Area:
Psychopharmacology, Behavioral Neuroscience
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High-probability grants
According to our matching algorithm, Elizabeth N. Holly is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2017 — 2019 |
Holly, Elizabeth N. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Role of Dorsomedial Striatum Low-Threshold Spiking Interneurons in Goal-Directed Behavior @ University of Pennsylvania
PROJECT SUMMARY Deficits in goal-directed behavior are the hallmark of many neuropsychiatric diseases. The dorsomedial striatum (DMS) has emerged as a key mediator of goal-directed actions, serving as a critical node for integration of sensorimotor, motivational, and cognitive information. Low-threshold spiking interneurons (LTSIs) exert strong inhibitory control over striatal spiny projection neurons (SPNs) and are positioned to regulate plasticity at cortico-SPN synapses through dendritic inhibition. While LTSIs are poised to play a key role in regulating goal-directed behavior, no evidence of DMS LTSI involvement in learning behavior has presently been reported. The overarching aim of this proposal is therefore to explore the role of DMS LTSIs in goal- directed behavior and examine how learning alters LTSI physiology and plasticity. The first proposed experiment investigates whether LTSIs are important for the acquisition of goal-directed behavior. To provide initial evidence for LTSI involvement in learning and behavioral flexibility, excitability of LTSIs has been reduced using cell-type specific viral expression of Kir2.1, an inwardly rectifying potassium channel, and mice subsequently trained in a goal-directed operant task. Preliminary data demonstrates that this reduction in LTSI excitability significantly enhances task acquisition. Efficient goal-directed behavior is comprised of learning action-outcome associations, selecting an appropriate action, evaluating the resultant outcome, and adjusting behavior if necessary. To temporally delineate the role of LTSIs in action selection and outcome valuation during the acquisition of an action-outcome contingency, an optogenetic approach will be implemented. Using halorhodopsin, DMS LTSIs will be selectively inhibited during the interval preceding lever choice (action selection period) or as mice retrieve and consume their reward (outcome valuation period). Prior work has shown a key role of the anterior cingulate cortex (ACC) in action selection, while the orbitofrontal cortex (OFC) has been strongly linked to outcome valuation. Interestingly, preliminary cell type-specific monosynaptic tracing data shows DMS LTSIs receive the densest innervation from the ACC and OFC. While results from the optogenetics experiment may implicate the ACC and/or OFC in LTSI function during goal-directed behavior, it will be important to more directly pursue the functional role of these circuits. As LTSIs are highly excitable and tonically active, learning may involve silencing their inhibitory effects within the striatum. This can be achieved through reductions in LTSI excitability, enhanced depression of excitatory ACC-LTSI or OFC-LTSI synapses, or reduced efficacy at LTSI-SPN synapses. The second set of ex vivo electrophysiology experiments will directly test these possibilities using projection-specific optogenetic recruitment of ACC and OFC synapses onto LTSI neurons in mice that have learned the goal-directed behavior task.
|
0.966 |
2021 |
Holly, Elizabeth N. |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Effect of Adolescent Social Isolation On Adult Decision Making and Corticostriatal Circuitry @ University of Pennsylvania
PROJECT SUMMARY/ABSTRACT Adolescence is a particularly important period in social and cognitive development, characterized in part by rapid increases in exploration, social interaction, and neural connectivity. Social isolation in adolescence has a clear, profound impact on a wide range of behavioral and physiological endpoints extending into adulthood. The overarching research goal of this proposal is to elucidate how adolescent social isolation in male and female mice alters value-based decision making in adulthood, as well as the underlying corticostriatal circuitry driving these complex goal-directed behaviors. This work is timely and vitally important as COVID-19 has subjected an increasing number of adolescents to social isolation through school closures and stay-at-home orders. A first aim of this proposal is to use operant tasks to systematically investigate how adolescent social isolation impacts how mice later value reward benefits and integrate expected costs during decision making. Preliminary data suggests that adolescent social isolation amplifies reward value, but specific aspects of decision-making behavior will be disentangled with computational modeling of value-based choice. The second aim builds on this behavioral work to test the hypothesis that adolescent social isolation disrupts corticostriatal circuitry and striatal output during adult value-based decision-making. A distributed neural network is engaged during decision- making, and the dorsomedial striatum (DMS) is a key node in this network. Prefrontal inputs to the DMS from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) are critically involved in action selection and outcome valuation, respectively. All three of these nodes undergo maturation and refinement during adolescence, and adolescent social isolation disrupts this development. However, how this impacts adult corticostriatal function remains unknown. Using in vivo electrophysiology, local field potential (LFP) and single- unit recordings will be used to test how adolescent social isolation affects synaptic strength and connectivity from these cortical regions to the DMS during value-based decision-making behavior. This work proposed in the Mentored Research Scientist Development Award will provide Dr. Elizabeth Holly with training in computational modeling of decision-making behavior and in vivo electrophysiology, which will be an important part of the foundation of her independent research career. By completion of this Award, the goal is for Dr. Holly to transition to a tenure-track faculty position and apply for an R01. The mentorship team Dr. Holly has assembled will ensure her successful training in these techniques, and prepare her to transition to her own independent research laboratory.
|
0.966 |