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Sex- and exposure age-dependent effects of adolescent stress on ventral tegmental area dopamine system and its afferent regulators

Molecular Psychiatry volume 28, pages 611–624 (2023)Cite this article

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Abstract

Adolescent stress is a risk factor for schizophrenia. Emerging evidence suggests that age-dependent sensitive windows for childhood trauma are associated more strongly with adult psychosis, but the neurobiological basis and potential sex differences are unknown.

Using in vivo electrophysiology and immunohistology in rats, we systematically compared the effects of two age-defined adolescent stress paradigms, prepubertal (postnatal day [PD] 21-30; PreP-S) and postpubertal (PD41-50; PostP-S) foot-shock and restraint combined stress, on ventral tegmental area (VTA) dopaminergic activity, pyramidal neuron activity in the ventral hippocampus (vHipp) and the basolateral amygdala (BLA), corticoamygdalar functional inhibitory control, and vHipp and BLA parvalbumin interneuron (PVI) impairments. These endpoints were selected based on their well-documented roles in the pathophysiology of psychosis.

Overall, we found distinct sex- and exposure age-dependent stress vulnerability. Specifically, while males were selectively vulnerable to PreP-S-induced adult VTA dopamine neuron and vHipp hyperactivities, females were selectively vulnerable to PostP-S. These male selective PreP-S effects were correlated with stress-induced aberrant persistent BLA hyperactivity, dysfunctional prefrontal inhibitory control of BLA neurons, and vHipp/BLA PVI impairments. In contrast, female PostP-S only produced vHipp PVI impairments in adults, with the BLA structure and functions largely unaffected.

Our results indicated distinct adolescent-sensitive periods during which stress can sex-dependently confer maximal risks to corticolimbic systems to drive dopamine hyperactivity, which provide critical insights into the neurobiological basis for sex-biased stress-related psychopathologies emphasizing but not limited to schizophrenia. Furthermore, our work also provides a framework for future translational research on age-sensitive targeted interventions.

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Fig. 1: Effects of prepubertal stress (PreP-S) and postpubertal stress (PostP-S) on adult ventral tegmental area (VTA) dopamine (DA) neuron activity and behaviors in males vs. females.
Fig. 2: Sex-selective and exposure age-dependent effects of PreP-S vs. PostP-S on adult ventral hippocampus (vHipp) pyramidal neuron activity.
Fig. 3: Sex differences in amygdala neuron firing rate following stress.
Fig. 4: Sex-specific effects of stress on PFC-BLA inhibitory control.
Fig. 5: Sex differences in the longitudinal impact of PreP-S and PostP-S on BLA parvalbumin (PV) interneurons.
Fig. 6: Sex differences in the longitudinal impact of stress on vHipp PV interneurons.

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Acknowledgements

This work was supported by National Institutes of Health Grant MH57440 (to AAG). We thank Niki MacMurdo and Christy Smolak for their technical assistance. We also thank Madhura Leninakan, Ruth Haider, Junhao Xu, and Dhruti Raghuraman for their assistance in data analysis.

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  1. Xiyu Zhu

    Present address: Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA

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  1. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    Xiyu Zhu & Anthony A. Grace

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Anthony A. Grace

  3. Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA

    Anthony A. Grace

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XZ: conceptualization, data acquisition, formal analysis, interpretation, writing—original draft. AAG: conceptualization, resources, interpretation, writing—review & editing, supervision, and funding acquisition.

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Correspondence to Anthony A. Grace.

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AAG received funds from the following organizations: Lundbeck, Pfizer, Otsuka, Asubio, Autofony, Janssen, Alkermes, SynAgile, Merck, and Newron. XZ reports no conflicts of interest.

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Zhu, X., Grace, A.A. Sex- and exposure age-dependent effects of adolescent stress on ventral tegmental area dopamine system and its afferent regulators. Mol Psychiatry 28, 611–624 (2023). https://doi.org/10.1038/s41380-022-01820-3

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