steinberg. East River Arch Bridge; pastel on wood, 1997
Courtesy of Torsten Wiesel
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/the-evolving-campus/1084/thumbnail.jp
The Emergence of Modern Philanthropy
No full textThe Emergence of Modern Philanthropy: The Rockefeller Story
A Centennial presentation of the Rockefeller University, 1999
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/the-evolving-campus/1088/thumbnail.jp
Generation of Memory of Infection During the CRISPR-Cas9 Immune Response
Get PDFClustered regularly interspaced short palindromic repeat (CRISPR) loci and their associated (Cas) proteins provide adaptive immunity against viral attack in prokaryotes. Upon infection, short phage sequences known as spacers integrate between CRISPR repeats and are transcribed into small RNA molecules that guide the Cas9 nuclease to the viral targets (protospacers). Streptococcus pyogenes Cas9 cleavage of the viral genome requires the presence of a 5′-NGG-3′ protospacer adjacent motif (PAM) sequence immediately downstream of the viral target. Before my graduate work, it was not known whether and how viral sequences flanked by the correct PAM are chosen as new spacers. My work revealed that Cas9 selects functional spacers by recognizing their PAM during spacer acquisition. The replacement of cas9 with alleles that lack the PAM recognition motif or recognize an NGGNG PAM eliminates or changes PAM specificity during spacer acquisition, respectively. Cas9 associates with other proteins of the acquisition machinery (Cas1, Cas2 and Csn2), presumably to provide PAM-specificity to this process. This was a newly identified function of Cas9 in the genesis of prokaryotic immunological memory. To further explore the link between Cas9 and spacer acquisition, I performed random mutagenesis of the RNA-guided Cas9 nuclease to look for variants that provide enhanced immunity against viral infection. I identified a mutation, I473F, which increases the rate of spacer acquisition by more than two orders of magnitude. This patented variant of Cas9 highlights the enzyme\u27s role during CRISPR immunization, provides a useful tool to study this otherwise rare process, and holds promise to be developed into a biotechnological application. Researching Cas9 and spacer acquisition involved many rounds of high-throughput sequencing of millions of spacers acquired by bacteria during phage infection. These experiments revealed that the abundance of each spacer in the surviving population was highly uneven. Since the molecular mechanisms underlying this bias were not known, I decided to look into the factors that affect the distribution of individual spacer sequences during phage infection of cells harboring the CRISPR system from Streptococcus pyogenes. My work has shown that spacer patterns are established early during infection and correlate with spacer acquisition rates, but not with spacer targeting efficiency. The data suggests that the rate of spacer acquisition depends on unique sequence elements within the spacers and therefore determines the abundance of different spacers within the adapted population. These results elucidate a fundamental mechanism behind the generation of immunological diversity during the type II CRISPR-Cas response
Quatuor Danel
No full text2019, May 10
Quatuor Danel, string quartet: Marc Danel and Gilles Millet, violins; Vlad Bogdanas, viola; Yovan Markovitch, cello, performing Beethoven: Quartet in B-flat Major, Op. 18, No. 6; Shostakovich: Quartet No. 6 in G Major, Op. 101; Weinberg: Quartet No. 6 in E Minor, Op. 35.https://digitalcommons.rockefeller.edu/tri-institutional-noon-recitals/1029/thumbnail.jp