Marc V Fuccillo, M.D., Ph.D.

faculty photo
Associate Professor of Neuroscience
Department: Neuroscience
Graduate Group Affiliations

Contact information
University of Pennsylvania, Department of Neuroscience
415 Curie Boulevard
Clinical Research Building, Room 226
Philadelphia, PA 19104
Office: (646) 483-6714
Lab: (215) 898-8744
B.A. (Molecular and Cellular Biology, Music Performance (Violin))
Brown University, 1998.
Ph.D. (Developmental Genetics)
New York University School of Medicine, 2007.
New York University School of Medicine, 2008.
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Description of Research Expertise

Research Interests: The synaptic and circuit mechanisms of behavioral control

Keywords: Synaptic transmission, striatal circuits, inhibition, mouse genetics, in vitro electrophysiology, in vivo imaging, goal-directed behavior, motor control, neuropsychiatric disease modeling

Research Details: My laboratory is interested in understanding how neural circuits of the striatum regulate mouse behavior – from simple motor patterns to complex goal-directed actions. To do this, we explore this system at the molecular, synaptic and behavioral level. We employ a range of technologies in seeking a more comprehensive understanding of the normal regulation of striatal function as well as its disruption in mouse models of neuropsychiatric disease.

During my postdoctoral training I initiated a project investigating the circuit and synaptic basis of autism-associated abnormalities in behavioral control. We focused on the enhanced motor learning of mice with mutations in Neuroligin3 (NL3), an autism-associated synaptic adhesion molecule thought to guide synapse assembly. We postulated that their improved performance on the accelerating rotarod - a phenotype displayed by many autism-relevant mouse mutants – might serve as a behavioral endophenotype for the repetitive motor routines commonly seen in autism spectrum disorders. Quantitative video-capture analyses of rotarod learning demonstrated that improved performance in mutant mice was associated with accelerated formation of stereotyped patterns of paw placement. Through targeted viral injections and genetic cell-type specific manipulation of NL3 function, we found that deletion of NL3 in D1 dopamine receptor positive medium spiny neurons (D1R+ MSNs) of the nucleus accumbens (ventral striatum) was sufficient to generate enhanced rotarod learning and other stereotyped behaviors. Subsequent analysis of synaptic transmission identified a cell-type specific deficit in inhibitory transmission onto D1R+ MSNs, which lead to an excitatory-inhibitory imbalance that likely enhanced formation of motor patterns in NL3 autism models. Current studies are using similar molecular/genetic techniques to explore the circuit basis of reward-related abnormalities seen in operant behaviors with NL3 mutant mice.

Neuroligins and their presynaptic Neurexin ligands are part of an intricate array of synaptic adhesion molecules (SAMs) that bestow circuit specific characteristics to synaptic connections. Understanding the diversity of SAM expression could provide an understanding of how synapse specificity is cooperatively determined, as well as reveal circuits that lack molecular redundancy and are thereby more vulnerable to individual genetics insults. To explore this concept, I investigated SAM diversity within striatal and hippocampal circuits through a single-cell transcriptional analysis. Using microfluidics-based quantitative-PCR technology combined with single cell isolation of neurons defined by transgenic reporter mice and viral synaptic tracing, I have begun to characterize circuit-specific expression of synaptic adhesion molecules as well as other gene families that may underlie diversity in synaptic connectivity, regulation and function.

Going forward, my lab will use complementary approaches to explore how neural circuits projecting to the striatum function in regulating behavior.

I. Is there a molecular logic to the composition of striatal circuits?
The striatum integrates neuronal connections from prefrontal and motor cortices, amygdala, hippocampus, thalamus, as well as dopaminergic and serotonergic neuromodulatory systems. Do these circuits possess unique molecular architectures that bestow specific synaptic connectivity, modulation and behavioral function?

II. How do striatal circuits shape behavioral control?
The striatum is considered a central node in action selection as it links neural circuitry that analyzes decision-relevant information to neuronal populations responsible for the execution of discrete behavioral responses. How do striatal circuits and their synapses support aspects of action selection and how does dysfunction within these circuits manifest behaviorally?

III. What can mouse models of autism, schizophrenia and OCD tell us about the role of striatal circuitry in disease pathophysiology?
Genetic mouse models of neuropsychiatric disease provide a unique opportunity to understand how genetic insults translate into behavioral abnormalities. Can striatal circuit and synaptic dysfunction explain deficits in behavioral control observed in mouse models of these diseases? Do common physiological abnormalities exist across disease models? How do environmental factors and genetic modifiers modulate disease-relevant striatal circuitry?

Rotation Projects:
Please contact Dr. Fuccillo regarding potential rotation projects.

Lab Personel:
Marc Fuccillo, MD/PhD, PI, fuccillo@mail.med.upenn.edu

Selected Publications

Holly EN, Diáz-Hernández E, Fuccillo MV.: A blueprint for examining striatal control of cognition. Trends Neurosci Jun 2022.

Choi K.*, Piasini E.*, Cifuentes-Vargas L., Díaz-Hernández E., Henderson N.T., Subramaniyan M., Gerfen C.R., Fuccillo, M.V. : Distributed processing for action control by prelimbic circuits targeting anterior-posterior dorsal striatal subregions. bioRxiv Dec 2021 Notes: https://doi.org/10.1101/2021.12.01.469698.

Zhang YF, Vargas Cifuentes L, Wright KN, Bhattarai JP, Mohrhardt J, Fleck D, Janke E, Jiang C, Cranfill SL, Goldstein N, Schreck M, Moberly AH, Yu Y, Arenkiel BR, Betley JN, Luo W, Stegmaier J, Wesson DW, Spehr M, Fuccillo MV, Ma M.: Ventral striatal islands of Calleja neurons control grooming in mice. Nature Neuroscience 24(12), Dec 2021.

Terzic B, Davatolhagh MF, Ho Y, Tang S, Liu YT, Xia Z, Cui Y, Fuccillo MV, Zhou Z.: Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits. J Clinical Investigation 131: e143655, Oct 2021.

Holly EN, Davatolhagh MF, España RA, Fuccillo MV.: Striatal low-threshold spiking interneurons locally gate dopamine. Current Biology 31: 4139-4147, Sep 2021.

Fuccillo, M.V. and Pak, C. : Copy number variants in neurexin genes: phenotypes and mechanisms. Current Opinion in Genetics and Development in press, June 2021.

Davatolhagh MF, Fuccillo MV.: Neurexin1⍺ differentially regulates synaptic efficacy within striatal circuits. Cell Reports 34: 108773, Feb 2021.

Alabi OO, Davatolhagh MF, Robinson M, Fortunato MP, Vargas Cifuentes L, Kable JW, Fuccillo MV.: Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction. Elife 9: e54838, Dec 2020.

Duan ZRS, Che A, Chu P, Modol L, Bollmann Y, Babij R, Fetcho RN, Otsuka T, Fuccillo MV, Liston C, Pisapia DJ, Cossart R, De Marco García NV.: GABAergic Restriction of Network Dynamics Regulates Interneuron Survival in the Developing Cortex. Neuron 105: 75-92, Jan 2020.

White KA, Zhang YF, Zhang Z, Bhattarai JP, Moberly AH, In 't Zandt EE, Pena-Bravo JI, Mi H, Jia X, Fuccillo MV, Xu F, Ma M, Wesson DW.: Glutamatergic Neurons in the Piriform Cortex Influence the Activity of D1- and D2-Type Receptor-Expressing Olfactory Tubercle Neurons. J Neurosci 39: 9546-9559, Nov 2019.

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Last updated: 07/18/2022
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