1981 — 1984 |
Glazer, Ellyn Basbaum, Allan |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Ultrastructural Analysis of Pain Control Systems in the Spinal Cord @ University of California-San Francisco |
0.915 |
1985 — 2016 |
Basbaum, Allan I |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Brainstem Control of Pain Transmission @ University of California San Francisco
DESCRIPTION (provided by applicant): The development of persistent pain conditions in the setting of tissue or nerve injury results to a great extent from significant reorganization of CNS circuits. These changes contribute to a central sensitization/hyperexcitability state that underlies allodynia and hyperalgesia, the hallmarks of persistent pain conditions. Many studies have focused on the injury-induced sprouting of primary afferents and on the physiological properties of altered "pain" response neurons in the spinal cord dorsal horn, but there is little information about the tissue and nerve-injury-induced local and long distant circuit changes that occur, in the spinal cord and at more rostral sites. Recently, we developed a transgenic mouse in which wheat germ agluttinin (WGA) synthesis, anterograde transport and transneuronal labeling of complex circuits can be triggered from neurons in any region of the brain or spinal cord, during development or in the adult. In the present proposal, we will use these mice and others that we will generate to study the development and adult organization of CNS circuits engaged by small diameter primary afferent nociceptors and to study their modifications after tissue or nerve injury. Through a highly novel modification of this transneuronal tracing method, in which the tracer is induced in primary afferent neurons only if their peripheral axon has been transected, we also propose to study nerve injury-induced reorganization of CNS nociceptive circuits. Both the normal circuits and the reorganization of circuits engaged by small and large diameter axons will be studied in these experiments. Finally, through the development of BAC transgenics, we propose to begin a detailed analysis of the circuits that arise from neurochemically distinct primary afferent nociceptors. Taken together, these studies will provide an entirely new anatomical perspective on the circuits that process the nociceptive messages resulting in acute and persistent pain.
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1993 — 1995 |
Basbaum, Allan Lisberger, Stephen (co-PI) [⬀] Fields, Howard (co-PI) [⬀] Merzenich, Michael (co-PI) [⬀] Stryker, Michael (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Multi-User Imaging Facility For Integrative Neuroscience @ University of California-San Francisco
This award provides funds to aid in the purchase of optical microscopy equipment. The equipment will be located in a central facility where it will be available to a group of neuroscientists in the Keck Center for Integrative Neuroscience. The scientists are all interested in various aspects of local circuit analysis of the mammalian central nervous system (CNS). The goal of their studies is an improved understanding of how small groups of neurons generate behavior. The instruments requested will be used for combined anatomical and physiological studies of brain function that include the use of double or triple labeling techniques. The development of new instrumentation for optical microscopy and of new methods that permit specific labeling of certain cells or certain cell constituents has been key to progress in our understanding of many aspects of cellular and developmental biology. Neuroscience has benefited greatly from these developments, since they permit the rapid and reliable identification of particular neurons or groups of neurons in the brain or at other sites that typically contain many nerve cells or similar morphology.
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0.915 |
1993 — 2002 |
Basbaum, Allan I |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Spinal Mechanisms of Opioid Analgesia and Tolerance @ University of California San Francisco
Our laboratory is interested in the mechanisms through which receptor selective opioids influence the neuronal activity of "pain" transmission neurons in the spinal cord. To this end, we have been studying the expression of the fos protein product of the c-fos proto-oncogene as a marker of noxious stimulus-evoked neuronal activity in large populations of spinal cord neurons. since the behavior of the animals as well as the presence of fos-like immunoreactivity can be assessed in the same animal, we have been able to correlate the inhibition of pain behavior produced by opioids with changes in the distribution and numbers of fos- immunoreactive neurons. Those studies demonstrated that behavioral analgesia can be produced without completely eliminating the noxious stimulus-evoked expression of fos in the spinal cord and that dose dependent changes differed in different regions of the cord. In the proposed studies we first will extend this analysis to the effects produced by opioids acting at the mu, delta and kappa receptors, administered supraspinally and at the level of the cord. Second, we will begin an analysis of noxious stimulus-evoked fos expression in the opioid tolerant animal. We will test the hypothesis that the pattern and magnitude of fos expression in the spinal cord is altered from that in normal animals, even though pain behavior returns to "normal". Since opioid antagonists precipitate a hyperalgesic state when the spinal cord is made tolerant to opioids, in related studies, we will compare the pattern of pain-evoked fos expression in tolerant animals with that produced when abstinence-associated pain is precipitated. Finally, since our studies have identified a critical contribution of neurons in the ventral horn of the spinal cord (laminae VII and VIII) to the transmission of nociceptive messages, we will begin a detailed analysis of the synaptic circuitry that regulates neurons in these regions. Taken together these studies will reveal how populations of neurons are affected under conditions of pain, opioid analgesia, tolerance and abstinence. Understanding how different neuronal populations respond is an important step in developing pharmacological approaches to selective regulation of these neuronal populations, so that better pain control, with reduced tolerance and side effects, can be achieved.
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1995 — 1999 |
Basbaum, Allan I |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Neurochemistry of Pain Modulation @ University of California San Francisco
pain; neuropeptide receptor; spinal cord mapping; brain mapping; neurochemistry; neurotransmitter transport; dorsal horn; NMDA receptors; receptor expression; neural information processing; gamma aminobutyrate; central neural pathway /tract; medulla oblongata; gene induction /repression; afferent nerve; substance P; receptor sensitivity; GABA receptor; analgesia; microdialysis; laboratory rat; immunocytochemistry; electron microscopy;
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1996 — 2000 |
Basbaum, Allan I |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Immunoreactive Tachykinins in Spinal Cord Releasates @ University of California San Francisco
There is considerable evidence that noxious stimulation produces N-methyl- D-aspartate (NMDA)-mediated long-term changes in the physiology and chemistry of dorsal horn neurons. Our laboratory has provided new evidence that links the neurotransmitter Substance P(SP) to these changes. We have demonstrated rapid internalization of the substance P receptor (SPR) in subpopulations of spinal cord neurons in response to stimulation with SP. There is also a dramatic and reversible structural reorganization of the dendrites of neurons that express the SPR. The dendrites become highly varicose and the diameter of the dendrites between varicosities is significantly reduced, compared to normal. We have also demonstrated that intrathecal injection of NMDA or noxious stimulation of the hindpaw evokes these changes. This suggests that these changes are a normal response to SP-mediated inputs. Our proposed studies will further characterize the neurons that undergo these changes and will address the opioid regulation of these changes. In related study we will use antisera directed against the recently cloned opioid receptors to determine the relationship of neurons that express the SPR with those that express the opioid receptors. We hypothesize that the structural changes of neurons that express the SPR constitute a significant component of the noxious stimulus-evoked short and long-term changes in spinal cord neurons, and suggest that NMDA-mediated hyperalgesic states result at least in part from release of SP from primary afferent fibers. We will test these hypotheses using anatomical, neurochemical, physiological and pharmacological approaches. We will also test the hypothesis that changes in the process of SPR internalization contribute to the differences that characterize nociceptive and neuropathic pain models, which are respectively associated with chronic up and downregulation of SP levels in the dorsal horn. Taken together these studies will provide important new information on the pathophysiology and the clinical consequences of injury-evoked long-term changes in the spinal cord dorsal horn.
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2000 — 2002 |
Basbaum, Allan I |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Non-Peptide C-Fibers and Nociception @ University of California San Francisco
DESCRIPTION: (condensed from applicants abstract): This grant focuses on defining the role of non-peptide containing primary afferents C fibers in nociception. Previous studies in the Basbaum lab have concentrated on the contribution of substance P-containing primary afferent C-fibers. However, the number of C fiber nociceptors that do not express peptides predominate yet we have little information concerning their phenotype, their neurocircuitry, or the type of pain provoked by their activation. While the peptide-containing afferents target laminae I and II outer, the non-peptidergic afferents target inner lamina II. The PI has demonstrated that these afferents express the vanilloid/capsaicin receptor and selectively express the 5HT-3 receptor. Thus, the PI will use activity at this receptor as a window into the contribution of the non-peptidergic population to nociceptive processing and pain. In a multi-faceted approach, anatomical, behavioral and electrophysiological studies in wild type and 5HT-3 receptor null mice will be used to address the function of these non-peptidergic afferents. Combined in situ and immunohistochemical studies will identify the neurochemical phenotype of the primary afferent neurons that express mRNA for the 5HT-3 receptor. In EM studies, the central termination of the non-peptidergic afferents will be investigated. In behavioral and anatomical studies, the PI will test the hypothesis that projection neurons in lamina I transmit the pain messages signaled by nociceptive activity in non-peptidergic afferents. In electrophysiological studies in the mouse, the PI will test the hypothesis that activity at the spinal 5HT-3 receptor facilitates the transmission of nociceptive messages. The results of these studies will provide new insights into the factors that contribute to the development of acute and persistent pain.
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2007 — 2011 |
Basbaum, Allan I |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Anatomy @ University of California, San Francisco
Anatomy (Core B) While the Study Section acknowledged that the Scientific Core provides important support to all Projects, the core initially proposed employed a distinctly non-traditional format. In this revised application we have restructured the Scientific Core, based on a more traditional model. Dr. Basbaum, a dedicated senior level anatomist (25% effort), who could help in the development of sophisticated procedures needed for anatomical studies, and a technician, in the traditional (100% effort) to provide technical support, will be the Key Personnel. While a minimal supply budget is requested, for basic reagents and other supplies, more costly reagents will be acquired from individual components'budgets. Storage space for supplies for individual projects will be available in the Basbaum lab. Of note in this regard, Dr. Basbaum has recently moved to the Mission Bay campus (as part of the ongoing move of our neuroscience faculty to this new campus), providing him significant additional space than he had in his lab at the Parnassus campus site, a portion of which will be allocated to the Core. The shared antibody resource will also be physically located in the Basbaum lab, providing important reagents to all Pis. With respect to the use of confocal microscopes, all Pis have access to state-of-the-art confocal microscopes. Drs. Basbaum and Levine are on a funded multiuser equipment grant that has recently purchased a two-photon confocal that can image living cells, Dr. Messing has a confocal available to him at the Gallo Center and Dr. von Zastrow has access to two confocal microscopes in Genentech Hall, where his laboratory is located at the Mission bay campus, though none of the project Pis have the expertise in anatomical technique that will be provided by the Scientific Core. While all projects will have need for the Scientific Core, it is difficult to assign an exact percentage effort for the use of this Core by each project. Dr. Basbaum will assign the distribution of the time (percentage effort) of the technical personnel to support each of the projects. As noted by the review group, the Pis of this PPG proposal haye a long track record of working together, which we fully expect will include being able to accommodate each other's needs for the anatomist in the core. Finally, it should be noted that the role of Dr. Basbaum and the technical support person is to help develop the needed techniques and establish them in the individual component projects, not to perform all of the experiments in every project. Also, given the decreased number of projects, we expect that the anatomist will have adequate time and the ability to prioritize his/her effort for each project.
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2011 — 2015 |
Basbaum, Allan I |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Epigenetic and Genetic Contributors to Chronic Neuropathic Pain @ University of California, San Francisco
DESCRIPTION (provided by applicant): The transition from acute to chronic neuropathic pain following nerve injury, in many respects, results from a maladaptive plasticity of the nervous system, i.e. it is a disease of the nervous system. The plasticity is manifest at molecular, structural, biochemical and physiological levels, all leading to a condition in which there is ongoing, intense spontaneous pain, pain in response to normally innocuous stimuli (allodynia) and exaggerated pain in response to normally painful stimuli (hyperalgesia). The initiation and maintenance of neuropathic pain involves remodeling of injured nerve circuits, changes in synaptic strength as the pain message is processed through the spinal cord and brain as and perturbations in signaling processes, at all levels of the pain pathway. Many of these changes, however, are the product and/or the cause of long lasting alterations in gene expression. As the most stable modulation of gene expression programs is under epigenetic regulatory control, here we will perform studies to test the hypothesis that nerve injury induces significant alterations to the neuronal epigenome, and most importantly that some of these changes contribute to the generation and persistence of the neuropathic pain condition. In other words, we will dissect the epigenetic landscape of chronic neuropathic pain. Our initial studies will focus on changes that occur in the spinal cord following nerve injury, in standard rodent models of neuropathic pain. Our objective is to obtain a better understanding of the molecular underpinnings of this maladaptive process, which is a critical first step to identifying new targets for therapeutic intervention.
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2011 — 2015 |
Basbaum, Allan I |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Multiple Opioid Receptors and the Control of Pain @ University of California, San Francisco
DESCRIPTION (provided by applicant): The delta (DOR) and mu (MOR) subtypes of G protein-coupled opioid receptors are widely distributed in the central and peripheral nervous system. These receptors are targeted both by endogenous opioid peptides and by a host of exogenous opiate agonists, including morphine. Despite years of research, there are still numerous unanswered questions concerning the differential contribution of the DOR and MOR to the complex behaviors influenced by opioid agonists, including pain control, addiction and reward. In part, the lack of progress reflects the tools that are available to study the expression, interaction and function of the receptors in different CNS circuits. To this end, we have developed a delta opioid receptor (DOReGFP) reporter mouse that led to a complete reappraisal of the circuits that are influenced by agonists that act at the DOR. Contrary to the prevailing view, we find that the DOR and the MOR are expressed in non-overlapping subsets of dorsal root ganglia (DRG) pain transmission neurons (nociceptors) and regulate distinct pain modalities. The DOR is expressed in myelinated sensory neurons and in a subset of the non-peptidergic unmyelinated nociceptors and regulates mechanical pain and the mechanical hypersensitivity produced in the setting of injury. The MOR predominates in the peptidergic nociceptors, which express the capsaicin and heat responsive channel, TRPV1, and regulates heat pain. The present proposal builds upon these observations. Studies in Specific Aim 1 will use neuroanatomical methods to assess the extent to which segregation of the DOR and MOR also occurs in the spinal cord and brain, in the normal animal and in the setting of tissue or nerve injury. Specific Aim 2 uses a combination of behavioral, pharmacological and genetic methods to determine the differential contribution of the DRG and spinal cord neuron expression of the DOR and MOR to nociceptive processing and to the antinociceptive effects of opioid compounds. Finally, Specific Aim 3 will extend the pharmacological analysis to the differential contribution of DOR and MOR agonist action at supraspinal targets. Taken together these studies will not only provide new information as to the organization of endogenous opioid receptor systems, but will also assess the extent to which different modalities of pain can be controlled by opioid agonists that selectively target these receptors, in the peripheral and central nervous systems. Information derived from these studies will be an important contributor to the development of pain-relieving drugs with better side effect profiles.
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2012 — 2016 |
Basbaum, Allan I Braz, Joao [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Spinal Cord Transplants of Gabaergic Precursor Cells to Treat Chronic Pain @ University of California, San Francisco
DESCRIPTION (provided by applicant): Loss of inhibitory circuits in the spinal cord dorsal horn is one of the major contributors to persistent pain following nerve injury (neuropathic pain). The loss of inhibition contributes not only to the development of spontaneous pain, but also to the hyperexcitability that underlies the allodynia and hyperalgesia that are characteristic of thes clinical conditions. Pharmacological management of nerve injury-induced neuropathic pain is directed at enhancing inhibitory controls, but unfortunately, not all patients are responsive to such therapies. Furthermore, adverse side effects, which arise because treatments typically involve systemic drug administration, often limit the use of effective doses. We propose to develop a novel therapeutic approach (transplantation of precursor inhibitory neurons) that is designed to restore the inhibitory controls in the spinal cord. The treatment regime differs from traditional pharmacological therapies that are directed at symptom management; transplantation to replace missing interneuronal control is a disease modifying approach. Transplantation of embryonic precursor cells has, in fact, resulted in functional improvement in various neurodegenerative diseases, but still very little is known about the underlying therapeutic mechanisms and the extent to which connectivity exists between grafted cells and host tissue. We propose to transplant cells derived from the mouse embryonic medial ganglionic eminence (MGE). In Specific Aim 1, we will continue our analysis of the circuits in which the transplants participate and will use electrophysiology to assess the extent to which inhibitory controls derive from the transplants. In Specific Aim 2, we will assess the ability of the transplants to alleviate the persistent pain produced by peripheral nerve injury, including those produced by chemotherapeutic agents. Using selective antagonists to counter the effects of the transplants, we will determine whether GABA is indeed the major contributor to recovery. Finally, in Specific Aim 3, we will use a novel chemical-genetic approach to achieve in vivo spatio-temporal control of the activity of the transplants. These studies will establish that MGE-derived cells have the essential properties for a cell-based therapy, particularly when loss of inhibitory control is a major contributor to the clinical condition. Success in this endeavor will establish the proof of concept necessary for eventual studies of cell transplantation for persistent pain in humans.
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2015 — 2016 |
Basbaum, Allan I |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Influence of Drug Abuse On Neuronal Nuclear and Chromatin Architecture @ University of California, San Francisco
DESCRIPTION (provided by applicant): Opioids are essential to the management of acute and persistent pain, but their chronic use is associated with significant adverse effects, includin tolerance and dependence. There is now considerable information as to the physiological and molecular changes associated with chronic opioid use, but treatments that mitigate the problems are limited and generally ineffective. Unquestionably, the long lasting cellular changes that contribute to the development of tolerance and the manifestations of withdrawal are governed, at least partly, by stable changes in gene expression that are induced by pathways directly engaged during opioid receptor signaling. On the other hand, as manifestations of chronic opioid use, including psychological dependence, may persist long after the termination of opioid intake, we hypothesize that there are additional, maladaptive epigenetic mechanisms that retain transcriptional responses after the removal of the initial stimulus. Here, we propose t identify not only the transcriptional changes associated with tolerance and withdrawal, but also the epigenetic changes that we hypothesize induce and sustain them. We will use mouse models of morphine tolerance and withdrawal and we will focus our analysis on two brain regions, the locus ceruleus (LC) and the ventral tegmental area (VTA), both of which have been implicated in critical features of long term opioid use. We will perform genome wide, next generation sequence-based analysis of changes in the transcriptome (RNA-seq) and the epigenetic landscape (ChIP-seq) of FAC-sorted, pure neuronal populations. Importantly, we will extend our analysis to the 3-dimensional organization of the epigenome, which as is now recognized, provides an additional layer of epigenetic regulation that is likely more stable than chromatin and DNA post-translational modifications. To achieve the high-resolution, 3-dimensional and quantitative imaging of primary neurons isolated from the LC and VTA, we will use soft X-ray tomography (SXT). SXT, as we have recently demonstrated, is ideal for the study of nuclear architecture in primary neurons, and provides the most sensitive imaging method for generating an unbiased identification of the changes in chromatin organization and compaction associated with chronic opioid (morphine) use. This approach will be complemented by a genome wide chromatin conformation capture approach (Hi-C) and DNA FISH experiments. Thus, our proposed experiments will not only map the nuclear and epigenetic landscape of completely uncharted neuronal populations but will also have the potential to provide novel and fundamental insights into the epigenetic processes associated with tolerance and dependence. Together our findings will lay the foundation for the development of novel pharmacological interventions that may not only improve the management of pain by opioids, but also reduce the incidence of adverse side effects, including opioid abuse.
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2017 — 2021 |
Basbaum, Allan I. |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
From the Spinal Cord to the Brain: Neurology of the Pain and Itch Neurons @ University of California, San Francisco
Despite tremendous progress in our understanding of the primary sensory neurons and spinal cord interneuronal circuits that respond to and transmit pain and itch-provoking stimuli, how these stimuli are interpreted by the brain to produce the perceptions of pain and itch are still unclear. To a great extent, this gap in our knowledge reflects the much more limited information that we have about the projection neurons that carry the information from the spinal cord to the brain. That gap is critical as it is the signals carried by the projection neurons that are ?read? by the brain and that ultimately lead to a perception of pain or itch, and to their various submodalities (heat, cold, mechanical, etc.). Our research program is multidisciplinary, using novel viral, genetic and functional (electrophysiological, behavioral and imaging) approaches to characterize the properties of the projection neurons, the circuits that engage them, their supraspinal targets and the functional consequence of their activity. An important focus of the research program is on the question of convergence or segregation of the circuits that respond to painful or itch-provoking stimuli and the extent to which these circuits are altered in the setting of injury. Our program includes several highly innovative experiments that for the first time will not only determine the molecular heterogeneity of the projection neurons, but will also examine the responses of populations of neurons in the brain to activity in the projection neurons. Defining molecular subtypes of projection neurons and the development of Cre-expressing mice based on these molecular features will permit a host of experiments, including viral-based retrograde (rabies) and anterograde (HSV) tracing of circuits that influence subsets of projection neurons, as well as the behavioral consequence of selective ablation, or DREADD-mediated activation/inhibition of these neurons. Finally, using incredibly powerful Ca2+ imaging techniques that signal the activity of populations of neurons in awake, freely moving mice, we will obtain new information on the behavioral correlates of algogen and pruritogen-evoked supraspinal activity. Using novel behavioral paradigms our program will also provide important insights into the processes through which noxious, and even innocuous stimuli (in the setting of injury), are interpreted as painful. These new approaches will provide information about the quality of the pain that the animal experiences and also offer a powerful validation of the mouse models of chronic pain and itch and their translatability to the human condition.
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