Alev Erisir, Ph.D. - US grants

Developmental visual cortex plasticity, the susceptibility of the brain to be modified by the environmental changes during postnatal development, is deemed representative of many life-sustaining neural functions such as learning, memory, sensory plasticity and aging. Furthermore, this process underlies the formation of normal neural connections, which is assailed by conditions that prevent normal sensory stimulation, including strabismus and childhood cataract. A research plan is proposed to study the ultastructural basis of developmental plasticity, combining tract-tracing, immunocytochemistry and electron microscopy techniques for qualitative and quantitative ultrastructural analysis. The long term objective of this research is to understand the roles of the glutamate and the cholinergic receptors in activity dependent synaptic modifications that underlie the critical period of visual plasticity. A newly developed technique will be used to dually identify developing thalamocortical(TC) axons and the chemically specified target sites to determine afferent-target relationships between thalamic terminals and the neurotransmitter receptors. Specifically, 1) the morphological properties of sites contacted by thalamocortical axons, and the GABA content of the targets, 2) the connection pattern of TC axons on NMDA, metabotropic and AMPA type glutamate receptors, and 3) the relationships between TC axons and the muscarinic receptors, will be examined in visual cortex layer IV and the subplate, before, during and after the critical period of visual plasticity. The specific goals of the proposed research address the identification of transient cellular mechanisms that lead to refinement and segregation of thalamic axons into ocular dominance columns, and to termination of early cortical plasticity by synaptic consolidation. The knowledge on how the neural proteins that are implicated in plasticity are structurally utilized by neural circuitry may provide insights in understanding the mechanisms of normal brain function as well as the conditions result from the sensory deprivation.

SUBPROJECT ABSTRACT NOT AVAILABLE

The scope of this project is to understand how physiological changes induced by emotionally arousing events improve the degree to which affective experiences are stored into long term memory. This research is driven by the hypothesis that the vagus nerve and brainstem neurons that they synapse upon serve as an interface between autonomic arousal, produced by hormone secretion in the periphery, and accompanying changes in neurotransmitter release in the brain that then accelerates memory storage processing. The project will obtain electrophysiological recordings from the vagus nerve to assess how fluctuations in visceral signals regulate the release of the neurotransmitter norepinephrine in brain areas where affective and contextual components of newly learned events are encoded. Other experiments will use behavioral, neurochemical and immunocytochemical endpoints to identify how experiences of an emotional nature increase central noradrenergic transmission. They will also identify how potentiated norepineprhine initiates intracellular signaling cascades that convert novel experiences from labile traces into more permanent long term memory. The overall project is expected to reveal neural and molecular systems that permit arousal-induced changes in peripheral autonomic activity to regulate the strength in which new events are encoded into memory. This project will also provide extensive research training for undergraduate students majoring in Psychology, Cognitive Science and Neuroscience as well as provide an avenue for undergraduates to develop independent thesis projects prior to graduation. These types of opportunities have proven beneficial in not only training the next generation of behavioral neuroscientists, but also in ensuring their entry into productive graduate psychology or neuroscience graduate programs.

The malleability of neuronal circuits by environmental conditions is a crucial property in developing brain in fostering adaptive development of perceptual and behavioral faculties. This is particularly obvious in sensory systems. Brainstem taste pathway is potentially a suitable model system to understand competitive interactions and activity dependent reorganization, two possible mechanisms of neuronal malleability, also termed plasticity. Understanding the mechanisms of plasticity is a major step in developing strategies to avoid developmental defects, and to foster normal development of the brain function. A research program is designed to determine whether taste circuits have cellular and molecular components that may allow sensory systems to undergo changes during deviations from normal environmental stimuli. The first study aims to obtain evidence for whether distinct gustatory nerves converge upon individual neurons, using a combination of anterograde and retrograde tract-tracing anatomy, confocal microscopy using multiple markers and electron microscopy. How and when in development such input convergences occur will have important outcomes for our understanding of the role of competitive interactions in plasticity. The second aim of the proposed project will examine fine structure and glutamate receptor signature of axons that are destined to withdraw during development of taste pathways. The potential findings of the proposed experiments shall provide novel information on target selectivity of two gustatory nerves, as well as underlining gustatory afferent development as a model to study developmental plasticity and lifelong synaptic stability.

? DESCRIPTION (provided by applicant): This is an application to continue research originally started in 2001, and expanded into a longitudinal study, known as the Virginia Cognitive Aging Project (VCAP), in 2005. Over 2,300 adults 18 - 95 years old have now completed at least two longitudinal occasions, with an average of 2.7 occasions and an average time in study of 5.1 years. The research proposed in the next funding period will extend the investigation of short-term longitudinal change in a broad variety of cognitive measures, with particular emphasis on adults under the age of 80. Although previous studies have found little or no cognitive change in longitudinal comparisons involving young and middle-aged adults, this research employs three methodological innovations, variable retest intervals, measurement bursts at each occasion, and continuous recruitment of new participants, that help distinguish age effects from experience (retest) effects, and that increase sensitivity to detect change by taking into account normal short-term variability in performance. Among the primary questions to be investigated are when does normal age-related cognitive change begin, the degree to which changes in different cognitive variables are independent of one another at different periods in adulthood, the role of prior test experience on the direction and magnitude of cognitive change at different ages, the degree to which factors such as one's cognitive or physical lifestyle moderate the amount of age-related change in different cognitive abilities at various periods in adulthood, and how early can normal and pathological trajectories of cognitive aging be distinguished. Specific aims during the next grant period are to: (1) Expand the characterization of normal cognitive aging across the range from about 18 to 80 years old; (2) Extend the investigation of the role of experience effects on cognitive change; (3) Investigate the structure and nature of cognitive change across different levels of analysis and across a wide range of ages; and (4) Increase sensitivity of VCAP tests to detect early stages of cognitive pathology among VCAP participants.

ABSTRACT Perceptual decision-making is a fundamental cognitive ability that is vital to healthy, daily functioning and is impaired in many diseases. Although many brain regions are known to be involved, there is no clear brain-wide model of how perceptual decisions are formed and executed and the underlying circuit mechanisms are still largely unknown. Here, a team of investigators propose a series of experiments that will use behavioral measures, imaging, physiology, circuit dissection, and computational modeling to study how the midbrain superior colliculus (SC) participates in visual decision-making. Specifically, this new team of investigators will probe the contribution of two SC neuronal cell types, wide field vertical (WFV) cells in the visuosensory layers and predorsal bundle (PDB) cells in the motor layers. These experiments will be done in mice and tree shrews, to reveal the underlying circuits and computational principles across species and to lay the foundation for future experiments designed to dissect decision-making circuits in primates. In Aim 1, the investigators will establish and perform psychophysical experiments to assess perceptual decision-making in both species. The behavioral data will be fitted with computational models to arbitrate between different theories of decision-making. In Aim 2, two photon calcium imaging and/or physiological recording will be performed in mice and tree shrews to determine the activity of WFV and PDB neurons during the psychophysical measures established in Aim 1. In addition, WFV and PDB neurons will be silenced optogenetically during the behavioral tasks to reveal their specific roles in decision-making. In Aim 3, the investigators will use intersectional monosynaptic viral tracing techniques, multiplexed peroxidase labeling for confocal and ultrastructural analysis of synaptic connections and and optogenetics-assisted brain slice recording to investigate the intrinsic and extrinsic circuits that link WFV and PDB cells. Together, these experiments will generate novel knowledge of the synapse to circuit mechanisms underlying perceptual decision-making, and provide technical and theoretical foundations for future mechanistic studies of cognitive function in higher mammalian species directly relevant to humans.