Howard Casey Cromwell, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Our long-term objective is to advance the understanding of neurobehavioral systems and in particular, how neural systems produce goal-directed action. Goal-directed action is thought to be guided by a neural representation of the goal object. For a representation to guide the animal efficiently, it should access and use information concerning the internal state of the animal. The specific aim of the application is to study how reward devaluation influences striatal activity. The aim will be completed using in vivo electrophysiological recording of single striatal neurons while animals under different states of food satiation and deprivation perform instrumental discrimination tasks for different rewards. We focus on the striatum because this brain structure originally thought to be involved in general movement initiation and execution, is now believed to be involved in higher motor processing of reward information and production of goal- directed action. We believe the striatum is critical site of convergence for information regarding both external characteristics of the outcome with updates of the current internal state (i.e. hunger) to be used for motor output selection. A key component of the protocol is that we will utilize different prefeeding regimens to examine the different degrees of influence that internal state fluctuations can have upon behavior-related activity based on the similarity the prefeeding has with the expected reward outcome, these include 1) sensory-specific satiety. Here we prefeed the animal with one of the available outcomes in the testing situation 2) general satiety. Here we prefeed the animal with the food item normally delivered in the home cage setting and 3) food restricted with no prefeeding regimen. Differences in neural activity between the three prefeeding conditions for motor-related neural responses will support our hypothesis that behavior-related activity in the striatum gains access to and is influenced by alterations in motivational systems. We expect that the closer the relationship between the internal state change and learned properties of the available outcome, the greater the influence by these internal state deviations. The results have great implications for our understanding of basic mental operations that guide daily actions and in the treatment of mental health disorders characterized by emotional and behavior dysfunction. If we can pinpoint the different interactive influences at the neurobehavioral level that produce appropriate goal-directed action, then we can develop better treatments targeting pertinent neurobehavioral systems and more specifically, the intrinsic, integrative neural operations relevant to emotional and behavioral disorders. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant):This application's broad long-term objectives are to gain an understanding for the subtle yet potentially devastating effects that polychlorinated biphenyls (PCBs) have on psychologicalfunctions. PCBs are found everywhere in the world located in the global water supply, air and soil.Developing countries still utilize this potent endocrine disruptor in manufacturing and industry.The United States was forced to end all synthesis and use of the compound in the 1970s, but thetoxin remains ubiquitous, and the effects of exposure to crucial psychological processes during development are unknown. We believe that if we can understand the relationship between PCB [unreadable] Exposure and psychological development, we can work to remove the effects by environmental,nutritional and behavioral means. Our specific aims are to determine exactly what kinds of changes occur in social interaction after perinatal exposure. Our preliminary results stronglysupport an impact of low to moderate PCB on social behavioral expression in both the young neonate and juvenile animal. We intend to utilize three well established social behavioral paradigms to reach these aims: 1) Social Recognition Test- a test for social memories of young rats that examines how sensory cues are held in storage and subsequently direct approach behavior, 2) Social Play Behavior-A measure for the level of social interaction between juveniles and 3) Social Port Investigation-A measure of social-directed behavior in young adult rats. In addition, we will examine the relative environmental-genetic contributions on the social behavioral effects with a cross-fostering design and critically, examine general motor function in the animals to better grasp how our changes in social function relate to motoric alteration after PCB exposure. All of these paradigms 1) contain high reliability between animal models and are thought to be valid measures of social-directed behavior, 2) have been shown to reveal behavioral and physiological relationships essential to social development and 3) provide innovative profiles of social function that span development from neonate to young adulthood. Finally, our interdisciplinary team will investigate the relationship between these behavioral functions and endocrine status, specifically analyzing changes in neurohormones purportedly involved in social function such as oxytocin and vasopressin. Our ultimate mission merges with the National [unreadable] Institute of Child Health and Development in that we are interested in optimizing patterns of psychological organization and reducing in the influence of harmful factors like teratogens from the developmental process. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): One of the defining characteristics of mental disease is the loss of behavioral control and the rise of impulsiveness, poor decision making and a disconnect between what individuals do and what they want to do. There is a perceptive and straightforward measure or 'effect'that can be used to examine fundamental psychological processes involved in behavioral regulation of making choices and developing preferences. The relative reward effect (RRE) is observed as a neural or behavioral influence from past or future outcomes on the present outcome. It is a way of exploring primary outcome comparisons that is highly conserved across diverse organisms. It has been studied by numerous behavioral scientists, and the growing neuroscience literature supports involvement of the striatum and amygdala. Our own previous studies found significant RREs on neural activity in the striatum;however, we left the question open as to how these effects vary within this diverse brain structure. The dorsal and ventral striatum receive dramatically different inputs and are thought to be involved in distinct functions. Additionally, we intend to examine how the RRE varies between the striatum and amygdala- two interconnected brain regions involved in forming links between emotional states and motor output. We will use the most advanced neurophysiological methods to record single units in behaving animals during performance in relatively simple, single reward environments and more complex mixed reward environments. Comparisons on neural and behavioral data between these simple and more complex situations will be completed. Moreover, we include a study with inactivation of amygdala preceding recording striatal neural responses. This method is an innovative and sensitive way to explore the reliance between these two brain areas in processing relative properties of events. Our long-term goal is to decipher how the striatum and its diverse inputs distribute and compute reward information to produce appropriate behavior. The findings will open the way to understand how information flow breaks down in mental illness causing emotional and behavioral problems. The striatum and amygdala have both been found to be dysregulated in mental illness. Despite these major advances in understanding, there is limited knowledge for how outcome information is processed differently during pathological states and overall, what functional consequence to attribute to alterations in brain activity related to behavior. Data acquired will provide new ways to think about these issues and expand the study of neural processing related to mental health which is an essential part of the National Institute of Mental Health mission. The projects provide a rich and engaging environment for training students in methods that will be part of behavioral neuroscience in the long-term. New jobs will be created and careers fostered for young people eager to work on the biology of mental illness. PUBLIC HEALTH RELEVANCE: The project contains extensive relevance to mental health in that it is an investigation of how the brain makes comparisons over time and how these comparisons lead to better choices. This is an ubiquitous process and when done adaptively, it leads to positive affect, appropriate choices and healthy mental states. Delineating the details for how brain areas like the striatum and amygdala are involved in these fundamental processes opens the door to studying how the same abilities become disabled in mental illness and how new therapies can reinstate adaptive brain function and behavior.