자료유형  

 학위논문

Control Number  

0017160770

International Standard Book Number  

9798383211915

Dewey Decimal Classification Number  

616

Main Entry-Personal Name  

Cowen, Mara H.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Pennsylvania., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

167 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-01, Section: B.

General Note  

Advisor: Hart, Michael P.;Raizen, David M.;Ma, Minghong.

Dissertation Note  

Thesis (Ph.D.)--University of Pennsylvania, 2024.

Summary, Etc.  

요약Autism is a heterogeneous neurologic condition characterized by altered social communication, restricted interest/repetitive behavior, impaired sleep, and changes in sensory sensitization, which have a complex and interconnected relationship. This behavioral heterogeneity is also reflected in the genetics of autism, with hundreds of genes associated with increased risk for autism. Moreover, how mutations in these genes alter behavior and neural circuit function remains elusive. The transparent nematode, C. elegans, performs complex, stereotyped behaviors and has a compact neural circuitry that has been fully mapped. In this work, I use C. elegans to study two well-characterized neural circuits with clear behavioral outputs to determine the role of conserved autism-associated genes in circuit-level behavioral regulation. First, I determine that sleep deprivation resulting from genetic mutation or vibration/ chemo-genetic silencing of a sleep-active neuron during sexual maturation alters neurite extension of the GABAergic DVB neuron and leads to an increase in the time to spicule protraction, the functional readout of DVB, at day 1 of adulthood. I additionally find that loss of nrx-1 and nlg-1 prevents both day 1 DVB structural and behavioral plasticity caused by sleep loss and that DVB morphology in sleep deprived animals is indistinguishable from controls by day 3, suggesting the effects of sleep loss are transient. Next, I discover that mutations in several conserved autism-associated genes (NRXN1/nrx-1, NLGN3/nlg-1, GRIA1/2/3/glr-1, GRIA2/glr-2, and GLRA2/GABRA3/avr-15) lead to a reduction in aggregation behavior, controlled by a sensory integration circuit. I localize the function of NRX-1 in this simple social behavior, independent of NLG-1, to the glutamatergic chemosensory neurons, ADL and ASH. Social animals show faster glutamate release and a nrx-1 dependent increase in presynaptic puncta in ASH neurons, which when lost convert social to solitary feeding behavior. Finally, I show that aggregation behavior induced by neural circuit activation requires nrx-1; collectively indicating that social behavior tuned by complementary synaptic mechanisms is regulated by conserved autism-associated genes. In sum, this work defines diverse functions for conserved autism-associated genes in controlling neuronal morphology and signaling dynamics to regulate behavior, with implications for understanding the interplay of sleep, sensory sensitivity, and socialization. 

Subject Added Entry-Topical Term  

Neurosciences.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Biomedical engineering.

Subject Added Entry-Topical Term  

Psychology.

Index Term-Uncontrolled  

Autism

Index Term-Uncontrolled  

C. elegans

Index Term-Uncontrolled  

Sensory sensitivity

Index Term-Uncontrolled  

Sleep deprivation

Index Term-Uncontrolled  

Social behavior

Index Term-Uncontrolled  

Synaptic adhesion molecules

Added Entry-Corporate Name  

University of Pennsylvania Neuroscience

Host Item Entry  

Dissertations Abstracts International. 86-01B.

Electronic Location and Access  

로그인을 한후 보실 수 있는 자료입니다.

Control Number  

joongbu:657928