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

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 cholinergic interneurons (CINs) in the striatum 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, 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 synthesis 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 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 manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics. Keywords: Tourette syndrome, tics, allopregnanolone, stress

A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform

“…Building on this finding, targeted striatal depletion of cholinergic interneurons (CINs) in adult mice has been shown to increase the frequency of self-grooming responses to environmental stressors 13 . We recently confirmed similar results in mice subjected to early-life CIN depletion (CIN-d) 14 . Notably, we found that the exaggerated grooming responses in CINd mice were reduced by benchmark therapies for tic disorders, such as the dopamine D2 receptor antagonist haloperidol 14 .…”

“…We recently confirmed similar results in mice subjected to early-life CIN depletion (CIN-d) 14 . Notably, we found that the exaggerated grooming responses in CINd mice were reduced by benchmark therapies for tic disorders, such as the dopamine D2 receptor antagonist haloperidol 14 .…”

Pivotal Role of Slitrk1 in Adult Striatal Cholinergic Neurons in Mice: Implication in Tourette Syndrome

“…48 The responsiveness of CIN-d mice to D 1 R antagonists may be, similar to the observation in D1CT-7 mice, correlated with the stress response and increased neurosteroid allopregnanolone levels in the cortex. 48 Interestingly, a clinical trial using ecopipam for TS treatment also showed promising results. 49 Further investigation is needed regarding whether the D 1 R antagonist is beneficial only in TS patients under stress.…”

“…Another TS model is striatal ChI depletion mice (CIN-d mice) 12 with targeted ablation of 50$60% of ChIs in the dorsolateral striatum. They exhibited tic-like behaviors and significant PPI deficit 12 only under stress conditions, 48 which can be attenuated by haloperidol, SCH23390, and ecopipam, another D 1 R antagonist. 48 The responsiveness of CIN-d mice to D 1 R antagonists may be, similar to the observation in D1CT-7 mice, correlated with the stress response and increased neurosteroid allopregnanolone levels in the cortex.…”

“…They exhibited tic-like behaviors and significant PPI deficit 12 only under stress conditions, 48 which can be attenuated by haloperidol, SCH23390, and ecopipam, another D 1 R antagonist. 48 The responsiveness of CIN-d mice to D 1 R antagonists may be, similar to the observation in D1CT-7 mice, correlated with the stress response and increased neurosteroid allopregnanolone levels in the cortex. 48 Interestingly, a clinical trial using ecopipam for TS treatment also showed promising results.…”