1992 — 2002 |
Shepard, Paul D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Cns Da Neurons--Cellular Basis of Patterned Activity @ University of Maryland Baltimore
Alterations in the functional state of mesotelencephalic dopamine (DA)-containing neurons have been implicated in the etiology of a variety of pathological and iatrogenic conditions including schizophrenia and tardive dyskinesia. Involvement of these neurons in disorders of clinical relevance has led to a number of basic studies directed at obtaining a better understanding of the factors involved in their regulation at the cellular level. One area of potential importance that has remained largely unexplored pertains to the role of neuronal discharge pattern as a means of modulating neuronal activity and thus expression of dopaminergic systems in brain. The research proposed in our application seeks to explore the ionic and cellular basis of the diverse group of activity patterns exhibited by mesencephalic DA-containing neurons in the rat. Our initial studies will focus on intrinsic mechanisms of pattern generation. Experiments will be performed to identify and characterize several voltage- and ligand-gated ion conductances, which by virtue of their ability to become activated during the interspike interval, are likely to be involved in regulating neuronal discharge pattern. Single electrode voltage clamp techniques will be used in conjunction with several highly selective pharmacological probes to specify the contribution made by individual current components to repetitive single spike and burst firing patterns. The second series of experiments will focus on extrinsic factors likely to contribute to generation of normal patterned activity. In the first group of experiments, extracellular single unit recording techniques will be used to explore the contribution. made by excitatory amino acid-containing afferents to the firing patterns typically observed among identified DA neurons in vivo. Excitatory projections originating in the cortex and pedunculopontine tegmentum will be the focus of these experiments. Finally, we will examine the role of other neuroactive substances contained in afferents to the principle mesencephalic DA cell groups as possible modulators of the individual conductance mechanisms characterized in the earlier phases of the project. By more clearly understanding the nature of the contributions made by intrinsic and extrinsic mechanisms to the patterned electrical activity of DA-containing neurons, we hope to gain further insights into an important physiological process which may be centrally involved in regulating the expression of these neurons in normal and pathological states.
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0.972 |
2005 — 2008 |
Shepard, Paul D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dopamine Cell Impulse Flow, Reward and Schizophrenia @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): Dopamine (DA)-containing neurons are centrally involved in the neurobiological processes subserving the detection and transmission of reward. Encoding this signal involves changes in the instantaneous firing rate and thus the discharge pattern of mesotelencephalic DA neurons. Although increases in DA cell activity evoked by stimuli with positive motivational value are initiated by synaptic input(s), the output of these cells (i.e., impulse-dependent DA release) is constrained by several factors. These include the intrinsic electrical properties of the cell as dictated by its complement of voltage and ligand-gated ion channels and short and long-loop homeostatic mechanisms that strive to maintain the "status quo." The interaction between these three factors (afferents, intrinsic properties and homeostatic tone) constrain the activity of DA neurons to one of four distinct modes including single spike and bursting activity and two quiescence states mediated by membrane hyperpolarization or depolarization-induced inactivation of spike generating mechanisms (depolarization block). Under normal conditions, phasic changes in DA cell impulse flow maintain reward-appropriate signaling. Under abnormal conditions, such as those induced by administration of antipsychotic drugs, reward-appropriate signaling may fail. The central premise of the application is that the loss of autoregulatory tone, secondary to functional loss of DA D2 receptors, will increase the cell's responsiveness to excitatory (or disinhibitory) inputs predisposing it to enter a state of depolarization block (Specific Aim #1). It is further speculated that the ensuing loss of impulse-dependent DA release prevents normal transmission of rewarding signaling or predicting stimuli (Specific Aim #2). Finally, it is hypothesized that antipsychotic drugs (APDs) with a receptor binding profile that favors displacement by endogenous DA (so called "fast-off' APDs) will be less likely to induce depolarization block than APDs which bind more tightly and thus at reduced risk for compromising transmission of rewarding stimuli (Specific Aim #3). In order to address these aims, the research proposed in this application combines in vivo electrophysiological methods together with brain stimulation reward techniques to study the relationship between DA cell impulse flow and the neural mechanisms of reward. It is anticipated that the research proposed in this application will provide insight into neurobiological mechanisms responsible for neuroleptic dysphoria and a framework for prospectively designing antipsychotic drugs with a reduced liability for producing negative subjective responses in patients.
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0.972 |
2012 — 2016 |
Elmer, Gregory I Shepard, Paul D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Habenulomesencephalic Pathway in Aversion, Reward and Depression @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): Treatment resistant depression is a chronic, disabling and life-threatening disease that affects as many as 30% of individuals diagnosed with major depressive disorder. For these patients, traditional pharmacological treat- ments are often not effective, and deep brain stimulation of discrete brain regions has emerged as one of the only viable treatment options. One target area for such treatment is the lateral habenula (LHb), a component of the epithalamus that receives confluent input from emotional and motor systems, strongly influences activity of midbrain dopamine (DA) neurons, and is increasingly implicated in aversive stimulus processing, learning, and clinical depression. However, the circuitry of this system and the critical role of newly discovered components within the system remain incompletely understood. For example, the role of the newly identified rostromedial tegmental nucleus (RMTg), a GABAergic midbrain region which receives LHb input and projects intensely to DA neurons, is largely unexplored, although it's known properties suggest possibly central roles in depressive phenomena. Our proposal addresses several fundamental outstanding questions regarding these habenulo- mesencephalic circuits using a range of behavioral and electrophysiological techniques that are grouped into three related aims. In Aim 1, we will test the hypothesis that the physiological and behavioral effects associated with acute and chronic activation of the LHb are mediated via a projection from the LHb to the RMTg. Aim 2 will test the hypothesis that the LHb and RMTg critically contribute to maladaptive behaviors in two distinct animal preparations that model human depression endophenotypes. This aim uses lesion and stimulation studies to characterize the importance of this pathway in depression-related responses to both aversive and rewarding stimuli (despair, anhedonia). Finally, in Aim 3, we will test the hypothesis that depression-induced changes in LHb and RMTg patterns of firing underlie the behavioral and cognitive deficits seen in depressive disorders. Overall, these studies investigate the proposition that dysregulation of a fundamental circuit, LHb-RMTg-VTA, is involved in the maladaptive response to adverse events. Results obtained from these experiments will ad- dress a major focus of the NIMH Research Domain Criteria (RDoC) efforts to define mental disorders based on neurobiological measures that cross diagnostic boundaries. Dysfunction of brain reward systems has clear im- plications for depression, and also schizophrenia, bipolar disorder, and drug abuse. Given growing convergent preclinical and clinical data, these studies have clear translational relevance.
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0.972 |
2016 — 2017 |
Elmer, Gregory I Shepard, Paul D |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Anesthetic-Induced Burst Suppression as a Novel Antidepressant Mechanism @ University of Maryland Baltimore
Abstract Medication-resistant depression is associated with persistent vocational disability, substantially higher risk of suicide, and higher health care utilization costs. Electroconvulsive therapy (ECT) is an effective course of treatment for medication-resistant depression although it is often poorly tolerated due to memory and cognitive impairment and its mechanism of action remains elusive. Several clinical studies have indicated that repeated, short-term exposure to the volatile anesthetic isoflurane has antidepressant efficacy equivalent to a course of ECT in patients with medication-resistant depression. The antidepressant actions of isoflurane may be due to its ability to elicit cortical burst suppression, a distinctive EEG pattern resembling the postictal EEG following ECT-induced seizures. Recently, we found that that prior exposure to isoflurane in doses that elicit burst suppression reduces the incidence of learned helplessness in rats while comparable doses of halothane, which fail to elicit burst suppression, did not. This R21 application seeks to extend these preliminary findings by testing two overarching hypotheses. First, that cortical burst suppression is necessary and possibly sufficient to explain the antidepressant actions of isoflurane and second that cortical burst suppression and the antidepressant efficacy of isoflurane and related anesthetics are dependent on activation of the ATP-gated K+ channel, a conductance explicitly coupled to cellular energetics and metabolism. In Specific Aim 1, four anesthetic drugs that differ in their propensity to elicit cortical burst suppression will be evaluated for their ability to reverse maladaptive behaviors, including helplessness and anhedonia, in rats that model aspects of psychopathology in major depressive disorder. In Specific Aim 2, we will determine whether selective ATP- gated K+ channel antagonists are capable of blocking cortical burst suppression and whether loss of this activity prevents isoflurane and related drugs from exerting their antidepressant-like effects in animals. These experiments have the potential to have an important and immediate impact by extending the short list of therapeutic agents available to treat medication-resistant depression to include drugs capable of eliciting cortical burst suppression and by identifying a novel target for the development of drugs with the onset, therapeutic efficacy and duration of ECT but without the side effects that currently limit tolerability.
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0.972 |
2017 — 2018 |
Elmer, Gregory I Shepard, Paul D |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Rmtg Circuitry Mediates Psychiatric Consequences of Early Life-Threatening Trauma @ University of Maryland Baltimore
Project Summary Childhood trauma occurs at an unacceptably high rate. In the most recent National Survey of Children's Health, almost half of the children experienced at least one or more types of serious childhood trauma- nearly 35 million children. Childhood trauma has dramatic and costly effects in adulthood. Childhood trauma increases the risk of developing major depressive disorder (MDD), generalized anxiety, panic reaction, obsessive compulsive disorder (OCD), somatoform disorders, substance abuse and psychotic disorders. Childhood trauma significantly alters treatment trajectories and outcome for the worse. It is our contention that the ratio of basic research effort to clinical impact is too low. The purpose of this application is accelerate the development of a novel trauma model we believe delivers robust and relevant outcomes and to explore a novel hypothesis concerning the etiology of increased mental illness liability. We will pursue our studies in two research aims. Aim 1 is designed to further develop a novel live-predator model (snake) with the proposition that a highly salient, ethologically-relevant trauma will engage the nervous system in a manner relevant to studies of psychiatric disorders. We will systematically manipulate timing and number of adolescent trauma exposures and conduct large-scale mining in adulthood for physiological, behavioral and neurobiological profiles indicative of behavioral constructs that cross diagnostic boundaries (e.g. hyper arousal, anhedonia, depression and anxiety). Neural activation patterns will be assessed in key RMTg-centric circuitry via cFos activation patterns. A wealth of within subjects behavioral and neurobiological data will be subject to multidimensional scaling and categorical analysis to identify patterns of circuitry involvement associated with specific abnormal behavioral profiles. Aim 2 will test the novel hypothesis that adolescent exposure to ethologically-relevant trauma results in enduring behavioral and neurobiological disruptions that require rostral medial tegmentum (RMTg) function. The combination of roles hypothesized to involve the RMTg (threat, fear, avoidance and negative affect) place it in an ideal situation to mediate disruptive consequences of early trauma and some of the core symptoms found to cross diagnostic domains. We will systematically inhibit (RMTg-directed muscimol) or potentiate (RMTg-directed AMPA) RMTg function during trauma exposure to test our hypothesis. A similar analysis as described in Aim 1 will determine if RMTg inhibition or potentiation dampens or worsens, respectively, behavioral and neurobiological outcomes. Childhood trauma and the subsequent development of mood disorders is emerging as a pervasive theme in mental illness. Preclinical research is uniquely qualified to systematically investigate the consequences of early-life trauma. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies to help alleviate the individual and societal burden.
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0.972 |