Diane Lipscombe - US grants

This project is aimed at elucidating the regulation and functional role of voltage-gated calcium (Ca) channels in the peripheral nervous system of vertebrates. Voltage-gated Ca channels are essential for the normal function of the sympathetic nervous system. Ca ions, entering the neuron via voltage-gated channels that open in response to depolarizing stimuli, regulate a diverse spectrum of functions including neurotransmitter release, neurite outgrowth, neuronal excitability and gene expression. Several different types of Ca channels have been identified and each is likely to be specialized for regulating particular Ca-dependent processes. This proposal focuses on studying N and L type Ca channels of sympathetic neurons and on determining their relative importance in the control of neurosecretion and neuronal excitability. Single Ca channel currents will be recorded with the use of patch-clamp technique from sympathetic neurons isolated from adult rats and frogs. The behavior of N and L channels will be studied in high resolution single channel recordings in order to characterize the gating pattern of each component. A direct comparison of neurons from adult frog and rat will be essential in addressing possible species-based differences in the behavior of Ca channels. Receptor-mediated inhibition of Ca channel currents is important in pre-synaptic inhibition of transmitter release. The effect of norepinephrine (NE) on the gating of single Ca channel currents will be studied in detail to determine the mechanism of inhibition. The consequences of directly activating various second messenger systems proposed to be involved in transducing the effects of NE and other neurotransmitters on Ca channel function will also be determined. Neurotransmitter release in isolated sympathetic neurons will be monitored by measuring, in the same patch, both the changes in membrane capacitance and the properties of the resident Ca channel currents. This will be achieved with a modified version of the patch clamp recording technique. The location of specialized zones of transmitter release will be determined in cell-attached patches obtained from cell bodies, axons and growth cones of sympathetic neurons. The hypothesis that N channels cluster within specialized transmitter release zones will be tested by monitoring single Ca channel currents and capacitance changes in the same cell-attached patches. The functional role of different classes of Ca channels in activating two distinct Ca-activated K channel currents (KCa and KAHP) in sympathetic neurons will be determined. Cell-attached patches from various cellular regions will establish whether a particular type of Ca channel co-localizes with a specific Ca-activated K channel. A better appreciation of the inter-relationship between different classes of Ca and K channel currents will provide new insights into the mechanisms by which neuronal excitability and neurotransmitter release are regulated.

This application requests five years of salary support for Dr. Diane Lipscombe to develop her research program that addresses the regulation and function of neuronal calcium channels. The three main projects proposed incorporate modern molecular and electrophysiological methods to study Ca2+ channel structure, regulation, expression and function in both normal and neuropathological states. The first project addresses the structure and regulation of an N-type calcium channel cloned from sympathetic neurons. The second, an assessment of the functional importance in sympathetic neurons, of the expression of different potential splice variants of the N type Ca2+ channel; and in the third, in a collaborative study with Dr. Heidi Scrable (Univ. Virginia), the potential role of Ca2+ channels in the pathophysiology of Type l neurofibromatosis. Brown University provides an exceptionally strong environment to develop this research program and is fully supportive of Dr. Lipscombe's career plans. Brown University already has highly respected Neuroscience research programs as well as training at the graduate and undergraduate level. In recognition of the Department's accomplishments the University has committed substantial new resources towards further development of the neurosciences at Brown. The Department, including Dr. Lipscombe's laboratories, will be newly renovated and expanded by May 1996, with a major new commitment to cell and molecular neurobiology. The expansion will include new tissue culture and molecular facilities and four new tenure-track faculty positions; two in molecular neurobiology and two in the area of synaptic function and learning and memory. During the award period Dr. Lipscombe will further develop her research skills through substantial additional time made available for (1) independent and collaborative work in her laboratory, (2) additional coursework in molecular neurobiology and, (3) increased interactions with members of the Brown Departments of Neuroscience and Molecular and Cell Biology and Biochemistry. This award is requested at a critical time for Dr. Lipscombe to devote herself fully to projects which are already providing new and important insights into Ca2+ channel function. The proposed plan is fully endorsed by Brown University.

This renewal application is to support predoctoral and postdoctoral training in the study of the brain at the level of neural systems and behavior. The program is intended to produce new Ph.D.'s and postdoctoral scientists capable of establishing independent research in the field of neuroscience. The training program will be operated by the highly successful, interdisciplinary Neuroscience Graduate Program at Brown University. The 18 members of the training faculty are drawn from the Departments of Neuroscience (13), Psychology (3), Cognitive and Linguistic Sciences (1), and Applied Math (1). Their research is on the mechanisms of the brain which cause behavior, with a strong focus on use of combined methods at different levels of analysis to understand specific brain systems. Some faculty work at the cellular level to understand processes which specifically manifest themselves in the overall performance of the systems to which these cells belong, while others work at the level of neuronal populations to understand their connectivity or information-processing functions in relation to behavior. Several faculty use behavioral measures in conjunction with physiological experiments and modeling of neural systems, while others work with computational models, bringing behavioral or physiological data to bear on testing the validity of the model. The breadth of training in the program is enhanced by emphasizing the advantages of using a variety of different methods and the different perspectives these methods bring to research, rather than having individual laboratories separately study brain function using anatomical, physiological, behavioral, or quantitative methods in isolation. The program uses courses, supervised laboratory research, a strong colloquium series, seminars, journal clubs, and special social-scientific functions to train students in the practical, day-to- day conduct of research on brain function from a multidisciplinary perspective. Funds are requested for 5 years, for 4 predoctoral trainees and 4 postdoctoral trainees.

DESCRIPTION (provided by applicant): In this renewal we take full advantage of our expertise in molecular and functional analyses of splice variants of the voltage-gated N-type Ca channel alph-1 subunit. We outline an integrated approach to study the molecular basis of functional diversity among N and L-type Ca channels expressed with regional variation in the nervous system. At center stage is the role of alternative splicing in generating this diversity. By systematically analyzing RNA isolated from distinct regions of the nervous system and combining this information with analysis of newly released human Ca channel alpha 1B sequences, we discern the extent of alternative splicing among N-type Ca channel alpha2.2-1B and L-type Ca channel alpha1.3-1D subunit gene families (aims 1 and 3). The functional impact of alternative splicing on the biophysical properties of N-type and L-type Ca channels will be elucidated. Expression systems have already been developed in our lab for this purpose. Where new techniques are proposed such as in situ hybridization, we have established key collaborations with recognized experts. In aim 2 we focus on beta-subunit-specific modulation of associated alha-1 subunits. With the use of brief, high frequency stimulation including action potential wave-forms we will investigate frequency-dependent inactivation of N channels. These more physiologically relevant stimuli will allow us to better predict how different alpha1/beta-subunit combinations might impact voltage-dependent Ca entry at the synapse. There are several potential benefits of our studies. (i) A comprehensive view of alternative splicing in N and L-type alpha 1 genes will significantly advance our understanding of the molecular origins of functional diversity in Ca signaling. (ii) Alternatively spliced exons that are under cellular control are invariably located in protein domains important for regulating function. By studying these domains we gain unique insights into structure/function relationships in Ca channel alpha 1 subunits and, more generally, in other voltage-gated ion channels that share the canonical six transmembrane domain structure. (iii) L-type and N-type Ca channels are important therapeutic targets. Alternative splicing has the potential to create pharmacological diversity among members of a single alpha 1 gene. Consequently, the identification of tissue-specific sites of alternative splicing may offer new strategies for improving specificity of drug action.

[unreadable] DESCRIPTION (provided by applicant): This renewal application is to support postdoctoral training in the study of the brain at the level of neural systems and behavior. The central objective of the postdoctoral training program in Systems and Behavioral Neuroscience is to train postdoctoral level neuroscientists in skills, methodologies, and an advanced comprehension of the scientific literature. Most importantly it is our aim to prepare postdoctoral trainees for independent professional careers. Our Program has been devoted to modern, multidisciplinary training in the study of the fundamental neural processes underlying behavior including: perception, orientation and communication; synaptic plasticity, learning and memory; and oriented motor actions. We offer training in the full-spectrum of state-of-the art methodologies that we deem essential for a successful career in the neurosciences. These include non-invasive functional MRI, applications of robotics and neuroprosthetics, advanced electrophysiological recordings, mouse and Drosophila transgenics, behavioral studies, molecular manipulations of neuronal genes, and functional proteomics. The breadth of training in our Program is enhanced by the Brown Brain Sciences Program that creates a unique network linking more than 75 faculty from ten different departments that has successfully integrated applied math, computer science, and biomedical engineering with neurosciences. This grant supports candidates early in their postdoctoral studies who display significant promise for a successful career in research. The program incorporates a number of training opportunities to attain our goals. These include mentorship, laboratory research, grant writing, research seminars, retreats, skills workshops, and journal clubs. Funds are requested for five years of support for four postdoctoral trainees. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Our predoctoral training program in Neuroscience provides individualized, high quality training to predoctoral students interested in pursuing scientific research careers in the biological and biomedical sciences. In this competing renewal we request positions to support six students in their first two years of graduate studies, before they fully engage in their dissertation research. This level of funding would fund about 50% of training grant eligible predoctoral students in the first two years of their studies. We plan to recruit 10 to 12 students to the Neuroscience Graduate Program each year; growing overall enrollment from currently 30-40 students to about 60 over the next funding period. Graduate students in our program receive broad, multi-disciplinary training that spans many levels of inquiry, from genes through cognition, and emphasizes concepts, methodologies, and sophisticated analysis of the primary literature. Our core curriculum consists of team- taught graduate courses, seminars, and workshops that provide a strong foundation in Neuroscience and develop skills that are essential for successful, independent research careers in neuroscience, such as effective science writing and oral presentation, knowledge of scientific review processes, and training in ethics. We have successful initiatives that expose students to translational and clinical Neuroscience with our Bench to Bedside seminar series. In collaboration with our colleagues in Psychiatry graduate students have the unique opportunity to meet and talk with patients suffering from diseases of the nervous system including those with Obsessive Compulsive Disorder, Aphasia, Parkinson's Disease, and Addiction. On average, students in our program finish their PhD in 5.3 years, and the majority of our alumni continue their careers in academic or industry science positions. We foster an environment unconstrained by traditional discipline boundaries and where graduate students are encouraged to work at the exciting interfaces of these disciplines. The training program currently includes 26 primary participating faculty drawn from a large community of ~100 scientists associated with the Brown Institute for Brain Science. Faculty trainers are drawn from eight different Brown University departments that include Neuroscience; Cognitive, Linguistic, and Psychological Sciences; Molecular Biology, Cell Biology, and Biochemistry; Engineering; and Psychiatry and Human Behavior. They are a distinguished and energetic group of neuroscientists that collectively cover the spectrum of modern neuroscience research: they work with a wide variety of model organisms, from worms to humans, and use an impressive array of modern neuroscience techniques, including functional MRI, applications of robotics and neuroprosthetics, optogenetics, advanced in vivo and in vitro electrophysiological recordings, mouse transgenics, behavioral studies, molecular manipulations of neuronal genes, functional proteomics, and human genome-wide association studies. We encourage and facilitate collaborations between labs as well as research in computational and translational neuroscience that typically reside at the interface of disciplines. Key features of the Neuroscience Graduate Program at Brown include: Excellence in research along with excellence in education and mentorship; a history of interdisciplinary and translational research; and an environment of nationally recognized labs where graduate students are equal partners in the research process.

DESCRIPTION (provided by applicant): N-type calcium channels regulate release of glutamate and substance P from primary sensory afferents in the superficial dorsal horn of the spinal cord. Presynaptic N-type calcium channels in the spinal dorsal horn are major targets of drugs to treat neuropathic and chronic pain syndromes. However, we don't yet understand why N-type calcium channel blockade is so effective against neuropathic pain and we don't understand how important they are in mediating the spinal analgesic actions of opiates. In this second phase of our project we will test our hypothesis that a distinct isoform of N-type calcium channels is essential for spinal level analgesic actions of a sub-set of drugs including opiates in vivo. During the 1st funding period of this grant we discovered that this novel splice isoform the N-type calcium channel, CaV2.2-e37a, is significantly more sensitive to drugs that act through G protein coupled receptors, including morphine. This is important because i) we previously showed that CaV2.2-e37a channels are enriched in nociceptors whereas CaV2.2-e37b channels are found throughout the nervous system, and ii) spinal level analgesic actions of morphine and other drugs are, at least in part, mediated by inhibition of presynaptic N-type channels in the dorsal horn. We are now ready to test the functional significance of CaV2.2-e37a in vivo in normal and disease states. We have developed four novel mouse lines using single exon gene targeting. These mice are genetically modified to express exclusively N-type channels containing either CaV2.2-e37a or CaV2.2-e37b but not both. We have developed all the necessary technical expertise to assess these mice at electrophysiology, biochemical, immunohistochemical, and behavioral levels. We will ask if CaV2.2-e37a channels mediate basal nociception and basal analgesic effects of morphine. We will also ask if CaV2.2-e37a channels are required for hyperalgesia to develop with neuropathic pain, and if they are necessary to mediate the analgesic effects of morphine during neuropathic pain. Our studies are highly relevant to the challenge of finding effective treatment for neuropathic and more generally chronic pain. Peripheral neuropathies can develop following acute nerve injury, and are strongly associated with diabetes, autoimmune disorders, malnutrition, and infections. There are no effective treatments for the millions of neuropathic and chronic pain sufferers.

DESCRIPTION (provided by applicant): This is a new R21 application to study the role of a neuronal calcium channel in determining susceptibility to bipolar disorder. All excitable cells use calcium ion channels on their surface to read electrical signals and convert them into a change in intracellular calcium, a ubiquitous second messenger. Calcium controls a huge number of cellular processes including muscle contraction, neurotransmitter release, cell death and neuronal growth. Calcium ion channels are important drug targets for treating hypertension and neuropathic pain. Mutations in the CACNA1C calcium ion channel gene cause a rare hereditary disorder Timothy Syndrome and single nucleotide polymorphisms identified very recently in the same CACNA1C gene associate with bipolar disorder. Bipolar disorder is a chronic mental illness affecting close to 6 million adults in the United States characterized by cyclical episodes of mania and depression. The most common treatment is lithium but this agent is only partially effective, has numerous side effects, and a low safety margin. There is a clear inheritable risk in bipolar disorder. Recently a large, collaborative genome-wide association study analyzed >10,000 bipolar and control individuals and identified a region in human chromosome 12 that has significant association with bipolar disorder. Bipolar disease-associated single nucleotide polymorphisms mapped to a long intron in an uncharacterized region of the CACNA1C gene. This exciting discovery affords us a unique opportunity to understand how single nucleotide variations in the CACNA1C gene could disrupt normal calcium channel activity in the brain. We will use a combination of gene and RNA analyses, and electrophysiological recordings to explore how this potential site of bipolar susceptibility in CACNA1C controls calcium ion channel function. Our work has the potential to provide novel insights into the molecular mechanisms underlying bipolar disorder. ) PUBLIC HEALTH RELEVANCE: This R21 project will test the hypothesis that a long intron in the CACNA1C gene, recently identified as a risk factor in bipolar disorder, controls calcium channel function through alternative pre-mRNA splicing. We will use a combination of RNA, gene, and electrophysiological analyses to reveal the functional role of intron 4 in controlling L-type calcium channel activity in neurons.

DESCRIPTION (provided by applicant): Following peripheral injury, changes in tactile perception develop, including primary and secondary hyperalgesia and allodynia. A loss of GABAergic or glycinergic inhibition is one mechanism that can cause these changes in pain perception. Inhibitory neurons in the dorsal horn play a key role in controlling the flow of nociceptive information through ascending pathways to the brain where it is perceived as painful. Interleukin-1beta (IL-1beta) is an inflammatory cytokine released in the spinal cord during injury and is known to promote pain and cause hyperalgesia when introduced into the spinal cord. Using electrophysiological methods in spinal cord slices, we have found that IL-1beta upregulates inhibitory glycine receptors on inhibitory neurons in the dorsal horn. The rapid inhibition of inhibitory neurons is expected to promote the transmission of pain signals to the brain, and thus may explain how IL-1beta causes pain. Our preliminary results indicate that inflammation in vivo potentiates glycinergic synapses similarly to IL-1beta potentiation observed in vitro. IL-1beta is also released during neuropathic pain, and here we propose to test whether glycinergic neurotransmission on inhibitory interneurons in the pain pathway is upregulated in a model of neuropathic pain. Our work could suggest novel drug targets for the treatment of persistent pain conditions that are currently difficult to treat effectively.

? DESCRIPTION (provided by applicant): N-type, CaV2.2 calcium channels are critically important proteins that regulate release of glutamate and substance P from nociceptors in the superficial dorsal horn of the spinal cord. Nociceptors respond to harmful signals such as high heat and, when functioning normally, are highly protective. In certain chronic pain conditions, such as after peripheral nerve injury, normal heat and touch are perceived as painful, and ongoing spontaneous activity of pain circuits can cause unrelenting pain. Understanding the molecular and cellular changes that occur during the transition from normal to chronic pain states is the key to improving current - and inadequate - therapies to treat chronic pain. Presynaptic N-type calcium channels in the spinal dorsal horn are major targets of drugs, including morphine, that are used to treat neuropathic and chronic pain syndromes. In the first two phases of this project we discovered that distinct neuronal populations in the mammalian nervous system express different isoforms of N-type calcium channels. Most importantly, we discovered a novel N-type channel isoform in nociceptors, which we predicted is particularly sensitive to inhibition by morphine when neurons fire at high rates. This exciting discovery has raised the possibility that drugs or therapies might be developed that act selectively on the N-type channels in the nociceptors that are responsible for chronic pain with less influence on N-type channels elsewhere in the nervous system. In the third phase of our project we will i) identify genomic DNA and pre-mRNA mechanisms that control expression patterns of N-type calcium channel isoforms in nociceptors and how these mechanisms achieve cell-specificity, ii) identify the precise N-type calcium channel isoforms that function at presynaptic nerve terminals in the spinal dorsal horn and establish their unique responsiveness to opiates and other analgesics, and iii) show how the activity and properties of presynaptic N-type calcium channels are altered in chronic pain states. To complete this project we have generated several genetically modified strains of mice in which we remove individual splice options, reducing the number of N-type channel isoforms available. In addition we use optogenetics combined with retrolabeling to examine synaptic events in dorsal horn projection neurons that arise from light-induced activation of thermosensing afferents. We integrate analyses of gene regulation, ion channel function, synaptic transmission, behavior and pharmacology to advance our understanding of this highly important group of calcium ion channels. We aim to identify the precise calcium channel isoforms that control transmission of normal and abnormal pain signals from peripheral nociceptors to central processing sites in the brain. Our results should lead to new strategies to help millions of neuropathic and chronic pain sufferers.

DESCRIPTION (provided by applicant): The central objective of this advanced predoctoral training program in Neuroscience is to produce graduate students with a high level understanding of the theory, practice, and clinical importance of neural dynamics. Students with appropriate background coursework and research interests will be enrolled in this advanced training plan, a subset of 4 students will receive direct funding from this training grant. Deep knowledge of the basic mechanisms underlying neural dynamics is crucial to understand healthy behavior and many of the profound deficits observed in neurological disease. This topic spans almost all levels of neuroscience inquiry: Biophysics determines patterns of action potential firing, which in turn determines the probability of relay between neurons, and ultimately the information that a neural circuit or distributed representation can carry. Brown University has strong expertise across all these levels, ranging from the genetic bases of neural dynamics underlying behavior through the cognitive neuroscientific study of dynamic control of information processing based on high-level goals. Failures in neural dynamics are widely hypothesized to underlie the pathophysiology of maladies such as epilepsy and Parkinson's disease. The directors, Diane Lipscombe and Chris Moore, have complementary expertise ideal for an Advanced Training Plan in neural dynamics. They will receive advice from external and internal advisory groups and from students, to continue to adapt and improve the training plan. The Neural Dynamics training program will be managed and administered within Brown's Graduate Program in Neuroscience. The Neuroscience Graduate program at Brown offers student-centered, high-quality training and the majority of our graduates pursue careers in neuroscience. Students are also exposed to computational, translational, and clinical approaches. Early multi-disciplinary training dovetails well with this specialized advanced training in Neural Dynamics. This Training Program will provide three basic requirements to produce students with strong training in Neural Dynamics: First, a detailed understanding of the state of knowledge and the defining debates in the study of neural dynamics is required, and will be imparted to students in lectures and seminar courses. This training in basic knowledge will be paired with intensive training in experimental practice to teach students basic principles of scientific design of dynamics studies, and in the cutting edge methods used to resolve debates and test hypotheses in the study of neural dynamics. Students will also design their own experiment(s) on a topic in neural dynamics, and then execute these studies in an intensive 9-day practicum at the Marine Biological Laboratory (MBL). Second, a world-class environment of 29 laboratories investigating this topic at Brown is crucial to foster long-term, in-depth predoctoral research on this topic. Third, access to perspectives beyond those of the home institution, and most importantly beyond classical academia itself, will expand students' understanding and perspective on this important topic.

? DESCRIPTION (provided by applicant): The goal of this proposal is to assess the feasibility of an all-molecular method for activity-dependent feedback control of neuronal activity. We propose to generate calcium sensitive light emitting molecules (bioluminescent enzymes, luciferases) that drive light sensing optogenetic elements (channels or ion pumps, opsins) to control membrane voltage at the level of single cells for positive and negative feedback control. By adjusting calcium sensitivity and molecule location, light production can be made specific to large events such as bursts, or sensitive to individual spikes or single channel activity. By coupling these new luciferases to opsins, highly specific sensing of calcium at its source will trigger opsin activation for augmenting or suppressing neuronal activity, allowing a high degree of temporal and spatial precision in feedback control. Goals will be achieved by pursuing three aims: 1) Developing a calcium sensing split luciferase with significantly improved speed, brightness and range of sensitivity; 2) Targeting these new molecules to subcellular domains to enable highly specific biological outcomes; 3) Linking these new innovations to optogenetic readouts. Our strategy is non- invasive and it could be applied to large-scale manipulation of neural activity in behaving animals or in humans, where non-invasive, rapid feedback control of neuronal activity could be used to regulate clinically relevant activity in the brain. Our experiments are early stage, require proof of principle feasibility studies, but they have the potential to lead to a novel strategy to regulate activity only during periods of abnormal neuronal firing, such as attenuating runaway activity or amplifying local fluctuations. The molecular tools generated towards these feasibility experiments will be highly valuable in their own right, and achieving the goal of neural activity regulated self-control of neurons will be transformative.

Animals ranging from fireflies to jellyfish produce light, a process known as bioluminescence. In nature, bioluminescence is used for prey capture, mate attraction and self-defense. This unique form of light production occurs when a small molecule combines with an enzyme to release photons. Researchers have harnessed this distinctive form of living light production for a wide variety of uses, from measuring activity in cells by tracking light flashes, to controlling activity in cells by transforming bioluminescent signals into electrical current flow. These tools are powerful for answering scientific questions, and may also prove useful as novel treatments, for example in stimulating specific areas of the brain or regulating heart pacemakers. This NeuroNex Technology Hub advances science by innovating new bioluminescent technologies, and teaching others about it. New innovations include the development of brighter chemical reactions, able to transmit signals farther across the brain, and the creation of new microscopes to harvest bioluminescent activity. The Technology Hub also helps other scientists learn both the principles and the pragmatic details of how to use these methods in their own research, through workshops, emissaries sent to laboratories, and a comprehensive website. An additional key focus of this project is on developing curricula for general education, from the grade school to the high school level, and on outreach projects within the broader community.

This NeuroNex Technology Hub enables bioluminescence use for cellular imaging and control. Historical impediments to effective bioluminescence use included the prolonged time scale of light production and long recharging time (severe limitations in early calcium imaging attempts), and insufficient light production. The Technology Hub and other recent advances directly address these concerns, for example through discovery of new molecules, development of novel strategies for conferring calcium sensitivity to bright and fast luciferases, and brightness amplification e.g., by resonant energy transfer. All these innovations not only serve imaging, but also enable bioluminescence as a driver for optogenetic molecules, a new cellular control strategy termed BioLuminescent OptoGenetics ('BL-OG'). While BL-OG has already proven effective as a solution that allows chemigenetic and optogenetic control in a single molecule, the advances implemented here significantly elaborate and improve this functionality. The Hub role in providing technology transfer to other practicing scientists is tailored to the individuals seeking training. This specificity in dissemination of pragmatic knowledge is achieved by designing workshops at Brown University around the needs of attendees, and through sending bioluminescence-trained technicians and students directly to laboratories to demonstrate and trouble-shoot experiments. The comprehensive website lists existing bioluminescent options, where they can be acquired, and aggregate bibliographic references. In all activities, the Hub team seeks active input from the user community to ensure that the knowledge being disseminated is of use to advancing the exact goals of practicing scientists. This NeuroTechnology Hub award is part of the BRAIN Initiative and NSF's Understanding the Brain activities.

PROJECT SUMMARY / ABSTRACT Our Interdisciplinary Predoctoral Neuroscience Training Program strives to provide individualized, high quality training to predoctoral students interested in pursuing scientific careers in the biological and biomedical sciences. This training grant will support 8 students in their first two years of graduate studies, before they start their dissertation research. Graduate students in our program receive broad, multi-disciplinary training that spans many levels of inquiry, from genes through cognition, and emphasizes concepts, methodologies, experimental design, quantitative skills and program, and sophisticated analysis of the primary literature. Our core curriculum consists of graduate only courses, seminars, and workshops that provide a strong scientific foundation in neuroscience and develop skills that are essential for successful, independent research careers in neuroscience, such as effective science writing and oral presentation, knowledge of scientific review processes, and training in ethics. New initiatives include a revised advising system, more structured program evaluation, and greatly expanded quantitative training. We foster an environment unconstrained by traditional discipline boundaries, where graduate students are encouraged to work at the interfaces of these disciplines. The training program includes 39 core participating faculty and ~60 predoctoral trainees. The faculty trainers are drawn from eight different Brown University departments: Neuroscience; Cognitive, Linguistic, and Psychological Sciences; Molecular Biology, Cell Biology, and Biochemistry; Engineering; Molecular Pharmacology, Physiology and Biotechnology; Biostatistics; Neurology; and Neurosurgery. They are a distinguished and energetic group of brain scientists that collectively cover the spectrum of modern neuroscience research: they work with a wide variety of model organisms, from worms to humans, and use an array of modern neuroscience techniques, including functional MRI, applications of robotics and neuroprosthetics, optogenetics, advanced in vivo and in vitro electrophysiological recordings, mouse transgenics, behavioral studies, molecular manipulations of neuronal genes, functional proteomics, and human genome-wide association studies. We encourage and facilitate collaborations between labs as well as research in computational and translational neuroscience that typically reside at the interface of disciplines. Key features of the Neuroscience Graduate Program at Brown include: Excellence in research along with excellence in education and mentorship; a focused effort on addressing shortcomings related to diversity and equity across our program, including recruitment and retention of students as well as broad representation of trainer backgrounds; a history of interdisciplinary and translational research; rigorous training in experimental design and quantitative methods, and an environment of highly productive labs where graduate students are equal partners in the research process.