5430 research outputs found
Sort by
Non-Canonical Axonal Insulin Receptor Signaling Drives Aversive Olfactory Learning
Get PDFAnimals rely on their flexible nervous systems to learn to navigate the changing environment around them. One important function of the nervous system is to form associative memories. A simple model of associative learning is provided by nematode C. elegans, which can form memories of different types of odor stimuli through its simple yet sophisticated nervous system. C. elegans uses its sensory neurons to detect and navigate towards the odors of its food source - edible bacteria. Thus, it is crucial for worms to form memories between odors and availably of food. The volatile chemical butanone is a common product of bacterial metabolism, and therefore a bacterial odor that is attractive to worms. However, exposing C. elegans to butanone vapor while depriving them of food can suppress this attraction. C. elegans senses butanone with its AWCON neuron, and the information is further integrated before its delivery onto a network of interneurons, where it is processed for control of navigation. In my thesis, I systematically characterize aversive learning induced by pairing butanone odor with food deprivation. I employ a wide variety of experiments to understand C. elegans\u27 changes in molecular pathways, neuronal dynamics, and behavior output mechanics during aversive learning. In Chapter 1, I introduce how studying the neuronal and genetic mechanism of learning in C. elegans can contribute to the understanding of our brains and diseases of the brain. I briefly describe how insulin and insulin-like growth factor pathways regulate learning in humans and other mammals. In Chapter 2, I explore and refine the stimulation conditions that decrease or enhance C. elegans\u27s attraction to butanone. I separate the effect of odor exposure alone (desensitization) and odor-starvation paired conditioning (aversive learning) using a comprehensive behavior testing approach. I conduct a candidate gene screen for aversive learning defects, and identify the C. elegans homolog of the Insulin Receptor Substrate (IRS) (ist-1) as a gene required for aversive odor learning. I also demonstrate odor- and cell-specific functions of ist-1. In Chapter 3, I characterize insulin signaling in the aversive learning process. I describe the cell-specific activity of an axonally-localized isoform of the insulin receptor DAF-2 in aversive learning. I perform epistasis studies of ist-1 with other members of the insulin signaling pathway to ask how they regulate aversive learning together. In Chapter 4, I characterize neuronal mechanisms involved in odor detection and learning through AWCON cell body calcium imaging and pHluorin imaging of synaptic glutamate release, and ask how ist-1 modifies these mechanisms during learning. I show that these molecular and neuronal mechanisms result in behavior changes during biased random walk chemotaxis
Restriction of Food Intake by Dorsomedial Hypothalamus
Get PDFLeptin deficient ob/ob mice eat voraciously and their food intake is markedly reduced by leptin treatment. Leptin acts in part by regulating the activity of AGRP neurons and POMC neurons in the arcuate nucleus and neurons in other brain regions. In these dissertation, I will describe how we identify novel neuronal populations that are regulated by leptin directly or indirectly. In order to identify novel sites of leptin action, we used phosphotrap, to molecularly profile leptin responsive neurons in the hypothalamus and brain stem. In addition to identifying several known leptin responsive populations, we found that neurons in Dorsomedial Hypothalamus (DMH) expressing GSBS are activated in ob/ob mice and suppressed by leptin treatment. Because ob mice are hyperphagic, we hypothesized that GSBS neurons would activate food intake. However excitation of GSBS neurons decreased food intake and body weight in ob/ob mice while chemogenetic inhibition of GSBS neurons increased food intake and body weight. The DMH regulates Food Anticipatory Activity (FAA) and in a scheduled feeding protocol that elicits increased consumption, mice also ate more when GSBS neurons were inhibited and less when they were activated without altering food anticipatory activity, body temperature and oxygen consumption. GSBS neurons do not express the leptin receptor suggesting that GSBS neurons in the DMH play a key role to restrict excessive food intake when consumption is increased and that leptin suppresses their activity indirectly by reducing food intake. These findings reveal that neural pathways activated by acute increases of food intake can restrain food intake independent of metabolic state. This finding has potential implications for an understanding of binge eating and other nutritional disorders
Developmental Dynamics of 5-Hydroxymethylcytosine and its Role in the Terminal Differentiation of Neurons
Get PDFWhile epigenetic dynamics in mitotic differentiating cells have been characterized in depth, little is known about how postmitotic neurons regulate their chromatin state. Modulation of transcription through the regulation of accessibility of transcription factor binding sites is essential for the regulation of migration, synapse formation and terminal differentiation. Although 5-hydroxymethylcytosine (5hmC), the oxidized form of 5-methylcytosine, accumulates to high levels in neuronal lineages and refines the genomic binding of MeCP2, the functional consequences of 5hmC deposition in differentiating neurons have not been determined. We report high resolution characterization of the genomic landscape of developing postmitotic Purkinje neurons, confirm the relationship between 5hmC and gene expression and identify a novel class of genes that are demethylated in the absence of cell division. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic Purkinje cells alters cytosine modification in regulatory domains, impairs gene expression, hinders developmental transitions, and causes hyper-excitability and increased susceptibility to excitotoxic drugs. These data demonstrate that 5hmC and the Tet proteins are required for terminal differentiation of Purkinje cells through demethylation of important regulatory regions. Our data, along with recent reports of the role of Tet proteins in neurodegeneration suggest an essential role in development and function of all neurons
Finding Common Ground: The Common Marmoset as a Model to Accessing and Providing Insight into the Social Brain
Get PDFUtilizing the immense strengths of the common marmoset (Callithrix jacchus) as a model organism, we executed three efforts with the common goal of revealing key insights into dissecting the social brain. First, we examined the hypothesis that there is a neural, functional architecture underlying face processing. Faces form a unique category of stimuli that bridge visual perception and social cognition. They are processed in dedicated areas of cortex, face patches, which are organized into an interconnected network. While insight into neurons within face patches has been explored through extracellular electrophysiology, the functional architecture of local ensembles of cells has remained elusive. Recently discovered face patches in the lissencephalic common marmoset brain provide the cortical access necessary in order to employ optical techniques to resolve both the functional properties as well as the spatial organization of these neural ensembles. Unique to marmoset face patches, the cortical boundaries of these patches overlap with areas usually attributed to early stage visual processing. In particular, the occipitally located face patch O overlaps with V2, an area usually thought to be composed of neurons with tuning properties to low-level visual stimuli such as, but not limited to, orientation and direction. Here, in the anesthetized marmoset, we demonstrated the areal parcelization of function along the dimensions of low-level visual stimuli and high-level visual stimuli including faces, objects, and bodies using two-photon microscopy. We found that the functional architecture revealed best supports naturalistic stimuli processing more so than face processing. This suggests the interpretation that face patch O is a selective measure of recurrent activity or feedback activity into natural scene processing of faces rather than an area of pure face perception. As an area of natural scene processing, there may be cell-type specific populations supporting such segregation and suppression of low-level feature responses. We developed a novel approach to characterize the entire region using iterative antibody staining with volumetric immunohistochemistry. From a genetic and circuits approach, social cognition has been implicated in numerous circuits across brain structures. One such circuit includes pyramidal neurons projecting from layer V of the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAc), given its involvement in social-reward behaviors and depression in rodents and primates. This circuit presents an opportunity not only to study the genetic blueprint of a socially relevant circuit, but also to determine how it is conserved across rodents and non-human primates. Here we established retrograde viral Translating Ribosome Affinity Purification (retro-vTRAP), using techniques previously implemented only in rodents. retro-vTRAP enables sequencing of mRNA bound to EGFP-tagged polyribosomes from chosen projection neurons that have been virally labeled with an EGFP-L10a transgene. retro-vTRAP facilitates the study of gene expression patterns in specific neural cell types to be studied in the complex, heterogeneous tissue of the cortex, shedding new light on transcriptional differences in cognitively relevant cells across species. We implemented retro-vTRAP in marmosets, macaques, rats, and mice and found a single conserved, enriched gene ontology set across marmosets and the rodents. This gene set is involved in negative regulation of endoplasmic reticulum stress induced apoptosis and is implicated in depression and mechanisms of treatment. This enrichment specific to this projection may be part of a genetic signature of this projection and provide functional modulation in times of social stress. Lastly, from a developmental approach, we detailed a critical embryonic period of protracted growth resulting in a developmental delay in the marmoset compared to other species, relative to gestation length. This was revealed through use of highresolution, serial ultrasound scans of developing marmosets. We demonstrated that this delay period occurs during gastrulation and before neural tube closure. During this protracted period, the amnion undergoes massive restructuring and growth, creating a unique opportunity to utilize this window to introduce genetic manipulations creating a proxy of a transgenic animal without conventional transgenic methodologies. This may be transformative to building more accurate models of disorders, particularly cognitive disorders that cannot be fully replicated in rodent models
Details of the Exhibit
No full textDetails of the exhibit: First volume of JEM and page from Welch\u27s and Nuttall\u27s Gas bacillus notes (1891)
Welch\u27s career as a pathologist was remarkable for his co-discovery in 1882, with George H.F. Nuttall, of the organism that causes gas gangrene, known as Bacillus welchii, or Bacillus aerogenes capsulatus.
Idea, design: Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1013/thumbnail.jp
Map of the Town of Norfolk, Litchfield County, Connecticut
No full textMap of the town of Norfolk, Litchfield County, Connecticut, 1853
Courtesy of the Library of Congress
William H. Welch was born in Norfolk, Connecticut. He received his A.B. in 1870 from Yale University and his M.D. in 1875 from the Columbia University College of Physicians and Surgeons. After interning at Bellevue Hospital in New York, Welch studied at the universities of Strasbourg, Leipzig, Breslau, and Berlin from 1876 until 1878. Returning to Bellevue Hospital Medical College, Welch held an appointment as professor of pathological anatomy and general pathology. While there, he established the first pathological laboratory and discovered the organism named Bacillus welchi that causes gas gangrene.
In 1884, he agreed to take a position at the hospital and medical school that were being organized in Baltimore through the bequest of Mr. Johns Hopkins. In 1889, when the hospital was opened, Welch was named pathologist-in-chief. When the school of medicine opened in 1893, Welch was the first dean. He then helped organize the Johns Hopkins University School of Hygiene and Public Health and became its first director. He also founded and served as the first director of the Institute of the History of Medicine at the Johns Hopkins University. Welch took an active role in national and international medical affairs, serving as president of several organizations and associations.https://digitalcommons.rockefeller.edu/jem-the-beginnings/1000/thumbnail.jp
William Welch at Three
No full textWilliam Welch at three, 1853
William H. Welch was born on April 8, 1850, to William Wickham Welch and Emeline Collin Welch. His mother died on October 29, 1850, when William was only 6 months old. Young Welch grew up with an absentee father and an attentive, caring but sober, spiritual, and fastidious grandmother.
Source of the photograph: Simon Flexner, James T. Flexner. William Henry Welch and the Heroic Age of American Medicine, 1941https://digitalcommons.rockefeller.edu/jem-the-beginnings/1002/thumbnail.jp
Drawing by Max Broedel
No full textDrawing by Max Broedel, 1910
Courtesy of Medical Archives of The Johns Hopkins Medical Institutions
Within the sphere of Welch\u27s influence ...grew up a band of devoted followers who received their inspiration from him and were prepared, when their time came, to carry elsewhere the spirit of his laboratory and the influence of his magnetic personality. These men were in truth his earliest disciples, and amongst them were some who were destined to leave their mark upon American medicine.https://digitalcommons.rockefeller.edu/jem-the-beginnings/1015/thumbnail.jp
Details of the Exhibit
No full textDetails of the exhibit JEM: The Beginnings
Idea, design - Olga Nilova, Special Collections Librarian
Photo by Lubosh Stepanekhttps://digitalcommons.rockefeller.edu/jem-the-beginnings/1032/thumbnail.jp
Simon Flexner in 1909
No full textSimon Flexner, 1909
Courtesy of the Museum of the City of New York
Although Simon Flexner often commented that he had consciously modeled himself after Welch, the two men could not have been more different. Flexner was punctilious to details; Welch\u27s rooms were cluttered with books, papers, and unread manuscripts. Flexner was self-contained, soft-spoken, and slightly built; Welch was rotund, gregarious, fond of cheap cigars, amusement park rides, and baseball.
Their differences notwithstanding, the two men, working together, redirected pathology training at Hopkins form the traditional style of reading, listening, and memorizing to that of seeing and doing. Welch served on the board of scientific advisors of The Rockefeller Institute for thirty-two years.https://digitalcommons.rockefeller.edu/jem-the-beginnings/1030/thumbnail.jp