Michael Leon - US grants

The goal of this research is to understand the physiological basis of mammalian maternal behavior. The proposed research is focused on a model of mother-young interactions which implicates maternal temperature as the factor limiting the duration of contact between mothers and their young. The research constitutes the first analysis of the physiological basis for moment-to-moment changes in mammalian maternal behavior. The proposed experiments test the specific predictions of the model by continuously recording both maternal physiology and behavior. The first part of the proposal concerns the acute elevation in maternal temperature that limits maternal contact bouts. The role of the acute elevation in maternal brain temperature in limiting contact bout duration under different natural variations in maternal heat load will be determined. The role of REM sleep in altering the vulnerability of mothers to acute hyperthermia during pup contact will then be investigated. The second part of the proposal concerns the role that hormones play in chronically elevating the vulnerability of dams to the acute hyperthermia that limits contact bout duration. The model proposes that progesterone and corticosterone work in concert to elevate the chronic heat load of mothers, thereby making them vulnerable to acute hyperthermia during contact bouts. The specific proposal that progesterone elevates the body temperature that mother rats defend will be evaluated. The role of corticosterone in elevating maternal heat load will then be determined.

We have found that postnatal experience with an odor leads to an enhanced uptake of 14C 2-deoxyglucose in specific glomeruli in the olfactory bulb of young rats. We will investigate this phenomenon in several ways. We are first interested in the importance of the circumstances under which the odor is experienced for the induction of the enhanced neural response. We will then investigate the mechanism by which the neural alterations occur. Specifically, we will test the efficacy of different odors and odor concentrations. We will then determine the temporal parameters of the experience in the development and retention of the enhanced neural response. We will then determine the importance if maternal presence in inducing the neural response. The ability of odor exposure in different learning situations will then be assessed. The mechanisms that will be tested include: development of a differentially projecting olfactory field, differential glomerular size, differential mitral cell survival and differential mitral cell dentritic arborization. The thermal basis of mother-young interactions in Norway rats will also be investigated during the next year. Specifically, we will investigate the importance of the rise in brain temperature that we have found to be associated with the termination of the contact bouts between mother and litter. We will first determine the brain temperature response when mothers are faced with potentially different heat loads in different ambient temperatures, with litters of different sizes, with older litters, as well as with nests. We will also determine whether the mothers lose control of their brain temperature when they enter a period of REM sleep while they are with their pups. We will then determine the importance of steroid hormones in elevating maternal thermal set point for elevating maternal heat production and for suppressing heat loss.

The goal of this research program is to understand the role of early experience in changing the subsequent responses of the mammalian brain to environmental stimuli. The research is focused on our finding that early experience by Norway rat young with a particular odor not only induces a behavioral prefernce for that odor, but induces an enhanced response in the olfactory system of the young to that same odor. The pups normally develop an attraction to the odor of their mother during early life, allowing the young to maintain contact with their parent during a time in their lives when they are mobile enough to leave the maternal nest. The enhanced olfactory bulb response has been observed with the use of a technique that allows a comparison of the differential uptake of 14C 2-deoxyglucose, a glucose analogue that remains in the neurons in an incompletely metabolized state. This measure reflects what is most probably differential neural activity. We will first define the conditions under which the potentiated response occurs and then examine several possibilities for the structural changes underlying this phenomenon.

This is a proposal for a continuation of an ADAMHA Research Scientist Development Award in which I propose to examine the role of thermal and olfactory interactions between mother and young. During the term of the award, I will develop more expertise in neurobiological approaches to the study of these behavioral interactions in order to extend my analysis of these problems in that direction. The research should yield data concerning the means by which early experiences affect neural, and thereby, behavioral development. This study may be among the first to explore the ways in which normal variation in experiences produces the neural changes that underlie individual differences in physiology and behavior. In addition, we will examine the importance of stimulation-induced changes in brain temperature for mediating the ability to learn during early life. Finally, we will investigate the role of maternal brain temperature changes for determining the pattern of mother-young interactions. This research program is aimed to investigate the ways that mother-young interactions are controlled and how such interactions affect the developing brain and its consequent behavioral responses.

olfactory stimulus; animal developmental psychology; early experience; developmental neurobiology; neuroanatomy; olfactory lobe; laboratory rat;

This award provides funds to the Department of Psychology at the University of California, Irvine to continue to sponsor an undergraduate research experience in Neural Plasticity and Brain Function. The highly successful program originated with a one- week undergraduate Summer Institute that was expanded last year with NSF funding. The eight-week summer program begins with a one-week lecture/seminar series designed to introduce the students to the field and to the research of the various faculty. This is followed by an active research experience in faculty laboratories on a defined project tailored to the goals of students and their advisors. Throughout this period, students continue to interact with faculty in both formal and informal meetings. At the end of the program, students present their findings to other students in the Department and to the faculty.

detoxification; olfactions; receptor; neurotoxins; limbic system; aging; enzyme mechanism; free radicals; weanling animal; mature animal; animal old age; laboratory rat;

The goal of this revised proposal is to understand the neurobiology of early learning. Functional changes have been revealed in the olfactory bulb as a consequence of early preference conditioning by means of a technique that records the differential uptake of a glucose analogue. The proposed studies will determine both the precise nature of the cellular changes underlying this increase in metabolism and the specific cells in which these changes are occurring. Glucose pathways will be studied after early olfactory conditioning using three techniques. The first will involve the use of quantitative histochemistry to identify differential metabolic enzyme activity. The second will involve the use of differentially labelled glucose to determine the activation of different metabolic pathways as a consequence of early learning. The third technique will isolate those cells that are particularly active to response to a learned cue by studying the uptake of a glucose analogue, using a high-resolution procedure. The specificity of the cellular pathways, as well as the type of cell involved in the phenomenon will be identified.

We propose to continue our integrated investigation of the neurobiology of early olfactory learning. Our focus will be on the neurotransmitter and neurotrophic mechanisms involved in the neurobehavioral changes within the rat olfactory bulb induced by early olfactory learning. Dr. Leon will address the role of noradrenaline in the formation and expression of early olfactory learning by determining: the response of olfactory bulb neurons to noradrenergic stimulation; the possibility of a transient expression of beta noradrenergic receptors in the developing bulb; the role of alpha noradrenergic receptors in the expression of the neurobehavioral response; the function of the conditioned increase in bulb noradrenaline; the mechanism underlying the termination of the sensitive period; whether noradrenaline is a common critical factor for different reinforcing stimulation; whether "overstimulation" blocking of early olfactory learning is due to changes in noradrenergic responses. Dr. Gall will use the in situ hybridization technique to determine: the spatial localization within the olfactory bulb for both immediate early genes in response to odors presented under different stimulus conditions; the response to olfactory preference training; the dual response to novel and learned olfactory cues; the possible sharpening of the bulb response during development; the effects of early olfactory deprivation on subsequent olfactory bulb responses; whether changes in the immediate early genes can be linked to cellular changes in the expression of preproenkephalin and tyrosine hydroxylase. Dr. Neve will examine the role of GAP-43 in the early dopamine response of the bulb by: analyzing developing bulb for the expression of both GAP-43 and protein kinase C, a potential factor in the stabilization of GAP-43 mRNA; determining whether there is a change in GAP-43 and protein kinase C after early olfactory learning; changing the expression of GAP-43 in the bulb with a recombinant virus, then determining the change in dopamine release in response to early olfactory preference training; constructing transgenic mice that have a mutant form of GAP-43 to suppress dopamine release and then determining their response to olfactory preference training.

The goal of this research program is to understand the neurobiology of early learning. To date, large metabolic, morphological and neurophysiological changes have been described as a consequence of such learning. In the proposed research, we will investigate the mechanism for a striking increase in the number of cells in the region of the rat olfactory bulb that is involved in the processing of the learned odor. Five alternative hypotheses are described to account for the increase in cell number as a function of early learning. An increase in cell production, a decrease in cell death, and a change in the patterns of cells migration are possibilities that will be evaluated by differential labelling of dividing cells after different time periods during development. An increase in the size of the dendritic arbors that may attract an increased number of migrating cells will be determined with the use of vital dyes. Finally, an increase in the concentration of the radial glia, on which the neural population migrates, or an increase in a focal astrocyte population will be determined with immunohistological techniques. All of these techniques will be combined with a technique to isolate focal regions of increased metabolic activity that are characteristic of different olfactory cues. In these ways we hope to identify the mechanism that underlies the reorganization of olfactory bulb circuitry during early life.

biomedical equipment purchase;

The goal of this research project is to understand the neural and cognitive impairments imposed by perinatal cocaine exposure. We will use a unique, well-established model system that may allow us to gain an increased understanding of the role of cocaine action on the developing brain and cognitive behavior. Specifically, we have reported large metabolic, neuropharmacological, morphological and neurophysiological changes in young rats as a consequence of early olfactory preference conditioning, a form of learning that normally occurs during both human and rat development These established neural features should allow us to identify and understand the basis for any impairments induced by early cocaine exposure.

This award provides funds to the Department of Psychobiology at the University of California, Irvine to continue to sponsor a successful undergraduate research experience in Neural Plasticity and Brain Function. The program originated with a one-week undergraduate Summer Institute that was expanded with NSF funding. The eight-week summer program begins with a one-week lecture/seminar series designed to introduce the students to the field and to the research of the various faculty. This is followed by an active research experience in faculty laboratories on a defined project tailored to the goals of the student and their advisors. Throughout this period, students continue to interact with faculty in both formal and informal meetings. At the end of the program, students present their findings to other students in the Department and to the faculty.

This award provides funds to the Department of Psychology at the University of California, Irvine to continue to sponsor an undergraduate research experience in Neural Plasticity and Brain Function. The highly successful program originated with a one-week undergraduate Summer Institute that was expanded last year with NSF funding. The eight- week summer program begins with a one-week lecture/seminar series designed to introduce the students to the field and to the research of the various faculty. This is followed by an active research experience in faculty laboratories on a defined project tailored to the goals of students and their advisors. Throughout this period, students continue to interact with faculty in both formal and informal meetings. At the end of the program, students present their findings to other students in the Department and to the faculty.

DESCRIPTION: Seven experiments are described in this proposal to study neural activity in the olfactory bulb as the basis of stimulus coding in the olfactory system. Preliminary data indicates that isoamyl acetate and isoamyl butyrate activate the same regions of the olfactory bulb glomerular layer, but that these regions of the olfactory bulb are not activated by ethyl acetate of ethyl butyrate. This finding suggests that isoamyl may be an olfactory "primitive," "odotype," or "epitope." Experiment 1 will determine if isoamyl propionate also activates these same regions and the activation pattern by this odorant will be compared to ethyl propionate. A second part of this experiment will determine if the branched structure or number of hydrocarbons on the "O-side" of the ester bond lead to differential activation of these regions. Subsequent experiments address issues such as, is the same glomerulus activated by isoamyl acetate and isoamyl butyrate (Exp. 2) ; what is the influence of hydrophobicity on patterns of 2DG uptake (Exp.3); what is the effect of carbon chain length and terminal functional group on 2DG foci (Exp.4); what is the effect of the terminal functional group of straight-chain alphatic compounds of 6 and 8 carbons on the pattern of 2DG uptake (Exp. 5); 2DG uptake patterns resulting from stimulation with odorless compounds (Exp. 6); and changes in 2DG uptake patterns as a function of changes in concentration of stimulating compounds (Exp. 7).

DESCRIPTION: A change in early olfactory experience can have profound affects on the number of neurons that survive during development. Enhanced sensory experience during early post-natal development can induce an increase in olfactory bulb neurons, and early olfactory restriction stimulates cell death in a population of olfactory bulb neurons. Thus, changes in sensory stimulation may induce or suppress apoptosis during development and influence the number of neurons in target tissues. In other systems, Bcl-2 has been shown to be a protein that blocks apoptotic cell death, and in the olfactory bulk, the mRNA for BCL-2 is elevated in oder-restricted postnatal rat olfactory bulbs. The proposed experiments will test the hypothesis that there is an increase in apoptotic cell death in odor-restricted rat and mouse pups. Other experiments will test the hypothesis that the Bcl-2 protein plays a critical role in either protecting or promoting normal cell death during development and increased cell death induced by early olfactory restriction. Additional experiments will test the hypothesis that a reduction in cell death during enhanced early olfactory experience occurs during a mechanism mediated by the Bcl-2 protein family.

Through FOCUS (Faculty Outreach Collaborations Uniting Scientists, Students and Schools), the University of California, Irvine (UCI) unites the efforts of mathematics, science, education and research library faculty and staff with educators from local community colleges, school districts and local educational support agencies. The partnership builds on prior established relationships between UCI and three high-need California school districts: Compton Unified, Santa Ana Unified and the Westside of Newport-Mesa Unified. These schools serve 106,695 students of whom 82% are Hispanic and 11% are African American.

The work of FOCUS will include the construction of a "future teacher highway" to increase the number, quality and diversity of preK-12 teachers of mathematics and science; involvement of math and science professionals in "Discipline Dialogues" that cross segmental boundaries, and the creation of systemic reform in the professional development of preK-12 teachers of mathematics and science. FOCUS will ultimately impact the number of new mathematics and science teachers; the number of high school students prepared for and enrolled in advanced mathematics and science coursework; the achievement gap between the general student population and English Language Learners; and the number of higher education faculty engaged in efforts with preK-12 educational systems.

DESCRIPTION (provided by applicant): The goal of this proposal is to use direct experimental approaches to test the predictions of two models of olfactory coding. One model suggests that many low-specificity neural elements represent each odorant and the other model suggests that fewer, more specific olfactory receptors combine to convey information regarding multiple molecular features to characterize each odorant. The low-specificity model predicts no effect of any lesion on the coding of any odorant, while the combinatorial model predicts specific deficits with focal lesions. To test these predictions, we will determine the effects of focal olfactory bulb lesions on the recognition, discrimination, and detection of specific odorants. To that end, our laboratory has been studying the glomerular activity evoked by a large number of systematically differing odorants and we have characterized the response domains that combine to form their unique focal representations. Importantly, we have identified odorant pairs that evoke glomerular patterns differing only by a single response domain. Guided by the locations of these domains, we propose to lesion specific areas of focal glomerular activity of rats and we then propose to apply behavioral tests to reveal their resulting odor perceptions. These experiments should help us understand the mechanism by which the olfactory nervous system codes complex stimuli.

DESCRIPTION (provided by applicant): Our goal is to use neuroinformatics to help resolve the conflicting findings from which two models of olfactory coding have emerged. One model proposes that very many low-specificity neural responses represent each odorant and the other model suggests that fewer, more specific olfactory receptors bind to particular molecular features and that the combination of these specific responses characterizes each odorant. Since much of the data supporting the low-specificity model has been collected without regard for the exquisite spatial heterogeneity of the olfactory system, it is possible that the differences in conclusions could be resolved if the distinct types of data that are collected by various laboratories were placed into spatial register with one another. To that end, we have been building an archive of the spatial patterns of glomerular responses evoked by a wide range of odorants, and we have been able to test hypotheses regarding strategies of olfactory coding by calculating homologies across glomerular-layer response patterns. To facilitate our analytical task, and to make it feasible for others to place their data in register with this odorant response archive, we propose to continue to develop analytical and visualization software for olfactory bulb data. We also propose to extend this approach to both the olfactory epithelium and olfactory cortex to be able to understand both the initial coding and synthetic levels of the olfactory system. These efforts will be freely available via the web site on which our olfactory activity archive is posted. We propose to improve the site by incorporating meta-data, as well as data from labs using other species and other types of data, such as lesions and neurophysiological data that can be located in space. Finally, the wide range of odorants that we must test to capture a sense of the system also will necessitate the use of an informatics approach to allow us to test hypotheses regarding the complex means by which chemical structure is represented in the system. The combination of these approaches should help resolve the differences between the conflicting models of olfactory coding.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Enriched sensorimotor experiences greatly enhance the ability of animals to withstand a wide range of neurological challenges, and we considered the possibility that humans challenged by autism would have similar gains in functionality following exposure to increased olfactory and tactile stimulation. Indeed, preliminary studies have shown that after being exposed to daily sensory enhancement, autistic individuals experienced measurable, significant improvement over a wide range of their symptoms. The aim of this project is to test the efficacy of this autism treatment with a randomized controlled trial.