Suzanne Haber - US grants

The globus pallidus is a structure commonly divided into two segments: the external segment (the globus pallidus in lower mammals is the homologus structure) and the internal segment (the entopeduncular nucleus is thought to be the homologous structure). It is likely that the ventral pallidum, a subcommissural extension of the external portion, should be considered a unique segment based on its limbic-related rather than motor-related afference, its neuropeptide content, and possibly limbic-related efference. Recently, this subcommissural compartment of the globus pallidus has been shown to encompass a larger region than previously thought, invading much of the basal forebrain area in both the rat and the monkey. It is set apart from the more dorsally placed pallidum both with respect to its circuitry and its histochemistry. The evidence available indicates that the afference to the ventral pallidum is derived solely from the limbic-related striatum and preliminary studies suggest that its efference may be a mixture, projecting to both motor-related and limbic-related structures. Furthermore, dense substance P-like immmunoreactivity is confined within the ventral pallidum while only weak staining is observed in the dorsal pallidum. Enkephalin-like imunoreactivity, on the other hand, is very dense in both pallidal components. The specific aim of this proposal is to study the afference and efference of the ventral pallidum, with special reference to the chemical specificity of its circuitry. While the motor-related circuitry of the dorsal pallidum has been studied extensively, little is known about the circuitry of the limbic-related ventral pallidum. It is likely that the limbic-afferented part of the pallidum not only has an efferent system which is different from the non-limbic part but that it continues this conduction line to non-motor related areas. Knowledge of these relationships may help identify brain structures involved in non-motor function of the striatum, conceivably including functions whose disorders can lead to mental illness.

Millions of Americans suffer from debilitating mental disorders. Most of them have motor dysfunctions as well. The pharmacological agents used to treat these patients often involve drugs thought to exert their therapeutic effects by acting on neuromodulators in the basal ganglia and the subcortical forebrain area. A common complaint concerning these drugs is the motor side effects. A more complete knowledge of the chemical circuitry of this large, complex region in the primate, would be an important contribution to the understanding of the extent to which motor and limbic systems interact and would provide a sounder basis for the development of effective pharmacological agents used for the treatment of mental disorders. The primary aim of the studies proposed here is to understand the chemical organization of the primate basal ganglia and forebrain with particular emphasis on its relationship to functional circuitry. Immunohistochemistry and tract-tracing methods will be used in combination to study the interface between the basal ganglia and the limbic system. Our points of departure are the following recent developments: 1) the striatum can be divided into a limbic-related segment and motor-related one which project topographically to the globus pallidus; 2) circuitry studies in the rat indicate that the differential peptide (enkephalin, substance P, and dynorphin) distributions in the pallidum originating from striatal cell bodies, reflect different functional (limbic vs. motor) connections; 3) the distribution patterns of the three neuropeptides in primates are markedly different from that of the rodent, which strongly indicates that the basal ganglia circuitry is distinct and more complex in primates; 4) embedded in the peptide-positive striatal efferent fibers of pallidum are large cholinergic neurons of the basal nucleus of Meynert, thus suggesting another way in which the basal ganglia can influence the limbic system. The proposed studies will: 1) examine the afferents and efferent connections of the primate globus pallidus; 2) analyze these projections with respect to function (limbic vs. motor) circuitry; 3) determine the neuropeptide involvement in these circuits; and 4) examine the interface between the basal ganglia and the limbic-related basal nucleus of Meynert.

prosencephalon; central neural pathway /tract; neurotransmitters; neural transmission; neurochemistry;

DESCRIPTION (Adapted from applicant's abstract): Neuropathology of the mesolimbic dopamine system remains a major focus in the study of neurochemical correlates of schizophrenia. Research has generally focused on the dopamine neurons of the ventral tegmental area (VTA) and their projection to the ventral striatum, the main components of the basal ganglia limbic loop. Recently, studies have turned to areas of the prefrontal cortex that receive dopamine input. These studies suggest that the differential regulation of dopamine in the ventral striatum and in cortex might underlie the pathology of the disease. The midbrain dopamine cells are unique in basal ganglia circuitry in that they are in a position to integrate different cortical/basal ganglia loops. They receive amygdala and ventral striatal input and project to wide areas of both the cortex and striatum. The basal ganglia limbic loop is both a closed and open system. As such it is able to influence the limbic system specifically (closed loops) and, at the same time, integrate limbic, cognitive and motor functions (open loops), primarily through the midbrain dopamine neurons. The general goal of these experiments is to understand how the midbrain dopamine system can integrate information from several functional domains of striatum and cortex. Results from the tracing experiments, as well as other anatomical and physiological studies, demonstrate that the midbrain DA neurons are in a unique position to integrate several basal ganglia circuits. Furthermore, pharmacological studies suggest that dopamine effects in the striatum and cortex may be regulated differently. During the previous funding period we found two populations of dopamine cells that have different levels of the dopamine transporter and the D2 receptor. These two groups may have different cortical targets. Despite the fact that the midbrain dopamine system is one of the most studied in the CNS and is a prominent player in several diseases, there are surprisingly few studies that address circuitry as it relates to striatal/cortical balance. The proposal addresses the issue of the ventral basal ganglia as a complex structure with both segregated and integrated circuits. The main foci are: 1. how the midbrain dopamine circuitry can integrate different functional domains, and 2. how the midbrain dopamine circuitry can differentially regulate various cortical and striatal pathways through levels of DAT and receptor subtypes.

Neuropathology of the basal ganglia has been clearly demonstrated of implicated in a number of debilitating disorders that involve motor, and emotional deficits, including Parkinson's disease, and Huntington's disease. The basal ganglia is a set of structures well known for their interconnectivity and their 'loop' systems, which have been associated with different cortical functions. The pathways through the basal ganglia of the limbic loop have not been as well identified as the corresponding pathways of the motor loop. The main objective of this proposal is to identify these pathways and the extent to which they are integrated with those of the motor system. A through knowledge of the circuitry of the basal ganglia and the potential integration between motor- and limbic- related pathways will contribute to a better understanding of basal ganglia organization and of the constellation of clinical symptoms in diseases affecting these structures. Electrophysiological and circuit tracing techniques will be used to identify pathways and immunocytochemical methods to identify transmitter systems. By electrophysiological mapping techniques, anterograde tracers will be placed into limbic-related pallidal regions (or those regions known to receive input from the limbic-innervated striatum). Terminal fields from these injections will be compared to those originating in motor-related pallidum. Retrograde tracers will be placed in the regions of the striatum known to receive input from either limbic- or motor- related cortical regions and the distribution of midbrain dopamine cells projecting to these regions will be charted to determine whether these functionally different striatal regions input from subpopulations of dopamine neurons. Finally, the distributions of neurotransmitter systems in animals and human ganglia will be compared. These studies will contribute to the understanding of the organization of these structures in the human.

Neuropathology of the basal ganglia has been clearly demonstrated of implicated in a number of debilitating disorders that involve motor, and emotional deficits, including Parkinson's disease, and Huntington's disease. The basal ganglia is a set of structures well known for their interconnectivity and their 'loop' systems, which have been associated with different cortical functions. The pathways through the basal ganglia of the limbic loop have not been as well identified as the corresponding pathways of the motor loop. The main objective of this proposal is to identify these pathways and the extent to which they are integrated with those of the motor system. A through knowledge of the circuitry of the basal ganglia and the potential integration between motor- and limbic- related pathways will contribute to a better understanding of basal ganglia organization and of the constellation of clinical symptoms in diseases affecting these structures. Electrophysiological and circuit tracing techniques will be used to identify pathways and immunocytochemical methods to identify transmitter systems. By electrophysiological mapping techniques, anterograde tracers will be placed into limbic-related pallidal regions (or those regions known to receive input from the limbic-innervated striatum). Terminal fields from these injections will be compared to those originating in motor-related pallidum. Retrograde tracers will be placed in the regions of the striatum known to receive input from either limbic- or motor- related cortical regions and the distribution of midbrain dopamine cells projecting to these regions will be charted to determine whether these functionally different striatal regions input from subpopulations of dopamine neurons. Finally, the distributions of neurotransmitter systems in animals and human ganglia will be compared. These studies will contribute to the understanding of the organization of these structures in the human.

DESCRIPTION (Adapted From The Applicant's Abstract): Studies of the ventral striatum and its connections are of key importance for understanding the neurobiology of drug abuse and mental disorders. Anatomical, physiological and pharmacological studies in these brain regions have been central in gaining insight into the mechanisms underlying motivation, reward, and goal-directed behaviors. The "motive" or drug-reward circuit involves the orbital and medial prefrontal cortex (OMPFC), the ventral striatum (VS), the ventral pallidum/substantia nigra, pars reticulata (VP/SNr), and the medial dorsal N. of the thalamus (MD), which links the circuit back to cortex. The opiates and excitatory amino acids through their interactions with ventral striatal transmitters and receptors, are central to studies on goal-directed behaviors, drug addiction, and behavioral disorders. During the previous funding period we identified important components of this circuit in primates along with the histochemical organization of the ventral striatal shell/core sub-territories. Using retrograde tracer injections, we demonstrated the OMPFC and thalamic projections to the VS. Based on these studies, the region of the striatum that can be associated with goal directed behaviors appears to be extensive. Furthermore, we demonstrated an integrative network of connections via the midbrain. The next step is to link together these components. The experiments proposed here will test the hypothesis that the ventral cortical- basal ganglia-cortical pathways via the thalamus and substantia nigra are also governed by an integrative network of connections with information flowing from limbic to more associative cortical regions in a step-wise manner through the ventral striatum. The experiments will first use anterograde tracer injections to delineate the rostro-caudal extent of the OMPFC projection fields to the VS, their relationship to the VS shell/core sub-territories and to the distribution of the mu receptor and GluR1 sub-unit receptor subtype. These experiments will also examine the relationship between MD and midline thalamic projections to the shell/core regions, how these relate to OMPFC inputs, and the mu and GluR1 receptors. A final set of experiments will address the connections between the output pathways from specific shell/core regions to the VP/SNr to the MD nucleus. These studies will link together how the OMPFC and thalamic inputs to the VS are related to the shell and core sub-territories, and the mu and GluR1 receptors and follow the outputs via the VP/SNr to the MD.

learning; neural plasticity; meeting /conference /symposium; corpus striatum; behavior; genetic regulation; neurophysiology; neuropharmacology; neuroanatomy;

DESCRIPTION (provided by applicant): The midbrain dopamine (DA) system is comprised of a diverse group of neurons involved in reward, motivation, cognition and motor control. Recent studies indicate that DA cells may provide a substrate for associative learning suggesting that neuronal plasticity is a significant component of the DA-striatal pathways. The consequences of dopamine dysfunction in this regard are emphasized in pathological conditions that are thought to involve DA, including drug abuse and addiction, schizophrenia, and Parkinson's disease (PD). One of the principal causes of Parkinson's disease, for instance, is a reduction in DA levels due to the death of DA cells in the basal ganglia. In its earliest stages PD is associated with cognitive deficits which precede the onset of motor control dysfunction. We will use a regime of chronic, low dose MPTP treatment as a model of early Parkinson's disease to investigate the behavioral and anatomical effects of DA depletion. Before significant cell loss (in early PD or from low-dose MPTP treatment) cellular and molecular mechanisms work to maintain extracellular DA levels. As a result, there is compensation for the early deficits in cognitive and motor function resulting from an initial DA depletion. The proposed research will use the oculomotor system as a sensitive and quantifiable assay to identify behavioral and cognitive changes produced by depletion of DA. By dissociating motor and cognitive components of visual orienting tasks, we are able to evaluate differential effects of partial DA lesions on these behavioral components. These measures gives us precise control over the effects of MPTP-induced lesions. These experiments will provide important insight into the regulation and plasticity of dopamine neurons by comparing behavioral and cellular consequences of a partial DA lesion at the onset of cognitive and/or motoric dysfunction and after recovery of function resulting from endogenous compensatory mechanisms. The ability to recognize the early behavioral effects of DA depletion and to understand the cellular consequences of this loss will promote the development of treatments for PD which utilize existing cellular and molecular functions while most DA cells are still intact.

DESCRIPTION (provided by applicant): In June, 2002 there will be a meeting consisting of a series of workshops focusing on "The role of the ventral striatal network in emotional processing: regulation of positive and negative states." The conference will take place at the Congres Hotel Leeuwenhorst, Noordwijkerhout in the Netherlands. The Principal Investigator is Suzanne N. Haber, and the co-organizers are: Drs. Barry Everitt, Anthony Grace, Henk Groenewegen, Ann Kelley, Jacqueline McGinty, Bita Moghaddam, Celeste Napier, Cyriel Pennartz, Linda Porrino, and Daniel Weinberger. To stimulate active, informal discussion, the meeting will be relatively small. In preparation for the meeting, six focus groups have been created to develop the topics for the workshops and prepare the workbook. The six groups are: anatomy, physiology, pharmacology, behavior, clinical, and genomics/proteomics. The goal of each focus group is to address three issues prior to the meeting: 1. Summarize the current state of knowledge for the each research area; 2. Develop questions that each focus group would like to raise for consideration by other focus groups; and 3. Develop questions that address broad issues that cut across the focus groups. These will form the basis for meeting workshops. Communication will take place through our web site and internet message boards. A meeting workbook will be developed containing background material and focus groups summaries for use as a tool for the participants at the meeting. The workshops will be an open forum, led by two discussion leaders, representing different focus groups. Sessions will begin with a brief summary of the question(s) to be addressed, including a summary of how they were formed and the relevant background material. Following this opening, workshops will be devoted to active participation from all attendees, addressing new questions and directions that cut across the specific areas of expertise. This unique format, which was very successful at our last meeting, encourages free exchange of ideas to address the question "what is the role of the ventral striatal network in emotional processing?

DESCRIPTION (provided by applicant): Obsessive Compulsive Disorder (OCD) is a chronic psychiatric illness that affects from 2-3% of the worldwide population. It is estimated that 20% of OCD patients are refractory to available psychological and pharmacological treatments. While the pathophysiology of OCD remains incompletely understood, recent evidence indicates abnormalities in the medial and orbital frontal-basal ganglia circuit. Indeed, correction of hyperactivity in orbital frontal cortex (OFC) is a common factor across effective pharmacological, behavioral, and neurosurgical therapies. Furthermore, our pilot studies using deep brain stimulation (DBS) show that the most promising target for DBS for OCD is in the ventral anterior internal capsule (VC) and adjacent ventral striatum (VS). However, there are several afferent and efferent projections that course through and converge at this location that may modulate OFC activity. The goal of this grant is to delineate the neural network and physiology underlying the effects of deep brain stimulation (DBS) for obsessive compulsive disorder (OCD), using a series of integrated translational experiments that involve: 1. functional neuroimaging in humans (aim 1), 2. tract tracing in nonhuman primates (aim 2), and 3. electrophysiology in rodents (aim 3). We will focus on two competing hypotheses: 1. that DBS acts primarily via fibers directly connecting the OFC with the thalamus, and 2. that DBS indirectly modulates OFC activity primarily through its stimulation of the VS pathways. Furthermore, an additional goal of the experiments is to delineate other key structures and transmitters, most specifically dopamine, (DA); and serotonin, (5HT), that may be involved at different points of DBS in the VS. Aim 1 will test the hypothesis that acute electrical stimulation at the VC/VS target will affect activity in OFC, ACC and functionally related areas, including the striatum, globus pallidus, and thalamus. Aim 2 will test the hypothesis that different regions of the VC carry specific cortical circuits and those circuits will differ substantially from those activated in the VS. Aim 3 will determine which candidate pathway (direct, via the thalamus; or indirect, via the VS and ventral pallidum) activated during DBS primarily modulates OFC activity patterns. A better understanding of the underlying neural circuitry of psychiatric disorders is a key element for developing the next generation of effective treatments.

In May, 2005 there will be a meeting consisting of a series of workshops focusing on "Regulation and Development of the Prefrontal Cortex: Basic and Clinical Perspectives". The conference will take place at the Sheraton Sand Key Resort in Clearwater, Florida. The Principal Investigator is Suzanne N. Haber, University of Rochester, and the co-organizers are: Barry Everitt, Stan Floresco, Anthony Grace, Ahmad Hariri, Ann Kelley, Jacqueline McGinty, Bita Moghaddam, Celeste Napier, Linda Porrino, Jeremy Seamans, and Daniel Weinberger, NIMH. This meeting will be dedicated to the memory of Pat Goldman-Rakic. To stimulate active, informal discussion, the meeting consists of a series of workshops and will be relatively small. In preparation for the meeting, we have chosen four workshop topics. Four focus groups have been created to develop the questions and issues for discussion in the workshops. The focus groups are comprised of a cross section of 5-6 scientists to include clinical and basic scientists, and a mixture of junior and senior scientists. These groups will also prepare an introductory summary that begins each workshop on a specific topic. Following each workshop there will be summary session for all of the participants. These will comprise a meeting summary to be published in Neuropsychopharmacology. The workshops will be an open forum, led by a facilitator, with a written summary by a scribe. Workshops will be devoted to active participation from all attendees, addressing new questions and directions that cut across the specific areas of expertise. This unique format, which was very successful at our last meeting, encourages free exchange of ideas. A specific emphasis is on recruiting young scientists to the field. Therefore each workshop will engage at least one young scientist in a leadership role, (as facilitator, scribe, or presenter).

[unreadable] DESCRIPTION (provided by applicant): In May 2007 there will be a meeting consisting of a series of workshops focusing on "Reward, compulsions and habit formation". The conference will take place at IGESA Resort in Porquerolles, France. The Principal Investigator is Suzanne N. Haber, University of Rochester, and the co- organizers are: Paul Apicella, Christelle Baunez, Martine Cador, Barry Everitt. Anthony Grace Ann Kelley, Jacqueline McGinty, Bita Moghaddam, Celeste Napier, Patricio O'Donnell, Linda Porrino and Daniel Weinberger Ph.D., NIMH. To stimulate active, informal discussion, the meeting consists of a series of workshops and will be relatively small. In preparation for the meeting, we have chosen four workshop topics. Four focus groups have been created to develop the questions and issues for discussion in the workshops. The focus groups are comprised of a cross section of 7-9 scientists to include clinical and basic scientists, and a mixture of junior and senior scientists. These groups will also prepare an introductory summary that begins each workshop on a specific topic. Following each workshop there will be summary session for all of the participants. The workshops will be an open forum, led by a facilitator, with a written summary by a scribe. Workshops will be devoted to active participation from all attendees, addressing new questions and directions that cut across the specific areas of expertise. This unique format, which has been very successful at our previous meetings, encourages free exchange of ideas. A specific emphasis is on recruiting young scientists to the field. Therefore each workshop will engage at least one young scientist in a leadership role (scribe or presenter). Furthermore, there will be a special workshop for junior scientists devoted to questions and issues related to career development. [unreadable] [unreadable] In pathologies involving motivational disorders, the problem of building/breaking habits is intermingled (Volkow and Fowler, 2000; Bechara, 2003; Groenewegen et al., 2003). In order to improve our understanding of these pathologies, it is therefore highly important to better identify the behavioral establishment, as well as the neuronal basis of habit formation. The topic of habit formation and compulsive disorders is particularly timely as it brings together motivational and motor aspects of cortico-basal ganglia systems. This field of research is currently considering parallels between drug addiction and compulsive eating behavior leading to obesity (Volkow and Wise, 2005; Kelley et al., 2005; Kelley and Berridge, 2002), as well as the commonalities and differences in other compulsive disorders such as OCD and Tourette's Syndrome. [unreadable] [unreadable] [unreadable]

The Administration Core will oversee ail aspects of the Center and coordinate its activities. This includes a plan for information transfer between projects as well as information dissemination to the scientific community and to the public. Core A will be responsible for assuring that milestones are met, and in consultation with NIH, will appoint and Interact with the External Advisory Board. The graduate and post graduate training programs, as well as the undergraduate training program will be administered through Core A. Finally, Core A will oversee standard administrative tasks such as the budget and resource allocations and maintain the Center web site. The PI of the Center will be responsible for the overall direction of the Center. The Co-PI will specifically coordinate interaction with the funded clinical grant and lead the outreach program. Dr. Quirk will lead the training program. A steering committee chaired by the PI of the Center, will include the Pis and Co-PIs of all Projects and Core. This committee will meet bimonthly and be responsible for meeting scientific goals and milestones In a timely manner;interact with the External Advisory Board;Training, including the graduate and undergraduate programs;oversee resource allocation and reallocation; oversee the web site, and resource and data sharing components of the Center. RELEVANCE (See instructions): Obsessive Compulsive Disorder (OCD) is a chronic psychiatric illness that affects 2-3% of the worldwide population. This is disease is in the top ten dehabilitating diseases. This study will examine the neural network and mechanisms that underlie behaviors associated with OCD. These behaviors not limited to OCD, but are associated with a range of affective and addictive disorders. The collective proposed studies will generate new hypotheses of how dysfunctions within these brain networks are expressed across diseases and provide insight into the mechanisms underlying normal behavioral responses.

The overall goals of this center are to delineate the neural networks that underlie core behavioral features of OCD in order to broaden our understanding of the disease and the effects of continuous high frequency stimulation (DBS) on those neural networks. A driving hypothesis is that OCD symptoms are, in part, due to impaired extinction of fear that interferes with the normal balance between avoidance and reward-seeking. The neural network that underlies avoidance behaviors, including regions of the prefrontal cortex, ventral striatum and amygdala, is the same general circuit that underlies reward-seeking behaviors. Dysfunction within this circuit, (the anterior cingulate/orbital-basal-ganglia connections), is strongly implicated in OCD. Our goal to improve our understanding of the neural network that underlies OCD-related behaviors will be accomplished through a series of integrated translational experiments that involve high frequency stimulation effects of the ventral internal capsule and ventral striatum on behavior, functional imaging, systems and cellular electrophysiology, and the circuits that are associated with this stimulation. Of particular importance is that dysfunction in the prefrontal-basal ganglia circuit is also implicated across affective, anxiety, impulse-control and addictive disorders. Collectively, this work will provide a blueprint for devising new therapies not only for OCD, but also for other psychiatric disorders. Its interdisciplinary nature will expand our basic knowledge of the neurocircuitry that underlies specific behaviors, (extinction, avoidance and reward seeking behaviors). Results from these studies will also make important new contributions to our understanding of the basic mechanisms of DBS.

The deep brain stimulation target for OCD is centered in the ventral internal capsule, and the ventral striatum. The hypothesis of this proposal is that the behavioral impact of stimulation will vary with electrode location, due to differentially activating subcomponents of the ascending and descending prefrontal circuits. Our laboratory is developing a 3-D atlas of fiber connections and terminals, based on data collected from conventional track tracing methods to delineate and compare of terminal fields and fiber bundle locations from specific cortical regions. This data will be used to develop a model for how cortical fibers travel through the internal capsule leading, to predictions about which structures are most likely be affected for each stimulation site. We will use it to test the validity of diffusion tensor imaging acquisition and analytic algorithms, and explore the ability to extend our findings to humans. There are 3 aims: Aim 1 will delineate the course of prefrontal cortical and subcortical fiber bundles that pass through different regions of the IC and VS. Aim 2 will determine which bundles are likely to be the most effective target sites for affecting avoidance-reward conflict behaviors, and the brain regions they connect;Aim 3 will identify the network activated during DBS within the VCA/S. P2 will inform and be informed by all the proposed projects in the Center. In collaboration with P1, 3, 4, &5, we will gain insight into which pathways (and structures) are involved in avoidance, reward, and extinction behaviors that may be associated with OCD. Results from aims 1 &2 will impact on the choice of stimulation sites used in PI-5. Aim 3 will inform, and be informed by, rodent models of activation that underlie the mechanisms (P4-6). Overall, combining tracing in monkeys, DTI in monkeys and humans, and computational methods will provide a blueprint for further studies of the anatomical principles that underlie the organization of pathways and terminal fields involved in avoidance and reward. RELEVANCE (See instructions): Obsessive Compulsive Disorder (OCD) is a chronic psychiatric illness that affects 2-3% of the worldwide population. This is disease is in the top ten dehabilitating diseases. This study will examine the neural network and mechanisms that underlie behaviors associated with OCD. These behaviors not limited to OCD, but are associated with a range of affective and addictive disorders. The collective proposed studies will generate new hypotheses of how dysfunctions within these brain networks are expressed across diseases and provide insight into the mechanisms underlying normal behavioral responses.

Project Summary The overall goal of this Center is to understand the neural network associated with obsessive-compulsive disorder (OCD). The data collected by Center investigators comes from a wide range of sources including studies of rodents, primates and humans. One of the major aims of the Center will be to broaden our understanding of the functional neurocircuitry of the anterior cingulate, orbital, and ventrolateral prefrontal cortices as they relate to abnormalities in OCD. The overall mission of the anatomy core is to provide the bridge between projects to identify structures that are likely to be affected by the disorder and modulated by neural stimulation across species. To achieve this goal, the anatomy core will work closely with each of the individual projects and Core C, to develop cross-species models of structures and pathways. The first aim of Core B is to provide support for the rat histology studies (P5) by assisting in tissue-processing in developing a rodent model of the cortical and striatal nodes that connect the amygdala and infralimbic cortex to the dorsal anterior cingulate and orbitofrontal cortex. The second aim of core B is to provide support for dMRI studies that require assistance in acquisition, processing, and data analysis (P1, 4). For this aim, Core B will be responsible for collecting diffusion dMRI data on non-human primate brains that will have been injected with tracers for P1. It will also be responsible for collecting dMRI data on cingulotomy patients for P1 & 3. Finally, it will provide support to P1-2, and 4 for analysis and data sharing.

DESCRIPTION (provided by applicant): In May 2010 there will be a meeting consisting of a series of workshops focusing on "The Reward circuit: emerging, re-emerging, and forgotten areas". Shell Island Oceanfront Suites in Wrightsville Beach, North Carolina. The Principal Investigator is Dr. Suzanne N. Haber, University of Rochester, and the co- organizers are: Drs. Christelle Baunez, Anthony Grace, Jacqueline McGinty, Celeste Napier, Patricio O'Donnell, Linda Porrino, Philip Winn and Scott Zahm. To stimulate active, informal discussion, the meeting consists of a series of workshops and will be relatively small. In preparation for the meeting, we have chosen four workshop topics. Four focus groups have been created to develop the questions and issues for discussion in the workshops. The focus groups are comprised of a cross section of 7-14 scientists to include clinical and basic scientists, and a mixture of junior and senior scientists. These groups will also prepare an introductory summary that begins each workshop on a specific topic. Following each workshop there will be summary session for all of the participants. The workshops will be an open forum, led by a facilitator, with a written summary by a scribe. Workshops will be devoted to active participation from all attendees, addressing new questions and directions that cut across the specific areas of expertise. This unique format, which has been very successful at our previous meetings, encourages free exchange of ideas. A specific emphasis is on recruiting young scientists to the field. Therefore each workshop will engage at least one young scientist in a leadership role (scribe or presenter). Furthermore, there will be a special workshop for junior scientists devoted to questions and issues related to career development. PUBLIC HEALTH RELEVANCE: The reward circuit is central to pathologies involving motivational disorders, including addiction. Certain key structures, such as the prefrontal cortex, striatum and midbrain dopamine cells within this circuitry are the most associated with psychiatric diseases. However, to improve our understanding of these pathologies, it is essential to also focus on other structures within this system, not as commonly studied. The topic of this meeting, "The Reward circuit: emerging, re-emerging, and forgotten areas", is particularly timely as it brings together new, and exciting information on a variety of brain regions that are connected to the cortico-striatal reward system. Understanding these critical links provides potential opportunities for new therapeutic interventions for different psychiatric disorders including addiction OCD, depression and schizophrenia.

DESCRIPTION (provided by applicant): In July 2011 we plan to hold our first Mideast conference on "Depression and Anxiety Spectrum disorders: from basic science to the clinic and back", in Amman, Jordan. The Principal Investigator for the Conte Center and this meeting grant application is Dr. Suzanne N. Haber, University of Rochester. The Executive Committee for this meeting consists of the following members of the Center: Dr. Ben Greenberg, Brown University-Butler Hospital;Dr. Darin Doughtery, Harvard University-Massachusetts General Hospital;Dr. Emad Eskandar Harvard University-Massachusetts General Hospital, Dr. Anthony Grace, University of Pittsburg, Dr. Mohamed Milad, Harvard University-Massachusetts General Hospital, and Dr. Greg Quirk, University of Puerto Rico. The local organizing committee includes, Drs. Munther Haddadin and Dr. Azmi Mahafzah, Dean of the Faculty of Medicine, University of Jordan. The topic, "depression and anxiety spectrum disorders", was chosen as a result of the expressed interests and needs of clinicians and scientists we spoke to in the Middle East. The members of the Executive Committee are a cross-section of basic and clinical scientists, representing different fields of expertise, in the clinical aspects of depression and anxiety spectrum disorders, and its physiology, anatomy, and pharmacology. The proposed meeting therefore brings together a unique group of clinical and basic scientists specifically interested in these diseases as a worldwide problem. The goal of this first meeting is to bring together experts on the pathophysiology and treatment of depression and anxiety spectrum disorders in a culturally diverse environment, where such disorders are prevalent, but exposure to cutting-edge research is limited. We will explore the new directions in which science is driving this field by presenting data on experimental and therapeutic approaches to understanding and treating these syndromes. Finally, we will lay out an agenda for future research and training possibilities in the region that draws upon the diversity and expertise of multiple investigators. PUBLIC HEALTH RELEVANCE: Depression and Anxiety Spectrum disorders are serious, dehabilitating mental health diseases that share common clinical features. These illnesses are under diagnosed and under treated in several Middle East countries. This topic of this meeting, "Depression and Anxiety Spectrum disorders: from basic science to the clinic and back" and venue (University of Jordan, Amman, Jordan), was chosen based on expressed interests and needs of clinicians and scientists in the Middle East. The goal of this US-led meeting is to bring experts into the region where such disorders are prevalent, but exposure to research is limited.

DESCRIPTION (provided by applicant): The ventral, medial prefrontal cortex and cingulate cortex, the major white matter pathways that connect them (and their links to the basal ganglia) are central parts of the reward/motivation circuit. Dysfunction in these areas is associated with several psychiatric diseases including depression. Fibers from these cortical areas are captured at two surgical targets for treatment resistant depression (anterior cingulotomy and deep brain stimulation of the subgenual cingulate). The goal of this application is to gain insight into the anatomical substrates that underlie human functional connectivity profiles and changes in disease derived from imaging studies. Cortex and basal ganglia are generally organized in parallel functional circuits, yet emerging data indicate that specific subregions also serve as connectional nodes that integrate information processing across functional systems. Our work has focused on how prefrontal cortical regions are anatomically linked through the basal ganglia, to integrate across reward/motivation and cognitive domains. We have recently expanded these studies to examine cortico-cortical connections, particularly, the white matter pathways that connect them. By combining anatomical tracing and diffusion magnetic resonance imaging we are exploring the ability of imaging to replicate fiber pathways. The aim here is to build on our previous findings combining non-human primate anatomical tracing, non-human primate diffusion magnetic resonance imaging, and human dMRI to identify cortical and basal ganglia areas that anatomically link areas of prefrontal cortex and cingulate cortex. Data will be used to determine the pathways/structures involved at the cingulotomy and subgenual DBS targets. Aim 1 uses conventional tracing experiments to determine how cingulate and prefrontal cortical terminals and pathways interface. Aim 2 will determine their pathways through the cingulum, uncinate fasciculus, and corpus callosum, and the ability for diffusion imaging tractography to replicate these connections. Aim 3 will use the results from Aim 2 to evaluate and segment the cingulum and uncinate fasciculus, and the corpus callosum in healthy human subjects and delineate which connections are likely to pass through the surgical targets, the dorsal anterior cingulate (cingulotomy) and subgenual anterior cingulate (deep brain stimulation).

? DESCRIPTION (provided by applicant): The overall goal of this Center is to further our understanding of the neural network central to obsessive compulsive disorder (OCD) and the abnormalities within that network that are associated with the disease. Specifically, we will use a multimodal, network approach to: 1. localize specific regions and the pathways that connect them that are altered in the disease; 2. determine the effects of neuromodulation on the connectivity of the circuit(s); and 3. use these data to develop a non-invasive approach for individualized treatment. To understand the network underlying OCD, we use a multidimensional approach combining anatomy (structural analysis at the neuronal level) with global patterns of activity and connectivity (diffusion and functional MRI) to characterize the critical connections that underlie functional abnormalities in the OCD circuit, and the network changes following neuromodulation. Our central hypothesis is that OCD is characterized by hyperconnectivity between the amygdala/ventromedial prefrontal cortex and dorsal anterior cingulate (dACC) and orbitofrontal cortex (OFC), and decreased connectivity between dACC/OFC and dorsolateral and ventrolateral prefrontal cortex. This change in balance between emotion and cognitive control systems results in a heightened activity state in the dorsal striatum. We also posit that the structural basis for abnormalities in activity center aroun specific cortical regions (or nodes) that connect emotion-associated regions with those involved in cognitive control. Furthermore, we predict variability in the position of these nodes across individuals. Finally, we hypothesize that modulation of the circuit will return connectivity profils to relatively normal levels. The studies will provide a translational link to probe novel therapeutc targets. As this network has been linked to a wide range of psychiatric disorders including, depression, post-traumatic stress disorder, addictions, the resulting data will have implications that extend well beyond OCD.

Project Summary The pathophysiology of Obsessive Compulsive Disorder (OCD) is associated with dysfunction in prefrontal cortical and basal-ganglia circuits, in particular the dorsal anterior cingulate cortex (dACC), orbital frontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC) and dorsal striatum. These areas are linked to regions involved in both emotion (amygdala (amyg) and ventromedial PFC (vmPFC)) and higher cognitive and motor control (dorsolateral PFC (dlPFC) and presupplementary motor cortex (pSMA)), placing them in a pivotal position for bottom-up and top-down control for adapting behaviors appropriately. The dACC, vlPFC, and OFC fibers are connected by the cingulum bundle (CB), corpus callosum (CC) and uncinate fasciculus (UF). These white matter (WM) bundles, along with the internal capsule (IC) also show abnormalities in OCD. The overall goal of P1 is to determine the connectivity between the dACC, vlPFC, OFC, and striatum, and the amyg/vmPFC, and the dlPFC/ pSMA. We will use these data to explore connectivity abnormalities in OCD and the effects of noninvasive stimulation and cingulotomy on the WM. Our first hypothesis is that within the dACC, OFC, vlPFC, and striatum, there are specific regions (referred to as critical nodes) that contain converging terminal fields from each other, and from the amyg and/or vmPFC, and from the dlPFC and/or pSMA. These critical nodes would provide an anatomical substrate for modulation between emotional and cognitive systems. Our second hypothesize is that the abnormalities in the WM found in OCD will be located within specific WM segments that connect the critical nodes. Aim 1 will determine where critical nodes are located within the dACC, vlPFC, and OFC and aim 2 will segment the CB, CC, UF, and IC based on where node connections travel. Aims 1 and 2 combine tracer experiments and diffusion MRI (dMRI) animals and dMRI in humans to locate the nodes and segment the WM. Aim 3 will use the segmentation of WM is to evaluate more specifically connectivity differences between OCD and healthy subjects and changes due to neuromodulation. The combination of anatomical and dMRI experiments will provide a translational link for understanding the structural underpinnings of connectivity changes associated with OCD.

Project Summary Administrative Core The Administration Core will oversee all aspects of the Center and coordinate its activities. This includes a plan for information transfer between projects as well as information dissemination to the scientific community and to the public. Core A will be responsible for assuring that milestones are met and in consultation with NIH, will appoint and interact with the External Advisory Board. The training and outreach programs will be administered through Core A. Finally, Core A will oversee standard administrative tasks such as the budget and resource allocations and maintain the Center web site. Dr. Haber will be responsible for the overall direction of the Center. Dr. Greenberg will specifically coordinate the clinical aspects of the Center and lead the outreach program. Dr. Quirk will lead the training program. A steering committee chaired by the Dr. Haber, will include the PIs and Co-PIs of all Projects and Cores. This committee will meet monthly and be responsible for meeting scientific timelines and milestones in a timely manner; interact with the External Advisory Board; Training and outreach; oversee resource allocation and reallocation; oversee the web site, and resource and data sharing components of the Center.

Project Summary / Abstract On October 11-13, 2016, the University of Rochester Institute of Neuromedicine and the Silvio O. Conte Center will hold a meeting entitled ?Persistent, maladaptive behaviors: why we make bad choices?. The Principal Investigators are Suzanne N. Haber, Conte Center Director, and John Foxe, University of Rochester Institute of Neuromedicine, Director. The organizing committee includes, Benjamin Greenberg MD, Butler Hospital, Randy Buckner Ph.D., Harvard University, Hesheng Liu Ph.D., Harvard University, Mary Phillips MD, University of Pittsburgh, Gregory Quirk Ph.D., University of Puerto Rico, and Steven Rasmussen MD, Brown University. The local organizing committee includes Gregory DeAngelis, Ph.D., Benjamin Hayden, and Ph.D., Brad Mahon, Ph.D. The meeting will consist of relatively short talks and ample time for discussion. The program is designed to involve basic and clinical scientists with a specific focus on the fundamental elements that drive basic behaviors and action plans (reward, fear, and value assignment); circuit dysfunctions that underlie abnormalities in diseases with persistent, habit-like behaviors, despite some awareness that these behaviors are maladaptive; the circuit components that are common amongst diseases; computational approaches to understanding these circuits; and therapeutic approaches that effect these circuits. Each session will begin with a series of relatively short focused talks, followed by a discussion and coffee break. This gives ample time for both formal and informal discussions and interactions. Posters by young scientists will be set up in the same room as the coffee breaks and meals and will remain up throughout the meeting. As the formal presentations are short, we will ask each presenter to submit a review paper on their topic that will be posted on our web site prior to the meeting. This will give participants an opportunity to review background material before the meeting.