Central Viscerosensory Circuits - Structure and Function

Summary

Principal Investigator: LINDA M RINAMAN
Abstract: Clinical research has increasingly emphasized the importance of ascending viscerosensory pathways from the caudal brainstem, including noradrenergic (NA) pathways, in stress responses and affective/emotional state. Dysregulated NA signaling is implicated in the pathophysiology of stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of ascending NA pathways that modulate neural activity within interconnected regions of the paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and anterolateral bed nucleus of the stria terminalis (alBST). These pathways arise from NA neurons in viscerosensory regions of the nucleus of the solitary tract (NST) and ventrolateral medulla (VLM), with little or no direct contribution from the pontine locus coeruleus. Revealing the functional organization of these systems in rats has clinical relevance, and may contribute to the development of new therapeutic options for treating stress-related emotional dysregulation. Our working hypothesis is that both physiological (interoceptive) and cognitive/emotional stressors alter viscerosensory signals that are relayed by medullary NA neurons to the hypothalamus and limbic forebrain, and that these signals are critical for shaping emotional state as evidenced by stress responsiveness, motivated behavior, and emotional learning. NA neurons within the NST and VLM have branching axons that target more than one hypothalamic and limbic forebrain target. Retrograde tract-tracing experiments in Aim 1 will simultaneously examine NA axonal collateralization and ascending pathway recruitment by a malaise- inducing agent, lithium chloride (LiCl). The anatomical data obtained in Aim 1 will facilitate interpretation of functional data obtained in Aim 2, in which NA inputs to the PVN, CeA, and/or alBST will be selectively destroyed before rats are assayed for behavioral and physiological responses to three distinct challenges: (1) LiCl, (2) exposure to a fear- and anxiety-inducing predator odor, trimethylthiazoline (TMT), or (3) systemic yohimbine (YO), a pharmacological agent that robustly increases NA signaling throughout the brain. Parallel experiments in Aim 3 will test the hypothesis that direct communication between the CeA and alBST is necessary for behavioral and physiological responses to LiCl, TMT, and YO in rats with otherwise intact central NA circuitry. The proposed research will reveal new aspects of the functional organization of viscerosensory NA inputs to the hypothalamus and limbic forebrain that play a critical role in mediating physiological and behavioral responses to emotionally significant events. Dysregulated noradrenergic signaling in the brain is implicated in stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of noradrenergic pathways that modulate neural activity within interconnected regions of the hypothalamus and limbic forebrain. Experimental outcomes could lead to the development of new therapeutic options for treating stress-related emotional pathologies.
Funding Period: 1999-04-01 - 2014-09-30
more information: NIH RePORT

Top Publications

  1. ncbi Noradrenergic inputs to the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus underlie hypothalamic-pituitary-adrenal axis but not hypophagic or conditioned avoidance responses to systemic yohimbine
    Layla Banihashemi
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    J Neurosci 26:11442-53. 2006
  2. pmc Common and distinct neural inputs to the medial central nucleus of the amygdala and anterior ventrolateral bed nucleus of stria terminalis in rats
    Michael S Bienkowski
    Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA
    Brain Struct Funct 218:187-208. 2013
  3. pmc Yohimbine anxiogenesis in the elevated plus maze is disrupted by bilaterally disconnecting the bed nucleus of the stria terminalis from the central nucleus of the amygdala
    L Cai
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, United States
    Neuroscience 223:200-8. 2012
  4. pmc Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis
    Huiyuan Zheng
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Eur J Neurosci 37:1340-9. 2013
  5. pmc Overnight food deprivation markedly attenuates hindbrain noradrenergic, glucagon-like peptide-1, and hypothalamic neural responses to exogenous cholecystokinin in male rats
    James W Maniscalco
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States
    Physiol Behav 121:35-42. 2013
  6. pmc Organization of multisynaptic circuits within and between the medial and the central extended amygdala
    Michael S Bienkowski
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260
    J Comp Neurol 521:3406-31. 2013
  7. pmc Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews
    Charles C Horn
    Biobehavioral Medicine in Oncology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
    Am J Physiol Regul Integr Comp Physiol 306:R341-51. 2014
  8. ncbi Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals
    Alison D Kreisler
    University of Pittsburgh, Department of Neuroscience, Pittsburgh, PA, United States
    Physiol Behav 136:47-54. 2014
  9. pmc Early life experience shapes the functional organization of stress-responsive visceral circuits
    Linda Rinaman
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
    Physiol Behav 104:632-40. 2011
  10. pmc Immune challenge activates neural inputs to the ventrolateral bed nucleus of the stria terminalis
    Michael S Bienkowski
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Physiol Behav 104:257-65. 2011

Research Grants

  1. AMYGDALA GLUCOCORTICOID RECEPTOR FUNCTION IN STRESS
    LOUIS JOSEPH MUGLIA; Fiscal Year: 2013
  2. Dopamine and stress: connections of the BNST and central nucleus
    Julie L Fudge; Fiscal Year: 2013
  3. A role for orexins in fear learning
    ROBERT MILTON SEARS; Fiscal Year: 2013
  4. ORGANIZATION OF PREFRONTAL FEEDBACK CIRCUITS
    Helen Barbas; Fiscal Year: 2013
  5. Neural Substrates of Phasic versus Sustained Fear
    David L Walker; Fiscal Year: 2013
  6. Cardiovascular disease, depression, and oxytocin
    MELISSA SCOTTI; Fiscal Year: 2013
  7. Early Life Experience Shapes Visceral Circuits
    LINDA M RINAMAN; Fiscal Year: 2013
  8. Stress and CRF System Effects on Information Processing
    Victoria B Risbrough; Fiscal Year: 2013
  9. CRF-Oxytocin Interaction in the Regulation of Stress and Affect
    Joanna Dabrowska; Fiscal Year: 2013
  10. NEURAL PATHWAYS UNDERLYING EMOTIONAL CONDITIONING
    Joseph E LeDoux; Fiscal Year: 2013

Detail Information

Publications21

  1. ncbi Noradrenergic inputs to the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus underlie hypothalamic-pituitary-adrenal axis but not hypophagic or conditioned avoidance responses to systemic yohimbine
    Layla Banihashemi
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    J Neurosci 26:11442-53. 2006
    ..Conversely, NA-mediated activation of BNST and PVNmp neurons is unnecessary for YO to inhibit food intake or support CFA, evidence for the sufficiency of other intact neural pathways in mediating those effects...
  2. pmc Common and distinct neural inputs to the medial central nucleus of the amygdala and anterior ventrolateral bed nucleus of stria terminalis in rats
    Michael S Bienkowski
    Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA
    Brain Struct Funct 218:187-208. 2013
    ..The demonstrated similarities and differences in inputs to CEAm and BSTvl provide new anatomical insights into the functional organization of these limbic forebrain regions...
  3. pmc Yohimbine anxiogenesis in the elevated plus maze is disrupted by bilaterally disconnecting the bed nucleus of the stria terminalis from the central nucleus of the amygdala
    L Cai
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, United States
    Neuroscience 223:200-8. 2012
    ..p. saline. We conclude that the anxiogenic effects of increased NA signaling in rats after YO require direct CEA-algBST interactions that do not shape EPMZ behavior under baseline conditions...
  4. pmc Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis
    Huiyuan Zheng
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Eur J Neurosci 37:1340-9. 2013
    ..Thus, the ability of YO to increase anxiety-like behavior in the EPMZ depends on hindbrain NA neurons that target the anterior vlBST...
  5. pmc Overnight food deprivation markedly attenuates hindbrain noradrenergic, glucagon-like peptide-1, and hypothalamic neural responses to exogenous cholecystokinin in male rats
    James W Maniscalco
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States
    Physiol Behav 121:35-42. 2013
    ....
  6. pmc Organization of multisynaptic circuits within and between the medial and the central extended amygdala
    Michael S Bienkowski
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260
    J Comp Neurol 521:3406-31. 2013
    ....
  7. pmc Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews
    Charles C Horn
    Biobehavioral Medicine in Oncology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
    Am J Physiol Regul Integr Comp Physiol 306:R341-51. 2014
    ..Furthermore, the current neural tracing data suggest brain stem anatomical circuits that are activated by GI signaling in the musk shrew. ..
  8. ncbi Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals
    Alison D Kreisler
    University of Pittsburgh, Department of Neuroscience, Pittsburgh, PA, United States
    Physiol Behav 136:47-54. 2014
    ..Conversely, GLP-1 neurons may only be recruited in response to the homeostatic challenge of consuming a very large, unanticipated meal. ..
  9. pmc Early life experience shapes the functional organization of stress-responsive visceral circuits
    Linda Rinaman
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
    Physiol Behav 104:632-40. 2011
    ..Early life experience may contribute to meaningful individual differences in emotionality and stress responsiveness by shaping the postnatal developmental trajectory of central visceral circuits...
  10. pmc Immune challenge activates neural inputs to the ventrolateral bed nucleus of the stria terminalis
    Michael S Bienkowski
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Physiol Behav 104:257-65. 2011
    ..These results suggest that LPS treatment recruits central neural systems that actively suppress vlBNST neural activity, thereby removing a potent source of inhibitory control over the HPA axis...
  11. pmc Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions
    Linda Rinaman
    Dept of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA
    Am J Physiol Regul Integr Comp Physiol 300:R222-35. 2011
    ....
  12. pmc Visceral sensory inputs to the endocrine hypothalamus
    Linda Rinaman
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Front Neuroendocrinol 28:50-60. 2007
    ..The postnatal development of these ascending pathways also is considered...
  13. pmc Noradrenergic inputs to the paraventricular hypothalamus contribute to hypothalamic-pituitary-adrenal axis and central Fos activation in rats after acute systemic endotoxin exposure
    M S Bienkowski
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Neuroscience 156:1093-102. 2008
    ..These findings support the view that NA projections from hindbrain to hypothalamus are necessary for a full HPA axis response to systemic immune challenge...
  14. pmc Central Fos expression and conditioned flavor avoidance in rats following intragastric administration of bitter taste receptor ligands
    Shuzhen Hao
    Vet Med APC, 1330 Haring Hall, UC Davis, Davis, CA 95616, USA
    Am J Physiol Regul Integr Comp Physiol 296:R528-36. 2009
    ....
  15. pmc Ondansetron blocks LiCl-induced conditioned place avoidance but not conditioned taste/flavor avoidance in rats
    Linda Rinaman
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Physiol Behav 98:381-5. 2009
    ..These results support the view that CPA is an additional useful tool to reveal the experience of malaise and nausea in rats, whereas CT/FA demonstrated in bottle intake tests is insufficient for this purpose...
  16. pmc Repeated brief postnatal maternal separation enhances hypothalamic gastric autonomic circuits in juvenile rats
    L Banihashemi
    Department of Neuroscience, University of Pittsburgh, PA 15260, USA
    Neuroscience 165:265-77. 2010
    ....
  17. pmc A potential gastrointestinal link between enhanced postnatal maternal care and reduced anxiety-like behavior in adolescent rats
    Brittany C Weber
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
    Behav Neurosci 123:1178-84. 2009
    ....
  18. pmc Early experience alters limbic forebrain Fos responses to a stressful interoceptive stimulus in young adult rats
    Thomas J Koehnle
    Department of Biology, Hiram College, Hiram, OH, United States
    Physiol Behav 100:105-15. 2010
    ..The ability of MS-15 to alter limbic forebrain activation in rats after an interoceptive challenge may contribute to the effect of early life experience to modulate physiological and behavioral stress responses more generally...
  19. pmc Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure
    Linda Rinaman
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA
    Brain Res 1350:18-34. 2010
    ..e., hypophagic) responses to stress...
  20. pmc Systemic leptin dose-dependently increases STAT3 phosphorylation within hypothalamic and hindbrain nuclei
    James W Maniscalco
    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
    Am J Physiol Regul Integr Comp Physiol 306:R576-85. 2014
    ..Conversely, within the NTS, pSTAT3 only rarely colocalized with PrRP and/or DβH, and never with GLP-1...

Research Grants30

  1. AMYGDALA GLUCOCORTICOID RECEPTOR FUNCTION IN STRESS
    LOUIS JOSEPH MUGLIA; Fiscal Year: 2013
    ..The results of our planned studies on the role of glucocorticoid receptor function in the amygdala hold promise for new insights into brain pathways regulating the responses to stress and the genesis and treatment of mental illness. ..
  2. Dopamine and stress: connections of the BNST and central nucleus
    Julie L Fudge; Fiscal Year: 2013
    ..We will examine how brain regions involved in cognition influence stress circuits, as well as specific ways that stress-related information can influence motivated behavior through the dopamine system. ..
  3. A role for orexins in fear learning
    ROBERT MILTON SEARS; Fiscal Year: 2013
    ..Dysregulation of the orexin system may explain susceptibility to fear and anxiety disorders and provide both a diagnostic measure and treatment target for these disorders. ..
  4. ORGANIZATION OF PREFRONTAL FEEDBACK CIRCUITS
    Helen Barbas; Fiscal Year: 2013
    ....
  5. Neural Substrates of Phasic versus Sustained Fear
    David L Walker; Fiscal Year: 2013
    ..Recent studies indicate that the neural substrates of short-duration fear responses may be different from those of more sustained fear responses. The experiments proposed herein are meant to further explore these differences. ..
  6. Cardiovascular disease, depression, and oxytocin
    MELISSA SCOTTI; Fiscal Year: 2013
    ..abstract_text> ..
  7. Early Life Experience Shapes Visceral Circuits
    LINDA M RINAMAN; Fiscal Year: 2013
    ..abstract_text> ..
  8. Stress and CRF System Effects on Information Processing
    Victoria B Risbrough; Fiscal Year: 2013
    ..These studies will increase our understanding of risk factors and potential prophylactic treatments for PTSD. ..
  9. CRF-Oxytocin Interaction in the Regulation of Stress and Affect
    Joanna Dabrowska; Fiscal Year: 2013
    ..My career objective is to conduct independent research to understand how stress and affect interact and elucidate their respective roles in the etiology of mental disorders like depression and anxiety. ..
  10. NEURAL PATHWAYS UNDERLYING EMOTIONAL CONDITIONING
    Joseph E LeDoux; Fiscal Year: 2013
    ..abstract_text> ..
  11. Brainstem Mechanisms of Stress Regulation
    James P Herman; Fiscal Year: 2013
    ..Our studies are expected to provide preclinical data regarding new molecular targets for promoting stress resistance and adaptation. ..
  12. Sensory Perception of Threat in Anxiety
    Wen Li; Fiscal Year: 2013
    ..The project findings will create a body of knowledge that is likely to challenge the dominant limbic-centered conceptualization of anxiety, promoting a shift to a multi-system, multi-path theorization. ..
  13. Adolescent Alcohol,Dysregulated Stress System, and PTSD Vulnerability
    GERHARD H SCHULTEIS; Fiscal Year: 2013
    ....