Peter C. Brunjes - US grants

The experiments proposed examine the control of cell proliferation and death in the developing olfactory system. The olfactory system has many desirable characteristics for studies of the mechanisms of neural maturation. It is highly organized, with clear lamination and a well-studied wiring diagram, facilitating quantitative examinations and making subtle alterations relatively ease to discern. Understanding cell proliferation is important because this fundamental step provides the neural and glial elements from which the brain in constructed. Understanding cell death is equally as important as it is the process that ultimately refines the connections made during early life. While the two processes are crucial for the formation of any neural region, they are especially important for an understanding of the organization of the olfactory system, as both olfactory receptor cells and central elements are constantly formed and lost throughout life. The proposed experiments examine cell proliferation and death in the olfactory mucosa, which contains the olfactory sensory cells, the olfactory bulb, which is the first-order processing station in the central nervous system, and the subventricular zone/rostral migratory stream, a region that supplies cells to the bulb. The specific questions we seek to answer include: 1) Olfactory mucosa: a) Since reduced function can decrease cell production, can enhanced activity increase it? b) How important is cell death during early development? Can it be regulated by activity as well? 2) Central Structures a) Can activity or chemical factors that regulate cell production in other areas affect the process here? b) Are there differences in the fate of cell born at different times during early life? c) Can these fates be manipulated by changing the functional state of the olfactory bulb?

Olfaction is an important sense for recognition, particularly for young mammals that often are born before the eyes or ears are fully functional. Understanding how olfactory information is delivered to and handled by the central nervous system requires knowing the anatomical organization of the projections from the nose to the olfactory central targets, including olfactory cortex. The central olfactory system is highly organized, with clear layering, distinctive cell types, and well-studied projection areas. One approach to clarify how the system works is to observe how the functional circuits develop. Marsupials, such as the opossum, have a very slow early growth after birth, and so provide a particularly useful model system. This project will use anatomical techniques to trace the development of olfactory connections as they form, and to see how functional manipulations affect the early interactions which specify formation of the olfactory system. Results from this model system will be important to developmental biology and to systems neuroscience as well as to understanding brain organization and sensory processing.

[unreadable] DESCRIPTION (provided by applicant): Olfactory sensory neurons in the nasal cavity send odor information to the olfactory bulb, the first central relay in this chemosensory system. Mitral and tufted cells in the bulb then transmit the information to the anterior olfactory nucleus (AON) and piriform cortex (PC). The AON plays a crucial role in the processing of olfactory stimuli: it provides feedforward information from the bulb to the PC, and is involved in the retrograde flow of information from the cortex to the bulb. Importantly, it also serves as the point of intercommunication between the left and right olfactory bulbs and cortices. As such, it plays a fundamental role in the processing olfactory information. Indeed, it will be impossible to understand the function of the olfactory forebrain without greater insight into the circuitry and function of the AON. The proposed studies focus on a single concept: understanding the organization of the AON. The proposed work will a) uncover the fine-scale morphology of the afferent inputs from the olfactory bulb, b) examine possible olfactory coding strategies in the AON, c) demonstrate the intrinsic organization and connections of the region, and d) elucidate differences in regional output patterns. Each of the studies examines interlocking but independent aspects of the problem. Furthermore, each study uses state-of-the-art techniques, correlating refined morphological analyses with broader functional studies. The goal is to begin to understand variations in regional organization and investigate the possibility of the existence of different neuronal phenotypes. The results will make the area accessible for further study from a molecular biological perspective. The information we gather will be important for many reasons, including our ability to understand and model olfactory function. By gathering fundamental data on the number of AON cells each bulb afferent contacts, what synaptic patterns exist within the AON, and whether output pathways diverge or converge, we will begin to understand the larger circuit that comprises the olfactory system. Relevance: a) A more complete understanding of the AON also has clinical relevance as there are indications that pathological changes in the region occur in Alzheimer's and Parkinson's diseases, suggesting that changes in the AON may significantly contribute to the well-documented deficits in olfactory function that occurs in aging, b) Sensory systems are crucial for humans to navigate through the world, interact and learn. The present research will shed substantial light on this process. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Sensory systems are the means by which people receive the information they need to navigate about the world. Of all of the major modalities olfaction is perhaps the least understood, despite the fact that it plays many important roles in our lives. The work described in the present proposal is designed to examine carefully a very important region in the central olfactory pathways. The anterior olfactory nucleus (AON) has synaptic connections at nearly every point of information processing on both the ipsilateral and contralateral side of the olfactory regions of the forebrain. As such, it is capable of driving or modulating the synaptic activity of the entire central olfactory system. Nevertheless, it has been virtually ignored compared with studies of the olfactory mucosa, bulb and piriform cortex. The proposed research will continue our examination of the AON's structure and function. The work has two major foci. First, while the region may have one name, it is becoming obvious that it contains several different processing areas and is therefore more complicated than initially believed. The primary goal of this research is to define functional subregions in the AON to build fundamental information about its organization. Second, the existence of crossed connections in the olfactory system has received very little attention. In nearly every sensory, motor and neocortical system crossed connections are important in facilitating complex information processing and the work examining them has led to enormous advances in understanding system function. Understanding the contributions of interhemispheric connections in the olfactory system will doubtlessly also lead to more a sophisticated view of the mechanisms of odor perception.