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Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology

Neuropsychopharmacology volume 48, pages 1288–1299 (2023)Cite this article

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Abstract

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortem studies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, partially CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement - a mild acute stressor that increases AP levels in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in partially CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS-related manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.

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Fig. 1: Effects of early-life cholinergic interneuron depletion (CIN-d) in male and female mice.
Fig. 2: Effects of acute stress on the behavior of CIN-depleted (CIN-d) and control (Ctrl) male and female mice under the dark phase.
Fig. 3: Effects of Tourette syndrome (TS) treatments on repetitive behaviors, as well as prepulse inhibition (PPI) deficits in CIN-depleted (CIN-d) male mice exposed to spatial confinement (SC).
Fig. 4: Allopregnanolone (AP) increased Tourette syndrome- (TS) relevant responses in CIN-depleted (CIN-d) but not control (Ctrl) male mice.
Fig. 5: Blocking allopregnanolone (AP) synthesis and signaling normalized the adverse impact of spatial confinement (SC) in CIN-depleted (CIN-d) mice.

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Acknowledgements

We would like to thank Dr. Caterina Branca for her precious editorial assistance and suggestions.

Funding

This study was supported by the NIH grants R21 NS108722 (to MB and CP) and R21 NS125654 (to MB).

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Author notes

  1. These authors contributed equally: Christopher Pittenger, Marco Bortolato.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA

    Roberto Cadeddu, Karen Odeh & Marco Bortolato

  2. Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA

    Meghan Van Zandt, Deirdre Flanagan & Christopher Pittenger

  3. The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Luca Spiro Santovito & Graziano Pinna

  4. Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA

    Collin J. Anderson

  5. School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia

    Collin J. Anderson

  6. School of Biomedical Engineering, University of Sydney, Camperdown, NSW, Australia

    Collin J. Anderson

  7. Asarina Pharma, Copenhagen, Denmark

    Peter Nordkild

  8. UI Center on Depression and Resilience (UICDR), Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Graziano Pinna

  9. Center for Alcohol Research in Epigenetics (CARE), Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Graziano Pinna

  10. Department of Psychology, School of Arts and Sciences, Yale University, New Haven, CT, USA

    Christopher Pittenger

  11. Child Study Center, School of Medicine, Yale University, New Haven, CT, USA

    Christopher Pittenger

  12. Center for Brain and Mind Health, School of Medicine, Yale University, New Haven, CT, USA

    Christopher Pittenger

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Contributions

RC: Behavioral and pharmacological investigation, formal analysis, Writing – original draft, writing – review & editing. MVZ: Immunohistochemical investigation, quantification and images acquisition, formal analysis. LS: Steroid measurements. KOO: Behavioral investigation. CJA: Writing – review & editing. DF: Immunohistochemical investigation, Quantification and Images acquisition. PN: Writing – review & editing. GP: Data curation and analysis. CP: Conceptualization, Methodology, Data curation, Writing – review & editing, Funding acquisition. MB: Conceptualization, methodology, data curation, writing – original draft, writing – review & editing, funding acquisition.

Corresponding authors

Correspondence to Christopher Pittenger or Marco Bortolato.

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Competing interests

PN is CEO and CMO for Asarina Pharma, has a 1.2% equity stake in Asarina Pharma, and has filed patents for the use of sepranolone in the treatment of Tourette syndrome, obsessive-compulsive disorder, and pathological gambling. GP is a paid consultant to PureTech Health, GABA Therapeutics, and NeuroTrauma Sciences. He has a pending patent application on N-palmitoylethanolamine (PEA) and peroxisome proliferator-activated receptor alpha (PPAR-α) agonists, and another one on allopregnanolone analogs US11266663B2 granted on March 8, 2022 in the treatment of neuropsychiatric disorders. CP consults for Biohaven Pharmaceuticals, Ceruvia Lifesciences, Transcend Therapeutics, Freedom Biosciences, Nobilis Therapeutics, and UCB Biopharma and receives research funding from Biohaven, Transcend, and Freedom. He has filed patents for neurofeedback and psychedelics in the treatment of obsessive-compulsive disorder, unrelated to the current work. MB consults for Asarina Pharmaceuticals and receives research funding from Asarina and Lundbeck Pharmaceuticals. The other authors declare no conflict of interest.

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Cadeddu, R., Van Zandt, M., Santovito, L.S. et al. Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology. Neuropsychopharmacol. 48, 1288–1299 (2023). https://doi.org/10.1038/s41386-023-01603-6

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