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Differential regulation of synaptic plasticity, mood and reward behavior by circadian genes

Parekh, Puja (2017) Differential regulation of synaptic plasticity, mood and reward behavior by circadian genes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Endogenously generated circadian rhythms allow living organisms to entrain to photic and non- photic cues in a changing environment. The master pacemaker region, the suprachiasmatic nucleus (SCN) coordinates the activity of several sub-oscillators throughout the brain and periphery to produce daily variation in physiology and activity patterns. However, SCN-autonomous rhythms also exist in mesocorticolimbic brain regions. The disruption of these rhythms at the molecular level can have dire consequences for physical and mental health. Clinical and preclinical studies provide a strong link between circadian gene perturbations and the development and progression of mood and substance abuse disorders including bipolar disorder (BD) and co-morbid addiction. While much is known about the inner workings of the SCN clock, the specific underlying mechanisms governing the regulation of mood and reward-related behavior by extra-SCN clock proteins are yet to be fully elucidated.
Molecular rhythms are maintained by transcription factors, CLOCK and NPAS2, which are homologous in structure and function but differentially expressed throughout the brain. Genetic variants of both have been found to associate with neuropsychiatric illnesses in human populations. The expression profiles and uniquely regulated gene targets of these proteins however, may contribute to differences in their ability to modulate behavior. The work presented here focuses on how disruptions in CLOCK and NPAS2 alter mesolimbic excitatory neurotransmission and their effects on mood and reward-related behavior. We find that a mutation in CLOCK, which produces a dominant negative protein, and a behavioral phenotype in mice closely resembling human mania,
leads to a reduction in excitatory neurotransmission in the nucleus accumbens (NAc) a region critical for sensorimotor and limbic integration. These mice have also been characterized to be hyperhedonic with increased reward sensitivity. In contrast, a disruption in NPAS2 by viral- mediated knockdown, increases NAc excitatory synaptic transmission and incidentally decreases reward sensitivity in a cell-type specific manner. Electrophysiological, molecular, biochemical and behavioral studies contained within this dissertation aim to uncover the differential regulation of behavior by these core circadian proteins. The understanding of these mechanisms may help to inform targeted therapeutic strategies against BD and other disorders for which there is a strong circadian component.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Parekh, Pujapkp13@pitt.edupkp13
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMcClung,
Committee ChairMoghaddam,
Committee MemberHuang,
Committee MemberDong,
Committee MemberSchluter,
Committee MemberHan,
Date: 18 May 2017
Date Type: Publication
Defense Date: 20 February 2017
Approval Date: 18 May 2017
Submission Date: 18 May 2017
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 170
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Circadian, CLOCK, NPAS2, synaptic, mood, reward
Date Deposited: 18 May 2017 18:48
Last Modified: 18 May 2019 05:15


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