2013 — 2017 |
Medalla, Maria |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Physiology and Structure of Prefrontal Projections to Memory and Motor Circuits @ Boston University Medical Campus
DESCRIPTION (provided by applicant): The goal of this project is to understand the cellular pathway basis of prefrontal executive control of memory and motor information, for using past events to guide future action. Due to its strong reciprocal connections with the medial temporal entorhinal (EC) and premotor cortices (PMC), the medial prefrontal anterior cingulate cortex (ACC) is strategically positioned to serve as the interface between 'long-term memory' and 'motor planning' systems. The ACC coordinates activity-thereby gating information flow-within EC and PMC, which have distinctive anatomical circuits with unique network oscillatory dynamics. How the ACC regulates these two areas is largely unknown. While a number of neuromodulators influence cortical network dynamics, this project will focus on acetylcholine (ACh) due to its critical role in learning and memory. The overall hypothesis of this project is tht ACC projection neurons to EC and to PMC possess distinct intrinsic, synaptic, and cholinergic neuromodulatory properties that underlie differential control of their postsynaptic targets. Dr. Medalla will test this hypothesis by combining neuroanatomical tract-tracing with in vitro whole-cell patch-clamp recording and intracellular filling of retrogradely-labeled neurons in slices prepared from adult rhesus monkeys (Macaca mulatta). Structural analyses of neurons from which recordings are obtained will be conducted using high-resolution laser-scanning confocal imaging and electron microscopy of filled dendrites. This project will lead to a better understanding of prefrontal cortical microcircuitry and mechanisms underlying executive control of learning and memory systems, and the misattribution of context and drive for goal-directed action in depression and other mood and anxiety disorders. To date Dr. Medalla's research endeavors have been dedicated to understanding the structural synaptic pathway basis of functional specialization in the primate prefrontal cortex, using tract-tracing and electron microscopic techniques. The proposed project will use Dr. Medalla's experience in neuroanatomy combined with current training in electrophysiological techniques to address some outstanding issues in prefrontal circuitry, under the mentorship of Dr. Jennifer Luebke, one of the few world experts in whole-cell patch clamp in vitro slice recording techniques in primates. The project will also benefit from the support of collaborators, Dr. Alan Peters, a renowned expert in electron microscopy and cortical ultrastructure, and Dr. Douglas Rosene, an expert in primate neuroanatomy. Drs. Michael Hasselmo and Howard Eichenbaum will serve as consultants to this project; their expertise in learning and memory as well as cholinergic modulation of limbic and cortical systems will be invaluable during the implementation of these experiments. In the mentored phase, studies will focus on the intrinsic, firing and resonance properties of ACC projection neurons to EC and PMC, and their modulation by ACh. In the independent phase, studies will address the cholinergic modulation of excitatory and inhibitory synaptic responses and the structure of synapses onto these projection neurons, and the interaction EC and PMC pathways within ACC using dual patch-clamp recording and bi-directional pathway tracing. The work from the proposed studies will provide Dr. Medalla with data for high quality publications as well as preliminary data for formulating a competitive application for an R01, which will be centered on further studies of the structure and function of prefrontal cortical microcircuitry. The work in the proposed studies will be conducted at Boston University, an institution with a rich history of well-established multidisciplinary research in th field of Neuroscience. In particular, the Department of Anatomy and Neurobiology at the School of Medicine is a collaborative scientific environment with a long- standing history of seminal work on the structure and function of the primate brain. The main experiments in this proposal will be conducted in the Luebke Laboratory, located at the heart of the Medical Campus Evans Biomedical Research Center, which is fully equipped for preparation and electrophysiologic recording in acute and organotypic cortical slices and tissue cell cultures. Other aspects of the proposed experiments will be conducted in collaboration with the Rosene Laboratory for primate brain surgery and tissue processing, and the Peters Laboratory for examining tissue under the electron microscope. The confocal imaging for the proposed studies will be conducted in the Biology Imaging Core at the Life Science and Engineering Building, managed by Dr. Todd Blute, equipped with a state-of-the art Zeiss-510 laser-scanning confocal microscope. Through its extensive academic opportunities, resources, and state-of-the art facilities, BU provides an ideal environment for the mentoring and career development of Dr. Medalla, and the execution of the research goals in the proposed project. These resources at BU will facilitate the training of Dr. Medalla to become an expert electrophysiologist and initiate her own independent cutting-edge research program that investigates prefrontal pathway-specific interactions with receptors, channels, and diverse types of inhibitory neurons, using a structure-function framework at the synaptic, cellular and network levels.
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0.915 |
2019 — 2021 |
Medalla, Maria |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Circuit Structure and Dynamics in Prefrontal-Limbic Networks @ Boston University Medical Campus
PROJECT ABSTRACT The lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC) in primates interact with each other, as key components of the executive control network. However, these areas participate in distinct extrinsic circuits and exhibit temporally-distinct activation patterns as they enhance task-relevant and suppresses task-irrelevant information to guide behavior. The LPFC rapidly encodes and transiently stores sensory-motor information for continuous updating of information in ?working memory? for the task at hand. As temporal and cognitive- emotional demands increase (i.e., a higher number of temporally distinct motivational variables to consider), the ACC is additionally engaged. The ACC, as part of the limbic network, can integrate emotional and mnemonic information to modulate cognitive tasks that span both rapid and longer timescales. Cortical excitatory and inhibitory synaptic networks determine the spatial and temporal dynamics of signal enhancement or suppression in cognitive tasks. The scientific premise of this proposal is that the key differences in the temporal dynamics of processing in ACC vs LPFC in behavior are due to differences network excitatory-inhibitory (E:I) synaptic balance in these areas, which remain poorly understood. Our recent work suggests that higher inhibitory tone and longer membrane time constant in ACC neurons likely contribute to a longer temporal range for integration. The overall hypothesis of this proposal is that highly distinctive excitatory-inhibitory and neuromodulatory circuits in the ACC and LPFC underlie differential temporal dynamics of signal processing for cognitive-emotional integration by these two areas. Using multi-scale neuroanatomical, in vitro and in vivo electrophysiological, pharmacologic and optogenetic techniques in adult rhesus monkeys (Macaca mulatta), we aim to study the properties of inhibitory circuits that control the temporal dynamics of ACC vs LPFC pyramidal neuron activity, and how limbic input from the amygdala influences communication within the ACC-LPFC network. We will study GABAergic and neuromodulatory influences on these prefrontal networks that are highly implicated in the regulation of stress and emotions. In Aim 1 we will investigate the properties of temporally-distinct inhibitory circuits, using in vitro electrophysiological and pharmacological techniques to isolate fast versus slow inhibitory currents, as well as neuroanatomical techniques to classify inhibitory neurons based on their receptors and innervation patterns. In Aim 2 we will determine whether differential inhibitory signaling in ACC vs LPFC affects capacities for diverse network oscillations in vitro and in vivo. In Aim 3 we will study the properties of ACC?amygdala vs ACC?LPFC projections and how these neurons receive synaptic input from the amygdala, using optogenetics and 3D electron microscopy. Disruption of the E:I balance and oscillatory dynamics within this ACC-LPFC prefrontal-limbic network is the core neuropathology in cognitive-affective psychiatric disorders. The proposed study will shed light on the underlying circuit mechanisms of normal and disrupted cognitive-emotional integration in primates.
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0.915 |