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Principal Investigator: Kelsey Marie Tyssowski
Organization: HARVARD UNIVERSITY
Fiscal Year: 2024
Award: $130,815
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
The goal of the proposed research is to discover how variation in the number of corticospinal neurons
(CSNs) causes variation in motor circuit function and dexterous behavior, thus linking cells, circuits,
and behavior in the same system. The evolution of advanced cognitive and motor function is associated with
cerebral cortex expansion, including expansion of CSN neuron number, and it has long been hypothesized that
the expansion of CSNs in primates underlies their exquisite hand dexterity, such as that required for tool use.
In support of this, lesioning studies have demonstrated a role for motor cortex, and CSNs in particular, in
dexterous behaviors. However, CSN number has not been causally linked to dexterity, nor do we understand
the basic principles of how expanding a cell population alters circuit activity and thus behavior. The
experiments proposed here will test the hypothesis that animals with more CSNs have greater
dexterity, thus synthesizing cellular, circuit-level, and behavioral discovery, thus achieving the Goal 7
of the BRAIN Initiative. Specifically, this research will compare subspecies of deer mice (Peromyscus
maniculatus) that evolved in different habitats and have innate differences in dexterity as well as a difference in
CSN number. First, it will use single-nucleus RNA-sequencing to characterize which population(s) of CSNs
differ in abundance between subspecies and to identify candidate developmental mechanisms underlying CSN
population expansion. (Aim 1). At the circuit level, this research will determine whether neural activity during a
dexterity task and neural architecture, as assessed with viral tracing, differs between subspecies (Aim 2).
Finally, in the candidate’s independent research program (R00 phase), she will use the tools and datasets
generated in Aims 1 and 2 to manipulate CSNs to establish causal links between CSN number, neural activity,
and dexterity (Aim 3). This project will take advantage of recent technological advances in high throughput
experiments (e.g., single nucleus sequencing) and neural manipulation (e.g., virally delivered gene editing) to
work in a non-traditional model system, affording the unique ability to capitalize on naturally evolved behavioral
differences to elucidate general principles of how cellular and neural variation mediate behavioral variation.
This research is part of a comprehensive training plan that combines training in comparative behavior,
developmental and systems neuroscience, and computational analysis of datasets in these areas, as well as
training in communication and mentoring. This plan will be mentored by Dr. Hopi Hoekstra at Harvard
University, an expert in deer mouse comparative behavior, and Dr. Adam Hantman at the University of North
Carolina Chapel Hill, an expert in the neuroscience of motor systems. Additional mentorship will come from an
Advisory Committee in single cell sequencing analysis, developmental neuroscience, and analysis of neural
recording data. Together, this opportunity will provide excellent training for an independent research career in a
unique, interdisciplinary niche at the interface of molecular neuroscience, behavior, and evolutionary biology.
Terms: <ASD><Address><Advisory Committees><Affect><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Animals><Architecture><Area><Autism><Autistic Disorder><BRAIN initiative><Behavior><Behavioral><Biologic Models><Biological Models><Biology><Brain Research through Advancing Innovative Neurotechnologies initiative><Cell Body><Cells><Cerebral cortex><Cervical Portion of Spinal Cord><Cervical Spinal Cord><Cervical spinal cord structure><Cognitive><Communication><Computer Analysis><Corticospinal Tracts><Coupled><Data><Data Set><Deer Mouse><Development><Disease><Disorder><Distant><Early Infantile Autism><Engineering / Architecture><Evolution><Forelimb><Foundations><Gehrig's Disease><Genes><Genetic><Goals><Habitats><Hand><Histology><Human><Impairment><Individual><Infantile Autism><Kanner's Syndrome><Lesion><Link><Lou Gehrig Disease><Measures><Mediating><Medulla Spinalis><Mentors><Mentorship><Mice><Mice Mammals><Model System><Modeling><Modern Man><Molecular><Motor><Motor Cortex><Motor Skills><Movement><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Neurosciences><North Carolina><Output><Pattern><Peromyscus><Phase><Physiologic><Physiological><Population><Population Sizes><Position><Positioning Attribute><Primates><Primates Mammals><Research><Rodent><Rodentia><Rodents Mammals><Role><Single cell seq><Single-Nucleus Sequencing><Spinal Cord><Structure><System><Task Forces><Technology><Testing><Time><Training><Universities><Variant><Variation><Viral><Work><advisory team><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><behavior prediction><behavioral prediction><body movement><candidate identification><career><cell type><cognitive capacity><cognitive enhancement><comparative><computational analyses><computational analysis><computer analyses><deermouse><developmental><dexterity><experiment><experimental research><experimental study><experiments><forest><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><hands><high dimensionality><improved><molecular biomarker><molecular marker><neural><neural circuit><neural circuitry><neural correlate><neurocircuitry><neurological disease><neuron development><neuronal><neuronal circuit><neuronal circuitry><neuronal development><programs><sNuc-Seq><single cell next generation sequencing><single cell sequencing><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><skills><snRNA sequencing><snRNA-seq><social role><synaptic circuit><synaptic circuitry><tool>