Conference 2000

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Focus Group Abstracts

Behavior/Function

     Although the ventral striatum has been implicated in reward processes and motivation for three decades, it is only relatively recently that specific questions regarding learning and plasticity have been applied to this structure. The specific aim of the behavioral focus group is to develop and discuss issues related to the role of this structure in learning; that is, in associative processes per se on which learning depends and in the acquisition of goal-directed behaviors. Part of this renewed interest in learning properties of the striatum has been generated by converging data from molecular biological investigations of addiction as well as from cellular models of learning and memory. Our goal is to understand the nature of learning subserved by the ventral striatum. There are several principal areas of inquiry and interest. One question is whether the ventral striatum actually mediates associative processes, or rather integrates associative information from various input regions and conveys this to the motor system, acting more preferentially on response selection.
     A second major conceptual area focuses on the nature of the input to ventral striatum, from corticolimbic regions clearly involved in learning, such as amygdala, prefrontal cortex, and hippocampus. Do these various complex inputs contribute different types of information to one learning process, or are there parallel circuits mediating different types of learning? Moreover, there is considerable debate as to the nature of stimulus and response processing by ventral striatum in relation to appetitively versus aversively motivated behavior, particularly with regard to the amygdalo--striatal pathway. Clearly most work has implicated the ventral striatum in reward and appetitive functions. Is this a preferential or unique role or have we not yet developed appropriate strategies for evaluating the ventral striatum in aversive functions?

Anatomy

     The anatomy focus group section includes a summary section containing fundamental information on the ventral parts of the basal ganglia, extended amygdala and magnocellular basal forebrain complex and an exposition of some current areas of interest and/or controversy among neuroanatomists working with these structures. These issues focus on general questions that concern the function of the ventral striatum and related structures and their combined role in plasticity and learning.
     Summary of the field. The ventral striatopallidal complex in rat and monkey is covered in sections on its general, connectional and neurochemical organization. There is an extensive review of the intrinsic organization of the ventral striatum. Its boundaries and relationships to the prefrontal cortex, particularly the recently described medial and orbital prefrontocortical networks, are covered in some detail. There is a brief section on the synaptic relationships in the rat of prefrontal cortex with dopamine neurons, and an introductory description of the extended amygdala and magnocellular basal forebrain complex.
     Issues for Discussion. These include, but are not intended to be limited to, (1) separation of the dorsal from ventral parts of the basal ganglia; (2) separation of different parts of the ventral basal ganglia from each other and from extended amygdala, (3) the fundamental cellular and connectional organization of basal ganglia, extended amygdala and magnocellular basal forebrain, (4) brainstem relationships of extended amygdala vs. ventral parts of the basal ganglia, (5) the implications of the small-celled interface islands for function in the ventral basal ganglia and extended amygdala, and (6) feed-forward pathways vs. parallel segregated circuits in the basal ganglia. It is hoped that an increased appreciation of macrosystemic neuroanatomical substrates subserving cortico-subcortical interactions devoted to the synthesis and plasticity of neural processing related to motivation will emerge from discussions elicited by these preparatory ruminations.

Physiology

     Modern electrophysiological evaluations of the ventral striatum have provided important new insights into the mechanisms underlying striatal neuronal responses to stimuli and the way they adapt to long-term alterations in these stimuli. For example, recent investigations have shown that convergent excitatory inputs do more than merely provide additive influences; instead, the hippocampal and amygdalar input to the accumbens can gate the way that these neurons respond to other afferent inputs. Synaptic inputs also can modulate the integration of information via interaction with gap junctions which provides another means by which accumbal neurons are modulated by the network in which they are embedded.
     One factor that is pervasive within limbic systems is the capacity of the system for adaptive changes. It is now well established that these processes can occur at essentially every "level" of electrophysiologically determined function, including alterations in channel conduction and afferent inputs, that culminate in changes in firing rate and/or pattern of ventral striatal ouput neurons. Reconfiguration of this system can occur in response to environmental circumstance, damage (e.g., DA-depleting lesions), or pharmacological insult (e.g., repeated cocaine, amphetamine, or morphine administration). The type of alterations that the system is capable of performing, however, is strongly dependent on the developmental stage at which the insult occurs. Thus, lesions made during gestation or in neonatal rats produce far different consequences than those that occur in the adult animal. Particularly important advancements also have been made toward understanding the contribution of interactions among systems in the adaptive process. These interactions occur at the synaptic level (e.g., long-term potentiation, cortical regulation of subcortical DA systems) and involve the history of the insult (e.g., repeated drug drug administration or withdrawal time). Consequently, electrophysiological evaluations of the adaptive processes within the ventral striatum must be made with an understanding of the conditions that drive adaptation and include assessments of interactions among systems and how these interactions dictate the reconfiguration process. It is this aspect of the neurophysiology of ventral striatal adaptations that we focused our attention.

Psychopathology

     Historically the ventral striatum has been considered to play a central role in the development and expression of many psychiatric disorders including schizophrenia, affective disorders, substance abuse, and attention deficit disorder. Many of these disorders are unique to primate species, but investigations of the basis of these disorders has not been limited to humans. One important issue then is - what are the characteristics of animal models appropriate for the study of psychopathology? Our summary contains a brief description of the essential elements of the various kinds of models as they relate to psychopathology. Since substance abuse is a focus of the research efforts of several members of our group, it was used as an example.
     Although there is little disagreement about the mechanisms of action of many drugs of abuse, two issues are far less understood. First, is the way in which drugs of abuse influence the normal processing of information in the ventral striatum. This was addressed in a description of a hypothesis about the role of dopamine in associative processes. The second issue raised by our group was the concept of bindiing of motivational information over the temporal dimension.
     Because many psychopathological disorders are distinctly human in nature, a final issue was the way in which research with animal models is applied to our understanding of these uniquely human conditions. One question is that of vulnerability. Only a small subset of the population is subject to psychopathology. Although this is not directly related to the issue of plasticity (the focus of this meeting), an important question is whether the neuroadaptations of this group are different from those of less vulnerable individuals. Of primary importance, however, are the differences in anatomy between rodents and primates. A brief description of the differences in gene expression in rats, monkeys and humans is included

Gene Regulation

     Our focus is on the medium spiny projection neurons (MSNs) of the nucleus accumbens because (1) most stimulus-induced changes in gene expression which are relevant to ventral striatal plasticity take place in these neurons, (2) MSNs integrate dopamine and glutamate inputs via intracellular cascades that link neuronal activity to signal transduction, and (3) their projections are the main arteries that link the cognitive/motivational aspects to the locomotor aspects of behavior. Stimulation of dopamine and glutamate receptors on MSNs activates a complex network of phosphorylation/dephosphorylation events that modulate ion channel activity, cytoskeletal changes, and nuclear transcription. Short and long-term changes in these intracellular cascades are thought to underlie the altered physiological responses reflected in LTP/LTD, cortical gating, and experience-dependent adaptations in neuronal activity.
     Changes in gene expression have been detected for the last 20 years with what are now termed "conventional" hybridization techniques. These techniques are limited by the number of genes that can be manipulated at a time. Strategies to identify alterations in the expression of many, even novel, genes include PCR-based differential display and its newer variants, which select for low abundance genes of interest. The newest strategy that has augmented this toolbox is array-based technology. cDNA and oligonucleotide arrays allow investigation of gene expression levels and provide static and dynamic information on changes in the expression of hundreds to thousands of genes, many of unknown significance. Such gene screen strategies can identify gene products that can be manipulated in animals, knocked down with antisense oligonucleotides, knocked out or over-expressed in transgenic mice, or introduced into specific brain areas with viral vector constructs. These animals can then be treated with drugs in order to test their physiological significance in vivo.
     Specific issues addressed by this focus group include: (a) how the prototypical MSN integrates metabotropic and ionotropic signaling information via its complex intracellular cascades, (b) the relevance of this information to physiology and behavior, (c) whether the molecular models are too focused on the striatum and have not yet expanded adequately to address drug-induced molecular changes in other areas such as the prefrontal cortex, amygdala, and VTA, and (d) what combination of techniques are the most promising for the future of the investigation of gene regulation in this circuitry.