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Metabolic Tuning of Neural, Neuroendocrine, and Behavioral Responses to Stress

Maniscalco, James W. (2014) Metabolic Tuning of Neural, Neuroendocrine, and Behavioral Responses to Stress. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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In response to actual or anticipated stressors, the central nervous system elicits neural, neuroendocrine, and behavioral stress responses that facilitate survival and restoration of homeostatic balance. Caloric deficit attenuates many of these responses, including neural drive to the hypothalamic-pituitary-adrenal (HPA) axis, anxiety-like behavior, and stress-induced hypophagia. These alterations may represent an adaptive shift in stress responses during periods of negative energy balance, however, the neural mechanisms by which they occur remain unclear. Hindbrain glucagon-like peptide-1 (GLP-1) neurons and prolactin-releasing peptide-positive noradrenergic A2 (PrRP+ A2) neurons are stress-sensitive and receive robust ingestive/metabolic information. Moreover, signaling from these populations contributes to each of the stress responses altered during fasting. Considering this, we hypothesized that the ability of caloric deficit to decrease anxiety-like behavior, stress hypophagia, and central drive to the HPA axis depends on reduced signaling from hindbrain GLP-1 and PrRP+ A2 neurons.
In Chapter 2, we demonstrate that overnight fasting markedly reduces visceral stress-induced cFos activation of GLP-1 neurons, A2 neurons, and forebrain neurons implicated in HPA axis drive. Furthermore, the results of Chapter 3 reveal that overnight fasting nearly eliminates cognitive stress-induced activation of GLP-1 and PrRP+ A2 neurons. Fasting also decreased anxiety-like behavior, in conjunction with attenuations in cognitive stress-induced cFos expression within a limbic forebrain nucleus implicated in anxiogenesis and HPA axis activation. Finally, using central administration of a GLP-1 receptor antagonist, we demonstrated that central GLP-1 signaling is critical for cognitive stress-induced hypophagia. Together, these findings document the metabolic tuning of stress-induced GLP-1 and PrRP+ A2 neural activation and implicate fasting-mediated reductions in activation of these neurons in the attenuation of behavioral stress responses. Considering this, we investigated the mechanisms by which fasting alters activation of GLP-1 and PrRP+ A2 neurons. Our results revealed that systemic ghrelin receptor antagonist administration partially rescued stress-induced activation of GLP-1 and PrRP+ A2 neurons in fasted rats. In sum, the results of this dissertation work support the hypothesis that metabolic tuning of hindbrain GLP-1 and PrRP+ A2 neurons is a mechanism through which caloric deficit decreases central drive to the HPA axis, promotes anxiolysis, and attenuates hypophagic responses to acute stress.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Maniscalco, James W.jwm58@pitt.eduJWM58
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCard, J. Patrickcard@pitt.eduCARD
Committee MemberRinaman, Lindarinaman@pitt.eduRINAMAN
Committee MemberSved, Alan Fsved@pitt.eduSVED
Committee MemberGold, Michaelmsg22@pitt.eduMSG22
Committee MemberCameron, Judyjcameron@pitt.eduJCAMERON
Committee MemberHerman, JamesHERMANJS@UCMAIL.UC.EDU
Date: 24 September 2014
Date Type: Publication
Defense Date: 2 July 2014
Approval Date: 24 September 2014
Submission Date: 27 June 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 251
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: N/A
Date Deposited: 24 Sep 2014 15:38
Last Modified: 15 Nov 2016 14:21


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