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Adolescent stress-sensitive periods and dopamine system hyperactivity: implications for schizophrenia etiology and prevention

Zhu, Xiyu (2022) Adolescent stress-sensitive periods and dopamine system hyperactivity: implications for schizophrenia etiology and prevention. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Schizophrenia arises from interacting risk factors. Emerging evidence indicates childhood and adolescence are potential sensitive periods for stress to confer psychosis risks, but how early stress modulates pathophysiological factors, namely hippocampal hyperactivity and ventral tegmental area (VTA) hyperdopaminergic activity, is unclear. Current antipsychotic treatments have unmet therapeutic needs. As potential alternative treatments, the preventative efficacy of environmental enrichment (EE) and antioxidant treatment (N-acetylcysteine) have been moderately indicated in humans. In animals whether they positively modulate schizophrenia pathophysiological factors in the hippocampus and the VTA was undetermined.
Our previous study indicated that combined foot-shock and restraint stress during adolescence [postnatal day (PD) 31-40] and adulthood (PD65-74) of male rats can induce distinct activity disruptions to VTA dopamine and ventral hippocampus (vHipp) pyramidal neurons. Specifically, adolescent stress uniquely induced persistent hyperdopaminergic states, accompanied by vHipp hyperactivity and decreased markers of parvalbumin interneurons (PVIs) and their maturation (perineuronal nets). These effects contrasted with the transient hypodopaminergic state induced by adult stress, indicating stress-sensitive periods. To define the temporal boundaries of sensitive periods and elucidate sex differences, this dissertation compared consequences of prepubertal (PreP-S) and postpubertal stress (PostP-S) (at PD21-30 or PD41-50, respectively). Males were selectively vulnerable to PreP-S, exhibiting adult hyperdopaminergic activity, vHipp hyperactivity, and vHipp PVI impairments. In contrast, females were vulnerable to PostP-S in these outcome measures. Persistent male-selective activation of the basolateral amygdala (BLA) was found after PreP-S, suggesting that PreP-S and PostP-S might engage sexually dimorphic mechanisms to lead to similar adult neurophysiological outcomes relevant to schizophrenia.
The preventative potentials of early EE and N-acetylcysteine were determined in the methylazoxymethanol acetate (MAM) model. In MAM rats, PD21-40 EE prevented VTA hyperdopaminergic activity and vHipp hyperactivity but failed to prevent anxiety and related BLA hyperactivity. PD11-25 N-acetylcysteine treatment prevented adult hyperdopaminergic states, as well as the abnormal prefrontal regulation of dopamine neurons. This effect was accompanied by prevention of PVI oxidative impairments in the thalamic reticular nucleus.
Altogether, these results suggest that stress during age- and sex-dependent adolescent sensitive periods can lead to schizophrenia-related electrophysiological alterations. Moreover, EE and N-acetylcysteine could be promising prophylactic approaches for at-risk individuals.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhu, Xiyuxiz82@pitt.eduxiz820000-0001-5264-9387
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberMcClung,
Committee ChairGrace, Anthonygraceaa@pitt.edugraceaa
Committee MemberSesack, Susansesack@pitt.edusesack
Committee MemberDong, Yanyandong@pitt.eduyandong
Committee MemberSorrell, Shawnshawn.sorrells@pitt.edushawn.sorrells
Committee MemberBerretta,
Date: 6 June 2022
Date Type: Publication
Defense Date: 26 January 2022
Approval Date: 6 June 2022
Submission Date: 16 March 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 206
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: dopamine; stress; sex difference
Date Deposited: 06 Jun 2022 15:57
Last Modified: 06 Jun 2022 15:57

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