Susan M. Ferguson - US grants

human therapy evaluation; neoplasm /cancer chemotherapy; breast neoplasms; paclitaxel; antineoplastics; combination chemotherapy; neoplastic process; neoplasm /cancer classification /staging; clinical research; human subject; female;

[unreadable] DESCRIPTION (provided by applicant): [unreadable] There is increasing evidence that serotonin (5HT) neurotransmission plays an important modulatory role in the development of drug addiction. One promising target for the actions of 5HT are the 5HT6 receptors (5HT6Rs), given their high density in limbic brain regions, such as the nucleus accumbens (NAc). The overall aim of the proposed experiments, therefore, is to use molecular approaches to elucidate the role of 5HT6Rs in modulating the rewarding effects of cocaine. It is hypothesized that overexpression of 5HT6Rs in the NAc will attenuate cocaine-induced conditioned place preference (CPP), as well as both cocaineand stress-induced reinstatement of the CPP. In contrast, it is predicted that both downregulation and blockade of 5HT6Rs in the NAc will potentiate cocaine-induced CPP. Finally, it is hypothesized that one way in which 5HT6Rs may modulate the rewarding effects of cocaine is by regulating the phosphorylation states of the phosphoprotein DARRP-32. These experiments will provide additional insight into the role of 5HT6Rs in drug experience-dependent behavioral plasticity and will contribute to the further understanding of the processes that mediate the behavioral and neurobiological changes thought to underlie addiction. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

Tlie striatum is mostly comprised of GABAergic medium spiny projection neurons (MSNs) tlnat differ in thieir neuropeptide expression and form two major efferent patiiways. MSNs that contain the neuropeptides dynorptiin and substance P are part of the striatonigral, or 'direct', pathway whereas MSNs that contain the neuropeptide enl

DESCRIPTION (provided by applicant): The cortico-basal ganglia system is a complex neural network involved in motivation and reward. Dysfunction of this circuitry has been implicated in many neuropsychiatric disorders, including drug addiction. The striatum acts as the principal interface of this circuit, and guides behavioral output primarily through two pathways, the direct and the indirect. These striatal pathways have been shown to play important, but distinct roles, in addiction-related behaviors. In addition, plasticity at striatal neurons, which promotes the selection of appropriate actions based on prior experience and is profoundly altered by exposure to drugs of abuse, is regulated by glutamatergic signaling from the cortex. However, how corticostriatal afferents targeting specific striatal cell populations regulate the behavioral and neurobiological impact of drugs has never been isolated. Furthermore, these corticostriatal pyramidal neurons can be subdivided into two major types with distinct projections targets, morphologies and electrophysiological characteristics. Cortical neurons that have sparse apical tufts and minimal h-currents project intratelencephalically to striatum and contralateral cortex (IT-type) whereas cortical neurons that have thick apical tufts and prominent h-currents send their main axon into the pyramidal tract with collateral projections to striatum (PT-type). Although some evidence suggests that IT-type neurons preferentially target direct pathway striatal neurons and PT-type neurons target indirect pathway striatal neurons, this idea remains of debate. Cortical processing is crucial for the patterning of addiction- related behavior, so understanding which types of cortical cells target populations of striatal neurons as well as how discrete sets of cortical inputs produce adaptations within the direct and indirect striatal pathways will be critical for unraveling the circuitry underlying reward and motivated behavior. Thus, the overall goal of this proposal is to develop novel molecular targeting approaches to assess the phenotype of cortical neurons that target direct and indirect pathway striatal neurons as well as to define the role of sets of cortical afferents that target these two striatal pathwaysin one form of drug-induced behavioral plasticity, psychomotor sensitization. Through modeling how loss of top-down control from cortical inputs into the basal ganglia contribute to behaviors that are related to addiction, we will gain a better understanding of the intricacies of this circutry, which is likely to have a big impact on the development and application of treatments for addicts.

DESCRIPTION (provided by applicant): The cortico-basal ganglia system is a complex network involved in motivation and reward. Medium spiny projection neurons (MSNs) within the striatum serve as the primary relay station of this circuit, and guide behavioral output through two divergent pathways. Striatal MSNs that contain the neuropeptides dynorphin (DYN) and substance P are part of the direct pathway whereas striatal neurons that contain the neuropeptide enkephalin (ENK) are part of the indirect pathway. Repeated exposure to drugs of abuse can produce dysregulation in the cortico-basal ganglia circuit, in part through aberrant plasticity at sub-cortical structures, such as the striatum, as well as through a loss of top-down control from glutamatergic afferent systems. Direct and indirect striatal MSNs have recently been shown to play important, but distinct, roles in behaviors produced by psychostimulant drugs. However, little is known regarding the roles of these distinct cell populations, as well as their afferent connections, in models that produce patterns of compulsive drug-taking and drug-seeking that are characteristic of addiction, such as prolonged access drug self-administration. In addition, how signaling activity in these striatal cell populations changes following compulsive drug use, as well as regulates addiction-like behavior is not well understood. The overall aim of the proposed experiments is to use novel viral vectors expressing engineered DREADD (Designer Receptor Exclusively Activated by Designer Drug) receptors to define the role of direct and indirect pathway MSNs, as well as glutamatergic afferents, in compulsive drug-taking and drug-seeking behaviors. In addition, how compulsive patterns of drug use alter intracellular signaling activity in striatal cell populations will be examined. The central hypothesis of this proposal is that repeated drug use produces glutamate-dependent modifications to G-protein dependent signaling cascades in the striatum in a subset of individuals, leading to compulsive, addiction-like behavior (defined by high motivation to take drugs, and drug-seeking during periods of drug unavailability and during punishment). Specifically, we propose that ERK/MAPK signaling cascades are enhanced in direct pathway MSNs and suppressed in indirect pathway MSNs, which shifts the balance of these pathways towards the 'go' drive, thereby increase drug-taking and drug-seeking. This work has the potential to identify new targets for treatment (i.e., specific cell populations or afferent projections) as well as new types of treatments that may reverse addictive behaviors, such as DREADD receptor modulation of intracellular signaling cascades.

Project Summary Drug addiction is a major public health issue that has profound medical consequences to individuals, as well as costly social and economic impacts on our society. Unfortunately, treatment options are limited and relapse rates remain high. Unraveling the complex neurobiological changes that contribute to the transition to addiction in vulnerable individuals, therefore, is critical for effective therapeutic development. The cortico-basal ganglia- thalamic (CBGT) network is involved in decision-making, motivation and reward, and alterations within this circuit regulate the development of drug addiction. The prefrontal cortex serves as a key modulator of this circuit, providing strong glutamatergic drive to the striatum, as well as widespread input throughout the CBGT system. Of note, cortical processing is crucial for the patterning of appropriate behavior and loss of top-down cortical control during drug use is thought to play a major role in the transition to addiction, as well as relapse. However, cortical pyramidal neurons can be subdivided into two major types with distinct inputs and projections targets, molecular and receptor profiles, morphologies and electrophysiological characteristics. Cortical neurons that have sparse apical tufts, minimal h-currents, and are regular spiking project bilaterally to striatum and contralateral cortex (Intratelencephalic; IT) whereas cortical neurons that have thick apical tufts, prominent h-currents, and are burst firing send their main axon into the pyramidal tract with collateral projections to ipsilateral striatum and other subcortical structures (Pyramidal Tract; PT). As a result of the distinct connectivity patterns and cellular properties of these two neuronal populations, they are poised to integrate and convey distinct signals for guiding decision-making processes and motivated behaviors. Nonetheless, the role of these two cell populations in the regulation of addiction behaviors has not been examined. The overall goal of this proposal, therefore, is to begin to address this issue by using novel imaging and molecular tools to characterize how IT and PT neurons in PFC regulate drug-context associations, as well as drug-taking and drug-seeking behaviors in rats expressing distinct addiction-risk phenotypes. The guiding hypothesis of this work is that IT and PT neurons in the cortex work in concert to maintain optimal functioning of the CBGT network by regulating aversive and appetitive motivation states, respectively, and dysregulation of these cell types following drug use leads to aberrant signal relays to drugs and associated stimuli that drive compulsive and persistent drug use. This work, therefore, has the potential to uncover novel, cell-type specific processes that contribute to the development of addiction and relapse.

Abstract: Opiate addiction extorts a tremendous toll on society, but a mechanistic understanding of how repeated exposure to opioids such as heroin ultimately results in compulsive drug-taking and -seeking behavior in some individuals, but not others, is still not known. A longstanding idea is that enduring changes in neural circuit function occur because of drug-induced gene expression changes in certain brain cells. This facilitates subsequent drug-taking and -seeking behaviors in vulnerable individuals. Unfortunately, identifying cell-type specific alterations following drug use (typically performed in established animal models of addiction), is generally a slow and tedious process as changes in gene expression following in vivo drug exposure are typically assayed in series, within heterogeneous brain regions, in an a-priori hypothesis driven fashion (i.e. previous knowledge predicting a specific gene may be involved). This dramatically limits the throughput of data collection and likely complicates the subsequent interpretation as gene expression patterns data are typically captured from thousands to millions of homogenized cells. Given that the nervous system is composed of highly heterogeneous tissue, re-assessing cell type specific gene expression changes in an unbiased manner from 1000's of individual cells is desperately needed. Here, we propose to combine our expertise in order to generate comprehensive datasets aimed at understanding how single-cell gene expression, circuit connectivity, and neural activity patterns are impacted by previous drug-taking behavior. These data will provide a much-needed cellular atlas and resource for the addiction neuroscience community and will likely lead to the identification of many novel cell type, gene expression changes, and ensembles that can be leveraged for future study.