bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxygen Free Radical Signaling in Ischemic Preconditioninga
Authors: DAS DIPAK K. , ENGELMAN RICHARD M. , MAULIK NILANJANA
Published: February 2006

Abstract: This review will focus on the free radical signaling mechanism of preconditioning. The results from our laboratory as well as studies from other laboratories suggest that reactive oxygen species function as second messenger during myocardial adaptation to ischemia. This review provides evidence for the first time that tyrosine kinase and MAP kinases are the targets for reactive oxygen species generated in the preconditioned myocardium. The finding that p38 MAP kinase might be upstream of NFκB further supports our previous reports that MAPKAP kinase 2 could be the most likely link between the preconditioning and adaptation mediated by gene expression. p38 activation appears to be an important step in the translocation and activation of the nuclear transcription factor NFκB, which in turn may be involved in the induction of the expression of a variety of stress‐inducible genes.
Small Heat Shock Proteins and Protection against Injury
Authors: DILLMANN WOLFGANG H.
Published: February 2006

Abstract: The small heat shock proteins αB crystallin and HSP27 exert a protective effect in response to simulated ischemia. A model is proposed whereby proteins not in their final folding state bind to the outside of the large oligomeric small heat shock protein complexes thus finding a safe haven during ischemia. After the ischemia is resolved, these proteins may be released and, with the help of HSP70, are shuttled to a productive refolding pathway resulting in proteins in their final folding state, which can assume their normal activity in cells recovered from ischemic injury.
Inhibition of Myocardial TNF‐α Production by Heat Shock: A Potential Mechanism of Stress‐Induced Cardioprotection against Postischemic Dysfunctiona
Authors: MENG XIANZHONG , BANERJEE ANIRBAN , AO LIHUA , MELDRUM DANIEL R. , CAIN BRIAN S. , SHAMES BRIAN D. , HARKEN ALDEN H.
Published: February 2006

Abstract: Overproduction of tumor necrosis factor‐α (TNF‐α) contributes to cardiac dysfunction associated with systemic or myocardial stress, such as endotoxemia and myocardial ischemia/reperfusion (I/R). Heat shock has been demonstrated to enhance cardiac functional resistance to I/R. However, the protective mechanisms remain unclear. The purpose of this study was to determine: (1) whether cardiac macrophages express heat shock protein 72 (HSP72) after heat shock, (2) whether induced cardiac HSP72 suppresses myocardial TNF‐a production during I/R, and (3) whether preservation of postischemic myocardial function by heat shock is correlated with attenuated TNF‐a production during I/R. Rats were subjected to heat shock (42°C for 15 min) and 24 h recovery. Immunoblotting confirmed the expression of cardiac HSP72. Immunofluorescent staining detected HSP72 in cardiac interstitial cells including resident macrophages rather than myocytes. Global I/R caused a significant increase in myocardial TNF‐α. The increase in myocardial TNF‐α was blunted by prior heat shock and the reduced myocardial TNF‐α level was correlated with improved cardiac functional recovery. This study demonstrates for the first time that heat shock induces HSP72 in cardiac resident macrophages and inhibits myocardial TNF‐a production during I/R. These observations suggest that inhibition of myocardial TNF‐a production may be a mechanism by which HSP72 protects the heart against postischemic dysfunction.
Cardiac Adaptation to Ischemia‐Reperfusion Injurya
Authors: KINGMA JOHN G.
Published: February 2006

Abstract: Acute myocardial ischemia initiates a cascade of cellular events that lead to irreversible injury. We previously described the transient nature of heat‐shock induced cardioprotection; treatment with a catalase inhibitor abolished the cytoprotective actions without affecting expression levels of HSP71. Repeated, transient ischemic episodes augment the ischemic tolerance of affected myocardium but the fundamental cytoprotective mechanism(s) for both “early” and “delayed” preconditioning remains unclear. Increased cellular induction of protooncogenes, heat shock genes, and downstream effector proteins might play critical roles in the cytoprotection afforded by delayed preconditioning. We measured c‐fos, c‐jun, c‐myc, and hsp70 induction in preconditioned (2 × 5‐min ischemia/10‐min reperfusion) and control rabbit hearts that either underwent 30‐ or 120‐min coronary occlusion and 60‐min reperfusion, or did not undergo subsequent sustained ischemia; the latter hearts were allowed to recover for 0, 1, 3, 6, 24, 48, 72, or 96 hours. Both c‐fos and c‐jun in ischemic tissue were strongly induced by ischemia‐reperfusion injury and preconditioning pretreatment. However, expression levels diminished significantly by 1‐h reperfusion and remained depressed during the 96‐h recovery period. Hsp70 (inducible) mRNA expression levels were highest primarily in ischemic myocardium after 6‐h recovery post‐preconditioning; Hsp70 levels in ischemic myocardium were slightly stronger after 48‐h recovery but subsequently diminished to barely detectable levels by 96‐h post‐preconditioning. Induction of c‐fos and c‐jun preceded that of Hsp70. These findings support the concept that upregulation of immediate early genes and heat shock genes plays an important role in myocardial adaptation to acute ischemic stress.
Subcellular Remodeling and Heart Dysfunction in Cardiac Hypertrophy due to Pressure Overloada
Authors: DHALLA NARANJAN S. , GOLFMAN LEONARD , LIU XUELIANG , SASAKI HIDEKI , ELIMBAN VIJAYAN , RUPP HEINZ
Published: February 2006

Rats were treated with etomoxir, an inhibitor of palmitoyltransferase‐1, to examine the role of a shift in myocardial metabolism in cardiac hypertrophy. Pressure overload was induced by abdominal aorta banding for 8 weeks. Sham‐operated animals served as control. Left ventricular dysfunction, as reflected by decreased LVDP, +dP/dt, −dP/dt, and elevated LVEDP in the pressure overloaded animals, was improved by treatment with etomoxir. Cardiac hypertrophy in pressure‐overload rats decreased the sarcoplasmic reticular (SR) Ca2+ uptake and Ca2+ release as well as myofibrillar Ca2+‐stimulated ATPase and myosin Ca2+‐ATPase activities; these changes were attenuated by treatment with etomoxir. Steady‐state mRNA levels for α‐ and β‐myosin heavy chains, SR Ca2+‐pump, and protein content of SR Ca2+‐pump were reduced in hypertrophied hearts; these alterations were prevented by etomoxir treatment. The results indicate that modification of changes in myocardial metabolism by etomoxir may prevent remodeling of myofibrils and SR membrane and thereby improve cardiac function in hypertrophied heart.
In Vitro Analysis of SERCA2 Gene Regulation in Hypertrophic Cardiomyocytes and Increasing Transfection Efficiency by Gene‐Gun Biolisticsa
Authors: EIZEMA KARIN , VAN HEUGTEN HAN A.A. , BEZSTAROSTI KAREL , VAN SETTEN MARGA C. , LAMERS JOS M.J.
Published: February 2006

Abstract: The transcriptional downregulation of the SERCA2 gene is studied using neonatal rat cardiomyocytes stimulated with endothelin‐1 to induce hypertrophy. Liposome‐based transfection of cells with a 1.9 kb SERCA2 promoter fragment directed expression of a reporter gene identical to the down‐regulation of genomic SERCA2 expression by endothelin‐1. Results of a new gene gun technology for transient transfection of cardiomyocytes with a RSV‐β‐galactosidase construct are reported. This new method for propelling DNA‐coated gold beads into cardiomyocytes is extremely suitable for directly testing promoter/reporter gene DNA constructs since the transfection efficiency (approximately 10%) appears to be higher than traditional transfection methods.
Cellular Mechanisms of Infarct Size Reduction with Ischemic Preconditioning: Role of Calcium?
Authors: PRZYKLENK KARIN , SIMKHOVICH BORIS Z. , BAUER BARBARA , HATA KATSUYA , ZHAO LIN , ELLIOTT GARY T. , KLONER ROBERT A.
Published: February 2006

Abstract: Brief episodes of ischemia protect or “precondition” the heart and reduce infarct size caused by a subsequent sustained ischemic insult. Despite a decade of intensive investigation, the cellular mechanism(s) responsible for this paradoxical protection remain poorly understood. In this review, we focus on the emerging concept that alterations in intracellular calcium homeostasis may participate in either triggering and/or mediating infarct size reduction with preconditioning.
Pharmacologic Enhancement of Tolerance to Ischemic Cardiac Stress Using Monophosphoryl Lipid A: A Comparison with Antecedent Ischemia
Authors: ZHAO LIN , ELLIOTT GARY T.
Published: February 2006

Abstract:In comparison with ischemic preconditioning, MLA‐mediated cardioprotection seems to show numerous common features. Like ischemia, MLA induces a first and second window (biphasic profile) of heightened tolerance to ischemia. As with delayed ischemic preconditioning, MLA protects against infarction, stunning, and arrhythmias associated with ischemia‐reperfusion. In contrast with acute ischemic preconditioning, MLA reduces infarction and stunning. A role has been demonstrated for nitric oxide synthase and KATP channel activation in the mechanism of delayed preconditioning induced by ischemia and by MLA. Regarding acute preconditioning, kinase and KATPchannel activation have been implicated as involved in the mechanism of ischemic preconditioning and also in MLA cardioprotection. Use of MLA or related compounds as cardioprotectants may represent a method for inducing acute tolerance to ischemia‐reperfusion injury manifested as infarction or stunning, with the added benefit of a sustained delayed cardioprotective state being achieved.
Adaptation to Chronic Hypoxia Confers Tolerance to Subsequent Myocardial Ischemia by Increased Nitric Oxide Production
Authors: BAKER JOHN E. , HOLMAN PATRICIA , KALYANARAMAN B. , GRIFFITH OWEN W. , PRITCHARD KIRKWOOD A.
Published: February 2006

Abstract: Chronic exposure to hypoxia from birth increased the tolerance of the rabbit heart to subsequent ischemia compared with age‐matched normoxic controls. The nitric oxide donor GSNO increased recovery of post‐ischemic function in normoxic hearts to values not different from hypoxic controls, but had no effect on hypoxic hearts. The nitric oxide synthase inhibitors L‐NAME and L‐NMA abolished the cardioprotective effect of hypoxia. Message and catalytic activity for constitutive nitric oxide synthase as well as nitrite, nitrate, and cGMP levels were elevated in hypoxic hearts. Inducible nitric oxide synthase was not detected in normoxic or chronically hypoxic hearts. Increased tolerance to ischemia in rabbit hearts adapted to chronic hypoxia is associated with increased expression of constitutive nitric oxide synthase.
Quantitative Analysis of Collagens and Fibronectin Expression in Human Right Ventricular Hypertrophya
Authors: PETERS T.H. F. , SHARMA H. S. , YILMAZ E. , BOGERS A.J.J. C.
Published: February 2006

Abstract: One of the main features in human tetralogy of Fallot (TF) is right ventricular hypertrophy (RVH) due to pressure (sub‐pulmonary stenosis) and volume overload (ventricular septal defect). Currently, primary correction at a young age is the treatment of choice. To unravel the role of extracellular matrix in RVH, we examined myocardial expression of collagens and fibronectin in TF patients with primary correction (TF1, age 0.7 ± 0.2 yr.), secondary surgery (TF2, age 36.9 ± 4.6 yr), and in age‐matched control patients. Sirius red staining quantified by video imaging showed significantly increased interstitial staining for collagens in both TF1 and TF2 groups as compared to respective controls. Fibronectin was expressed in extracellular spaces, perivascular regions, and in some cardiomyocytes. Quantitative analysis of fibronectin revealed increased expression in only TF1 group as compared to respective control. Our results indicate an increased amount of myocardial extracellular matrix deposition as a sign of fibrosis during RVH in patients with TF.
Interaction of Bradykinin with Angiotensin, Prostacyclin, and Nitric Oxide in Myocardial Preservationa
Authors: SATO MOTOAKI , DAS DIPAK K. , ENGELMAN RICHARD M.
Published: February 2006

Abstract: This review focuses on the importance of bradykinin in myocardial preservation during ischemic arrest. Bradykinin is released from the heart spontaneously in response to ischemic stress, which may be viewed as a survival signal of the heart against ischemia. Bradykinin appears to function as a signaling molecule by controlling the release of other intracellular modulators, such as prostacyclins and nitric oxide, which also exert beneficial effects on the ischemic myocardium.
Optimal Myocardial Preconditioning in Humansa
Authors: COHEN GIDEON , SHIRAI TOSHIZUMI , WEISEL RICHARD D. , RAO VIVEK , MERANTE FRANK , TUMIATI LAURA C. , MOHABEER MOLLY K. , BORGER MICHAEL A. , LI REN‐KE , MICKLE DONALD A.G.
Published: February 2006

Abstract: We developed a model of ischemia and reperfusion (I and R) in human ventricular myocytes (CM). CM injury and metabolics were studied after various interventions: endogenous preconditioning (PC) with anoxia, hypoxia, and anoxic or hypoxic supernatants; endogenous PC with or without SPT or adenosine deaminase; and exogenous adenosine PC before, during, or after I or continuously, with or without SPT. To assess the clinical implications of PC and the possible mediating effects of adenosine, patients undergoing elective coronary bypass surgery (CABG) received either a high or low dose of adenosine. Patients not receiving adenosine served as controls. Adenosine levels, high‐energy phosphate levels, and metabolic parameters were evaluated from blood samples and left ventricular biopsy samples. Our cellular model studies indicated that preconditioning conferred protection to human CM via an adenosine‐mediated pathway. Adenosine simulated PC without a fall in ATP. Adenosine administered to patients during CABG stimulated myocardial metabolism while preventing the degradation of high energy phosphates. A prospective randomized trial of adenosine administered to high‐risk patients for myocardial protection is required.
Surgical Stress and the Heat Shock Response: In Vivo Models of Stress Conditioning
Authors: PERDRIZET G. A. , SHAPIRO D. S. , REWINSKI M. J.
Published: February 2006

Abstract: All forms of surgical therapy are stressful and injurious. The majority of surgical procedures are performed electively and provide an opportunity to condition the patient before surgery to maximize outcome. We have successfully protected the spinal cord and kidneys from warm ischemia‐reperfusion injury with whole‐body heat shock (42.5°C, 15 min, HS) and recovery (37°C, 6–8 h) before acute aortic occlusion. Control rabbits experienced an 88% incidence of paralysis (7/8) after acute spinal cord ischemia, while HS‐pretreated animals never became paralyzed (
0/9, p < 0.001

). Control pig kidneys showed partial function (4/8 survival) after 90‐min warm ischemia, while HS‐pretreated kidneys always functioned (
8/8 survival, p < 0.04
). A positive temporal association was made between the HS‐associated functional protection and the enhanced expression of inducible HSP70. The induction of the heat‐shock response (cellular stress response) to protect tissues from lethal acute ischemia‐reperfusion injury could be employed in a wide range of medical and surgical settings.
The Role of the Myocardial Sodium‐Hydrogen Exchanger in Mediating Ischemic and Reperfusion Injury: From Amiloride to Cariporidea
Authors: KARMAZYN MORRIS
Published: February 2006

Abstract: There is convincing evidence that the Na‐H exchanger (NHE) plays a pivotal role in mediating tissue injury during ischemia and reperfusion. Extensive studies with NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and animal species, particularly in terms of attenuating contractile dysfunction. These protective effects of NHE inhibition appear to be superior to other strategies, including ischemic preconditioning. Such studies have contributed greatly to the overwhelming evidence that NHE activation mediates ischemic and reperfusion injury. The NHE inhibitor HOE 642 (cariporide) is currently undergoing clinical evaluation in high‐risk cardiac patients. Moreover, there is now emerging evidence that NHE may be involved in mediating cardiotoxicity directly produced by various ischemic metabolites such as lipid amphiphiles or reactive oxygen species. NHE inhibition also attenuates apoptosis in the ischemic myocardium, a process that may be of importance in the subsequent development of postinfarction heart failure. In conclusion, NHE represents an important adaptive process in response to intracellular acidosis that results in a paradoxical contribution to cardiac tissue injury.
Regulation of Cardiac Sarcolemmal Na+/H+ Exchanger Activity by Endogenous Ligands: Relevance to Ischemiaa
Authors: AVKIRAN METIN , HAWORTH ROBERT S.
Published: February 2006

Abstract: The cardiac sarcolemmal Na+/H+ exchanger (NHE) extrudes one H+ in exchange for one Na+ entering the myocyte, utilizing for its driving force the inwardly directed Na+ gradient that is maintained by the Na+/K+ ATPase. The exchanger is quiescent at physiological values of intracellular pH but becomes activated in response to intracellular acidosis. Recent evidence suggests that a variety of extracellular signals (e.g., adrenergic agonists, thrombin, and endothelin) also modulate sarcolemmal NHE activity by altering its sensitivity to intracellular H+. Since sarcolemmal NHE activity is believed to be an important determinant of the extent of myocardial injury during ischemia and reperfusion, regulation of exchanger activity by endogenous ligands associated with ischemia is likely to be of pathophysiological importance.
Na+/H+ Exchangers: Molecular Diversity and Relevance to Heart
Authors: ORLOWSKI JOHN
Published: February 2006

Abstract: During the last several years, significant advances have been made in our understanding of the molecular, cellular, and physiological diversity of mammalian Na+/H+ exchangers. This transporter forms a multigene family of at least six members (NHE1‐NHE6) that share ∼20–60% amino acid identity. NHE1 is the most predominant isoform expressed in heart and it contributes significantly to myocardial pHi homeostasis, which is important for maintaining contractility. However, hyperactivation of NHE1 during episodes of cardiac ischemia and reperfusion disrupts the intracellular ion balance, leading to cardiac dysfunction and damage in several animal models, but which can be prevented by pharmacological antagonists of NHE1. Molecular studies have indicated that the predicted transmembrane segments M4 and M9 contain several residues involved in drub sensitivity. Molecular dissection of the drug binding region should facilitate the rational design of more potent and isoform‐specific drugs that may provide therapeutic benefit in the prevention of cardiac ischemia and reperfusion injuries.
Convergence and Segregation of Ventral Striatal Inputs and Outputs
Authors: GROENEWEGEN HENK J. , WRIGHT CHRISTOPHER I. , BEIJER ARNO V.J. , VOORN PIETER
Published: February 2006

ABSTRACT: The ventral striatum, which prominently includes the nucleus accumbens (Acb), is a heterogeneous area. Within the Acb of rats, a peripherally located shell and a centrally situated core can be recognized that have different connectional, neurochemical, and functional identities. Although the Acb core resembles in many respects the dorsally adjacent caudate‐putamen complex in its striatal character, the Acb shell has, in addition to striatal features, a more diverse array of neurochemical characteristics, and afferent and efferent connections. Inputs and outputs of the Acb, in particular of the shell, are inhomogeneously distributed, resulting in a mosaical arrangement of concentrations of afferent fibers and terminals and clusters of output neurons. To determine the precise relationships between the distributional patterns of various afferents (e.g., from the prefrontal cortex, the basal amygdaloid complex, the hippocampal formation, and the midline/intralaminar thalamic nuclei) and efferents to the ventral pallidum and mesencephalon, neuroanatomical anterograde and retrograde tracing experiments were carried out. The results of the double anterograde, double retrograde, and anterograde/retrograde tracing experiments indicate that various parts of the shell (dorsomedial, ventromedial, ventral, and lateral) and the core (medial and lateral) have different input‐output characteristics. Furthermore, within these Acb regions, various populations of neurons can be identified, arranged in a cluster‐like fashion, onto which specific sets of afferents converge and that project to particular output stations, distinct from the input‐output relationships of neighboring, cluster‐like neuronal populations. These results support the idea that the nucleus accumbens may consist of a collection of neuronal ensembles with different input‐output relationships and, presumably, different functional characteristics.
Involvement of the Pallidal‐thalamocortical Circuit in Adaptive Behavior
Authors: KALIVAS PETER W. , CHURCHILL LYNN , ROMANIDES ANASTASIA
Published: February 2006

ABSTRACT: Interconnections among the ventral mesencephalon, nucleus accumbens, and ventral pallidum are critical in the initiation of adaptive behavioral responses to environmental stimuli. Within this circuit are two highly topographically organized subcircuits that are differentially interconnected with limbic and motor circuitry in the brain. However, there is not a great deal of anatomical interconnection between the limbic and motor subcircuits. A polysynaptic connection between the two subcircuits involves projections from the limbic ventral pallidum to the mediodorsal thalamus to the prefrontal cortex back to the motor regions of the nucleus accumbens. In the present report we show that this connection is critical in the expression of motor behavior elicited by opioids and the capacity of a rat to perform in a task requiring spatial working memory.
Functional Specificity of Ventral Striatal Compartments in Appetitive Behaviors
Authors: KELLEY ANN E.
Published: February 2006

ABSTRACT:The nucleus accumbens and its associated circuitry subserve behaviors linked to natural or biological rewards, such as feeding, drinking, sex, exploration, and appetitive learning. We have investigated the functional role of neurotransmitter and intracellular transduction mechanisms in behaviors subserved by the core and shell subsystems within the accumbens. Local infusion of the selective NMDA antagonist, AP‐5, into the accumbens core, but not the shell, completely blocked acquisition of a bar‐press response for food in hungry rats. This effect was apparent only when infused during the early stages of learning. We have also recently shown that infusion of certain protein kinase inhibitors into the core also impairs learning in the same paradigm. These results suggest that plasticity‐related mechanisms within the accumbens core, involving glutamate‐linked intracellular second messengers, are important for response‐reinforcement learning. In contrast to the core, which primarily connects to somatic motor output systems, the shell is more intimately linked to viscero‐endocrine effector systems. We have shown that both AMPA and GABA receptors within the medial shell (but not the core) are critically involved in controlling the brain's feeding pathways, via activation of the lateral hypothalamus (LH). This effect is blocked by local inhibition of the LH in double‐cannulae experiments and also strongly and selectively activates Fos expression in the LH. These results provide a newly emerging picture of the differentiated functions of this forebrain region and suggest an integrated role in the elaboration of adaptive motor actions.
Functional‐anatomical Implications of the Nucleus Accumbens Core and Shell Subterritories
Authors: ZAHM DANIEL S.
Published: February 2006

The nucleus accumbens, a major part of the ventral striatum, comprises numerous subterritories and compartments, of which the core and shell appear to be dominant. Shell exhibits greater chemical neuroanatomical diversity than core and is rather directly connected to it by a robust, feed‐forward, striatopallido‐thalamocortico‐striatal pathway. Shell and extended amygdala share afferents, but the two are distinguished by their outputs, strongly toward cortex for shell and descendent toward brain stem effector sites for extended amygdala. Shell responds independently to stimulation by excitatory amino acids and dopamine, which are more mutually permissive in the core. Accordingly, the shell responds to a broad variety of physiological and pharmacological stimuli, including psychomotor and opioid drugs. Whereas locomotion and oro‐facial movements are elicitable from the shell, lesions and blockade of EAA transmission in the core reduce locomotion. It is hypothesized that core‐shell has a feed‐forward functional organization.
Modulation of Cell Firing in the Nucleus Accumbens
Authors: O'DONNELL PATRICIO , GREENE JENNIFER , PABELLO NINA , LEWIS BARBARA L. , GRACE ANTHONY A.
Published: February 2006

ABSTRACT:Pennartzet al.48have proposed that functions of the nucleus accumbens (NA) are subserved by the activity of ensembles of neurons rather than by an overall neuronal activation. Indeed, the NA is a site of convergence for a large number of inputs from limbic structures that may modulate the flow of prefrontal cortical information and contribute to defining such ensembles, as exemplified in the ability of hippocampal input to gate cortical throughput in the nucleus accumbens. NA neurons exhibit a bistable membrane potential, characterized by a very negative resting membrane potential (down state), periodically interrupted by plateau depolarizations (up state), during which the cells may fire in response to cortical inputs. A dynamic ensemble can be the result of a distributed set of neurons in their up state, determined by the moment‐to‐moment changes in the spatial distribution of hippocampal inputs responsible for transitions to the up state. Ensembles may change as an adaptation to the contextual information provided by the hippocampal input. Furthermore, for dynamic ensembles to be functionally relevant, the model calls for near synchronous transitions to the up state in a group of neurons. This can be accomplished by the cell‐to‐cell transfer of information via gap junctions, a mechanism that can allow for a transfer of slow electrical signals, including “up” events between coupled cells. Furthermore, gap junction permeability is tightly modulated by a number of factors, including levels of dopamine and nitric oxide, and cortical inputs, allowing for fine‐tuning of this synchronization of up events. The continuous selection of such dynamic ensembles in the NA may be disputed in schizophrenia, resulting in an inappropriate level of activity of thalamocortical systems.
Opioid Modulation of Ventral Pallidal Inputs
Authors: NAPIER T. CELESTE , MITROVIC IGOR
Published: February 2006

ABSTRACT: While the ventral pallidum (VP) is known to be important in relaying information between the nucleus accumbens and target structures, it has become clear that substantial information processing occurs within the VP. We evaluated the possibility that opioid modulation of other transmitters contained in VP afferents is involved in this process. Initially, we demonstrated that opioids hyperpolarized VP neurons in vitro and suppressed spontaneous firing in vivo. The ability of opioids to modulate other transmitters was determined using microiontophoretically applied ligands and extracellular recordings of VP neurons from chloral hydrate‐anesthetized rats. With neurons that responded to iontophoresed opioid agonists, the ejection current was reduced to a level that was below that necessary to alter spontaneous firing. This “subthreshold” current was used to determine the ability of mu opioid receptor (μR) agonists to alter VP responses to endogenous (released by electrical activation of afferents) and exogenous (iontophoretically applied) transmitters. μR agonists decreased the variability and enhanced the acuity (e.g., “signal‐to‐noise” relationship) of VP responses to activation of glutamatergic inputs from the prefrontal cortex and amygdala. By contrast, μR agonists attenuated both the slow excitatory responses to substance P and GABA‐induced inhibitions that resulted from activating the nucleus accumbens. Subthreshold opioids also attenuated inhibitory responses to stimulating midbrain dopaminergic cells. These results suggest that a consequence of opioid transmission in the VP is to negate the influence of some afferents (e.g., midbrain dopamine and accumbal GABA and substance P) while selectively potentiating the efficacy of others (e.g., cortical and amygdaloid glutamate). Interpreted in the context of opiate abuse, μR opioids in the VP may serve to diminish the influence of reinforcement (ventral tegmental area and nucleus accumbens) in the transduction of cognition (prefrontal cortex) and affect (amygdala) into behavior. This may contribute to drug craving that occurs even in the absence of reward.
Cross‐species Studies of Sensorimotor Gating of the Startle Reflex
Authors: SWERDLOW NEAL R. , BRAFF DAVID L. , GEYER MARK A.
Published: February 2006

ABSTRACT:Sensorimotor gating of the startle reflex can be assessed across species, using similar stimuli to elicit comparable response characteristics. As measured by prepulse inhibition (PPI), gating is reduced in patients with some neuropsychiatric disorders, and in rats after manipulations of limbic cortex, striatum, pallidum, or pontine tegmentum. This limbic “CSPP” circuitry can be studied in rats to reveal the neurochemical and neuroanatomical substrates regulating PPI at a high level of resolution. This detailed circuit information is used as a “blueprint” to identify substrates that may lead to PPI deficits in psychiatric‐disordered humans. Some human disorders with identifiable, localized lesions in CSPP circuitry, for example, Huntington's disease, provide direct validation for this cross‐species model. Studies have begun to assess the pharmacological homology of PPI across species, as an initial step towards translating detailed neural circuit information from rats to humans. These initial studies suggest the possibility that the effects of dopaminergic (DAergic) drugs on PPI (reducing PPI) may be homologous across species; nicotinic drugs may also produce similar effects on PPI across species (increasing PPI). By contrast, the effects of glutamatergic and serotonergic drugs may exhibit disparate effects on PPI across species. The use of DAergic agonists in human studies is complicated by their significant side effects, but new studies demonstrate that several “human friendly” direct DA agonists disrupt PPI in rats and are thus good candidates for further studies of the cross‐species homology of the DAergic regulation of PPI. In this manner, PPI can be used to probe the sensitivity of DAergic systems, and perhaps other CSPP elements, across normal and neuropsychiatric‐disordered populations.
Cortical Afferents to the Extended Amygdala
Authors: McDONALD ALEXANDER J. , SHAMMAH‐LAGNADO SARA J. , SHI CHANGJUN , DAVIS MICHAEL
Published: February 2006

ABSTRACT: The projections of the cerebral cortex to the extended amygdala were studied in the rat using anterograde and retrograde tract‐tracing techniques. Most cortical areas with strong projections to the extended amygdala preferentially targeted either the medial extended amygdala (including the medial amygdalar nucleus, ventromedial substantia innominata, and the medial part of the bed nucleus the stria terminalis) or the central extended amygdala (including the central amygdalar nucleus, dorsolateral substantia innominata, and the lateral part of the bed nucleus of the stria terminalis). Some cortical areas, however, had equal projections to both medial and central portions. The main areas projecting preferentially to the medial extended amygdala were the ventral subiculum, infralimbic cortex, ventral agranular insular area, and the rostral part of the ventrolateral entorhinal area. The main areas projecting preferentially to the central extended amygdala were the prefrontal cortex, viscerosensory and somatosensory portions of the insular cortex, and the amygdalopiriform transitional area. It is suggested that these cortical inputs may be important for cognitive, mnemonic, and affective aspects of emotional and motivated behavior.
Basal Forebrain Afferent Projections Modulating Cortical Acetylcholine, Attention, and Implications for Neuropsychiatric Disorders
Authors: SARTER MARTIN , BRUNO JOHN P. , TURCHI JANITA
Published: February 2006

ABSTRACT:Cortical acetylcholine (ACh) mediates the detection, selection, and processing of stimuli and associations, and the allocation of processing resources for these attentional functions. For example, loss of cortical cholinergic inputs impairs the performance of rats in tasks designed to assess sustained or divided attention. Intrabasalis infusions of benzodiazepine receptor (BZR) agonists block increases in cortical ACh efflux and impair attentional abilities. Studies on the regulation of cortical ACh efflux by nucleus accumbens (NAC) dopamine (DA) demonstrate that increases in cortical ACh efflux are attenuated by intra‐accumbens administration of D1 and, more potently, D2 receptor antagonists. These and other data support the hypothesis that NAC DA, via GABAergic projections to the basal forebrain, controls the excitability of basal forebrain cholinergic neurons. As increases in NAC DA have been hypothesized to represent a major neuronal mediator of schizophrenia and the compulsive use of addictive drugs, the data predict that the abnormal regulation of cortical ACh release represents a crucial neuronal mechanism mediating the cognitive components of these psychopathological disorders.
Functions of the Amygdala and Related Forebrain Areas in Attention and Cognition
Authors: GALLAGHER MICHELA , SCHOENBAUM GEOFFREY
Published: February 2006

ABSTRACT: This paper will concentrate on two features of the systems described by Alheid and Heimer 1 that have influenced research in our laboratory in recent years. In the first part, we describe our findings on a representational function of the amygdaloid basolateral complex that appears to depend on its interconnections with the prefrontal cortex. In the second part, we describe progress assessing the function of magnocellular corticopetal neurons within the basal forebrain and the strong input to this system from the central amygdaloid group. These lines of behavioral research have revealed that subsystems in the basal forebrain and amygdala serve adaptive functions beyond the domains of motivation and emotion to include attention and cognition.
Associative Processes in Addiction and Reward The Role of Amygdala‐Ventral Striatal Subsystems
Authors: EVERITT BARRY J. , PARKINSON JOHN A. , OLMSTEAD MARY C. , ARROYO MERCEDES , ROBLEDO PATRICIA , ROBBINS TREVOR W.
Published: February 2006

ABSTRACT: Only recently have the functional implications of the organization of the ventral striatum, amygdala, and related limbic‐cortical structures, and their neuroanatomical interactions begun to be clarified. Processes of activation and reward have long been associated with the NAcc and its dopamine innervation, but the precise relationships between these constructs have remained elusive. We have sought to enrich our understanding of the special role of the ventral striatum in coordinating the contribution of different functional subsystems to confer flexibility, as well as coherence and vigor, to goal‐directed behavior, through different forms of associative learning. Such appetitive behavior comprises many subcomponents, some of which we have isolated in these experiments to reveal that, not surprisingly, the mechanisms by which an animal sequences responding to reach a goal are complex. The data reveal how the different components, pavlovian approach (or sign‐tracking), conditioned reinforcement (whereby pavlovian stimuli control goal‐directed action), and also more general response‐invigorating processes (often called “activation,”“stress,” or “drive”) may be integrated within the ventral striatum through convergent interactions of the amygdala, other limbic cortical structures, and the mesolimbic dopamine system to produce coherent behavior. The position is probably not far different when considering aversively motivated behavior. Although it may be necessary to employ simplified, even abstract, paradigms for isolating these mechanisms, their concerted action can readily be appreciated in an adaptive, functional setting, such as the responding by rats for intravenous cocaine under a second‐order schedule of reinforcement. Here, the interactions of primary reinforcement, psychomotor activation, pavlovian conditioning, and the control that drug cues exert over the integrated drug‐seeking response can be seen to operate both serially and concurrently. The power of our analytic techniques for understanding complex motivated behavior has been evident for some time. However, the crucial point is that we are now able to map these components with increasing certainty onto discrete amygdaloid, and other limbic cortical‐ventral striatal subsystems. The neural dissection of these mechanisms also serves an important theoretical purpose in helping to validate the various hypothetical constructs and further developing theory. Major challenges remain, not the least of which is an understanding of the operation of the ventral striatum together with its dopaminergic innervation and its interactions with the basolateral amygdala, hippocampal formation, and prefrontal cortex at a more mechanistic, neuronal level.
Drug Addiction as a Disorder of Associative Learning: Role of Nucleus Accumbens Shell/Extended Amygdala Dopamine
Authors: DI CHIARA G. , TANDA G. , BASSAREO V. , PONTIERI F. , ACQUAS E. , FENU S. , CADONI C. , CARBONI E.
Published: February 2006

ABSTRACT: Conventional reinforcers phasically stimulate dopamine transmission in the nucleus accumbens shell. This property undergoes one‐trial habituation consistent with a role of nucleus accumbens shell dopamine in associative learning. Experimental studies with place‐ and taste‐conditioning paradigms confirm this role. Addictive drugs share with conventional reinforcers the property of stimulating dopamine transmission in the nucleus accumbens shell. This response, however, undergoes one‐trial habituation in the case of conventional reinforcers but not of drugs. Resistance to habituation allows drugs to repetitively activate dopamine transmission in the shell upon repeated self‐administration. This process abnormally facilitates associative learning, leading to the attribution of excessive motivational value to discrete stimuli or contexts predictive of drug availability. Addiction is therefore the expression of the excessive control over behavior acquired by drug‐related stimuli as a result of abnormal strenghtening of stimulus‐drug contingencies by nondecremental drug‐induced stimulation of dopamine transmission in the nucleus accumbens shell.
The Bed Nucleus of the Stria Terminalis: A Target Site for Noradrenergic Actions in Opiate Withdrawal
Authors: ASTON‐JONES GARY , DELFS JILL M. , DRUHAN JONATHAN , ZHU YAN
Published: February 2006

ABSTRACT: Hyperactivity of brain norepinephrine (NE) systems has long been implicated in mechanisms of opiate withdrawal (OW). However, little is known about where elevated NE may act to promote OW. Here we report that the bed nucleus of the stria terminalis (BNST), the densest NE target in the brain, is critical for NE actions in OW. (1) Many BNST neurons become Fos+ after OW. Pretreatment with the β antagonist, propranolol, markedly reduces OW symptoms and the number of Fos+ cells in the BNST. (2) Numerous neurons in the nucleus tractus solitarius (A2 neurons) and the A1 cell group are triple labeled for tyrosine hydroxylase, a retrograde tracer from the BNST, and Fos after OW, revealing numerous NE neurons that project to the BNST from the medulla that are stimulated by OW. Fewer such triple‐labeled neurons were found in the locus caeruleus. (3) Behavioral studies reveal that local microinjections of selective β‐adrenergic antagonists into the BNST attenuate OW symptoms. In particular, withdrawal‐induced place aversion is abolished by bilateral microinjection of a cocktail of selective beta 1 (betaxolol) plus the beta 2 (ICI 181,555) antagonists (1.0 nmol each/0.5 μL per side) into the BNST. Similar results were obtained with neurochemically selective lesions of the ventral ascending NE bundle, the pathway for A1 and A2 projections to the BNST. Similar lesions of the dorsal NE bundle of projections from the locus caeruleus had no effect on either aversive or somatic withdrawal symptoms. Together, these results indicate that β‐receptor activation in the BNST is critical for aversive withdrawal symptoms, and that A1 and A2 neurons in the medulla are the source of this critical NE.
Functional Magnetic Resonance Imaging of Brain Reward Circuitry in the Human
Authors: BREITER HANS C. , ROSEN BRUCE R.
Published: February 2006

ABSTRACT: To produce behavior, motivational states necessitate at least three fundamental operations, including (1) selection of objectives focused on goal‐objects, (2) compilation of goal‐object information, and (3) determination of physical plans for securing goal‐objects. The second of these general operations has been theorized to involve three subprocesses: (a) feature detection and other perceptual processing of putative goal‐object “rewards,” (b) valuation of goal‐object worth in the context of potential hedonic deficit states, and (c) extraction of incidence and temporal data regarding the goal‐object. A number of subcortical brain regions appear to be involved in these three informational subprocesses, in particular, the amygdala, sublenticular extended amygdala (SLEA) of the basal forebrain, and nucleus accumbens/subcallosal cortex (NAc/SCC). Components of the amygdala, SLEA, and NAc/SCC together constitute the larger anatomic structure of the extended amygdala. Functional magnetic resonance imaging (fMRI) studies of humans have recently begun to localize these subcortical regions within the extended amygdala during specific experimental conditions. In this manuscript, two human cocaine‐ infusion studies and one cognitive psychology experiment are reviewed in relation to their pattern of fMRI activation within regions of the extended amygdala. Activation in the NAc/SCC, in particular, is evaluated in relation to a hypothesis that one function of the NAc/SCC and associated brain regions is the evaluation of goal‐object incidence data for the computation of conditional probabilities regarding goal‐object availability. Further work is warranted to test hypothesized functions for all regions within the extended amygdala and integrate them toward an understanding of motivated behavior.
Epilepsy, Schizophrenia, and the Extended Amygdala
Authors: STEVENS JANICE R.
Published: February 2006

ABSTRACT: Propagation and prolongation of rapid neuronal discharge underlies the epilepsies. However, episodic focal rapid neuronal discharges limited to discrete nuclei and pathways of the amygdala‐hippocampal‐septal‐hypothalamic networks are the language of physiologic message systems for endocrine regulation and reproductive activities vital to the survival of the organism and the species. To prevent prolongation and propagation of physiologic pulsed excitation to areas outside specific networks and resultant epileptic seizures, these discharges must be limited in extent and time by powerful inhibitory processes. The nucleus accumbens, a unit of the extended amygdala, and the monoamines and GABA are components of the inhibitory networks that restrict physiologic rapid discharge in duration and in location. In parallel to the relationship of excessive neuronal excitation to epilepsy, evidence will be presented that excessive inhibition via one or more components of these inhibitory networks or diminished excitation underlies development of some psychoses, including schizophrenia.
Ventromedial Temporal Lobe Pathology in Dementia, Brain Trauma, and Schizophrenia
Authors: VAN HOESEN GARY W. , AUGUSTINACK JEAN C. , REDMAN SARAH J.
Published: February 2006

ABSTRACT: The ventromedial temporal area contains numerous anatomical structures collectively or selectively involved in a wide range of neurological and psychiatric disorders. Collective involvement is exemplified best by Alz‐heimer's disease where a host of anatomical structures and a host of cognitive and behavioral changes are manifested. Selective disease of the amygdala can yield deficits in the ability to judge and evaluate emotional expressions. While memory functions are nearly synonymous with the concept of ventromedial temporal area, they overshadow other functions associated with the diverse anatomical structures in this part of the brain. For example, it could be argued that in addition to output directed toward the hippocampal formation, the output of the ventromedial temporal area is equally strong to the ventral striatopallidal system of the basal forebrain. Denervation of these structures could be associated with the behavioral changes that occur in tandem with the memoryrelated changes of ventromedial temporal lobe pathology. Here we explore the anatomical and pathological correlates associated with ventromedial temporal area pathology and consider how these may impact on ventral striatopallidal conceptualizations. We conclude that ventromedial temporal area pathology deprives the basal forebrain of multimodal association information from the endstages of corticocortical sensory processing. This endstage information carries with it an analysis of real‐time sensory awareness, historical‐time or past sensory experiences, and decisions from hippocampal output structures regarding relevancy and novelty. In this sense, basal forebrain structures are in a unique position to regulate behavioral responses to a wide range of stimuli and to organize appropriate emotional, motor, autonomic, and endocrine responses to them.