Tourette disorder features pervasive neuronal and glial transcriptional remodeling in the dorsolateral prefrontal cortex

bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-14

Tourette disorder (TD) is a neurodevelopmental condition with a robust genetic basis, characterized by multiple motor and vocal tics. Tics arise from dysfunction within cortico-striatal-thalamo-cortical circuits, with pathological evidence largely implicating striatal interneuron deficits and microglial activation. Recently, the largest genome-wide association study (GWAS) meta-analysis of TD identified polygenic risk enrichment in Brodmann area 9 (BA9), corresponding to the dorsolateral prefrontal cortex (DLPFC), a region implicated in executive control and tic suppression. However, the molecular landscape of BA9 in TD remains unexplored. Here, we performed single-nucleus RNA sequencing of postmortem BA9 from five males with TD and five matched controls, yielding 72,340 nuclei across neuronal and glial populations. While cell-type proportions were preserved, transcriptional remodeling was pervasive. In particular, biosynthetic and translational programs were upregulated across microglia, interneurons, oligodendrocytes, and superficial- and middle-layer excitatory neurons. Most cell types showed enrichment for glucocorticoid-responsive and immediate early gene modules consistent with stress-associated transcriptional activation. Finally, cross-regional comparison with striatal datasets revealed conservation of microglial and oligodendrocyte programs. These findings point to extensive transcriptional reprogramming in the DLPFC of individuals with TD, characterized by stress-associated activation, most strongly in oligodendrocytes and neurons.

Sleep deprivation impairs information processing via dysregulation of chloride homeostasis in the prefrontal cortex

bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-18

Sleep deprivation (SD) impairs information processing through alterations of prefrontal cortex (PFC) function, yet the molecular underpinnings of this process remain poorly understood. We previously showed that SD disrupts sensorimotor gating by elevating prefrontal levels of the neurosteroid allopregnanolone (AP), a positive allosteric modulator of GABA-A receptors. Here we identify a complementary, mechanistically independent process whereby SD alters GABA-A currents in the PFC of mice and rats. SD reduced membrane expression of the chloride exporter KCC2, leading to intracellular chloride accumulation and a depolarizing shift in GABA-A receptor reversal potential that weakened GABAergic inhibition. Pharmacological normalization of chloride homeostasis with bumetanide fully rescued SD-induced deficits in sensorimotor gating and information encoding. SD also upregulated BDNF, and intra-PFC antagonism of its receptor TrkB restored KCC2 expression and normalized information processing, identifying BDNF-TrkB signaling as an upstream driver of chloride dysregulation. Notably, blocking AP synthesis rescued behavioral deficits without correcting chloride imbalance, confirming mechanistic independence. Finally, combined administration of AP and a KCC2 blocker produced information-processing deficits akin to those induced by SD. These findings identify TrkB-dependent disruption of prefrontal chloride homeostasis as a druggable mechanism underlying sleep loss-induced cognitive dysfunction.

Abstract 3984: Lymphotoxin alpha induces myeloid differentiation and programmed cell death in myeloid leukemic stem cells resulting in deep and sustained remission in vivo

Cancer Research · 2026-04-03

Abstract Frequent relapse driven by resistant leukemic stem or progenitor cells (LSC) represents one of the major challenges in acute myeloid leukemia (AML) therapy. Based on the concept of cytokine-induced myeloid differentiation as observed during emergency granulopoiesis of healthy hematopoeitic progenitors, we dissected individual cytokines for their effect on myeloid differentiation of LSCs.We identified that cytokines from the TNF family potently induced cellular differentiation in LSCs from a range of different genetic backgrounds of AML. The induction of this differentiation program is driven, at least in part, by the activation of programmed inflammatory cell death and subsequent release of pro-inflammatory cytokines such as IL-1beta. Mechanistically, we identified that TNFR receptor 1 (TNFR1)-mediated signaling induces Receptor-interacting protein kinase 3 (RIPK3) dependent cell death of LSCs upon loss of the pro-survival protein TNFR associated factor 2 (TRAF2). TNF family cytokines such as Lymphotoxin alpha (LTα3) efficiently repress leukemia by depleting TRAF2 from the intracellular pool of LSCs via activation of both TNFR1 and TNFR2. Competitive and simultaneous recruitment of TRAF2 to both TNFR1 and TNFR2 results in the failure of LSCs to generate a robust pro-survival signaling complex I at the proximal portion of TNFR1. This results in RIPK3-dependent inflammatory cell death of LSCs.Of note, in contrast to conventional therapies, LTα3 exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. This cytokine-induced propagation of healthy progenitor cells mimics the process observed during emergency granulopoiesis. Exposure of healthy primary human bone marrow progenitors to LTα3 resulted in propagation of healthy progenitors cells. Co-treatment of malignant and healthy progenitor cells from AML patients within the same culture repressed the malignant LSCs but propagated the healthy progenitors. Accordingly, this tumor-suppressive mechanism can be harnessed to simultaneously clear malignant progenitors cells and promote healthy hematopoiesis.In mouse model systems, genetic deletion of the TNF superfamily member gene lymphotoxin alpha (Lta) blocked cell death and accelerated leukemogenesis. In patient-derived xenograft mouse models, exposure to recombinant LTα3 resulted in deep and sustained remissions. Leveraging this endogenous tumor-suppressive mechanism may de-couple treatment efficacy on malignant cells from undesired bone marrow (BM) suppression. Citation Format: Philipp J. Jost, Ulrike Höckendorf, Sayantanee Dutta, Arnold Kloos, Marah Runtsch, Carina Zötsch, Sebastian Vosberg, Yongjie Wang, Sophie Kienreich, Bettina Flasch, Grazia Malovan, Vanessa Jäger, Stefanie Stanzer, Stefanie Preis, Timo O. Odinius, Celina V. Wagner, Lars Buschhorn, Veronika Dill, Bianca Perfler, Torsten Haferlach, Konstanze Döhner, Katharina S. Götze, Jürgen Ruland, Florian Bassermann, Adam Wahida, Mathias Heikenwälder, Caterina Branca, Johannes Schmöllerl, Johannes Zuber, Ann-Cathrin Burk, Robert Zeiser, Heinz Sill, Ashok Kumar Jayavelu, Armin Zebisch, Michael Heuser, Michael A. Dengler. Lymphotoxin alpha induces myeloid differentiation and programmed cell death in myeloid leukemic stem cells resulting in deep and sustained remission in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3984.

Targeting serotonin 5-HT2A receptors in the treatment of aggression: From antipsychotics to psychedelics

Aggression and Violent Behavior · 2026-02-10

Prefrontal 5α-reductase 2 mediates male-specific acute stress response

Science Advances · 2025-01-22 · 5 citations

A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). Although the rate-limiting step of this reaction is catalyzed by 5α-reductase (5αR), the role of its two primary isoenzymes, 5αR1 and 5αR2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Down-regulation of 5αR2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5αR2 knockout rats. Notably, 5αR1 regulated baseline AP synthesis, whereas 5αR2 enabled AP production under stress. Acute AP administration restored stress response in 5αR2 knockdown rats. Single-nucleus transcriptomics showed that 5αR2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5αR2 in mediating sex-specific differences in acute stress reactivity.

Lymphotoxin alpha eradicates acute myeloid leukemia and simultaneously promotes healthy hematopoiesis in mice

Science Translational Medicine · 2025-11-26 · 2 citations

Acute myeloid leukemia (AML) is characterized by frequent relapse, which is driven by resistant leukemic stem or progenitor cells (LSCs). Here, we reported on a tumor-suppressive mechanism that can be harnessed to simultaneously clear LSCs and promote healthy hematopoiesis. Genetic deletion of the tumor necrosis factor (TNF) superfamily member lymphotoxin alpha ( Lta ) blocked cell death and accelerated leukemogenesis in murine AML models. Accordingly, exposure of leukemic cells to exogenous recombinant lymphotoxin alpha (LTα 3 ) induced myeloid differentiation and, in part, cell death in AML progenitors. In syngeneic and patient-derived xenograft mouse models, exposure to recombinant LTα 3 resulted in deep and durable remissions. LTα 3 repressed leukemia by depleting tumor necrosis factor receptor (TNFR)–associated factor 2 (TRAF2) through activation of TNF receptors TNFR1 and TNFR2. In contrast with conventional therapies, LTα 3 exerted only minimal toxicity on the healthy hematopoiesis but instead promoted hematopoietic progenitors. Leveraging this endogenous tumor-suppressive mechanism may decouple treatment efficacy on malignant cells from undesired bone marrow suppression.

Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D3 dopamine receptors

Molecular Psychiatry · 2025-03-28 · 7 citations

Activation of M₄ muscarinic receptors in the striatum reduces tic‐like behaviours in two distinct murine models of Tourette syndrome

British Journal of Pharmacology · 2024-04-30 · 5 citations

Background and Purpose Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M 1 and/or M 4 receptors—the two most abundant muscarinic receptors in the striatum—reduced tic‐related behaviours in mouse models of TS. Experimental Approach Studies were conducted using CIN‐d and D1CT‐7 mice, two TS models characterized by early‐life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M 1 /M 4 receptor agonist, on tic‐like and other TS‐related responses. Then, we examined whether xanomeline effects were reduced by either M 1 or M 4 antagonists or mimicked by the M 1 /M 3 agonist cevimeline or the M 4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M 1 and M 4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c‐Fos. Key Results Systemic and intrastriatal xanomeline reduced TS‐related behaviours in CIN‐d and D1CT‐7 mice. Most effects were blocked by M 4 , but not M 1 , receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline‐like ameliorative effects in both models. M 4 , but not M 1 , receptors were down‐regulated in the striatum of CIN‐d mice. Additionally, VU0467154 reduced striatal c‐Fos levels in these animals. Conclusion and Implications Activation of striatal M 4 , but not M 1 , receptors reduced tic‐like manifestations in mouse models, pointing to xanomeline and M 4 PAMs as novel putative therapeutic strategies for TS.

Prefrontal 5α-reductase 2 mediates male-specific acute stress response

bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-08

ABSTRACT A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). While the rate-limiting step of this reaction is catalyzed by 5α-reductase (5αR), the role of its two primary isoenzymes, 5αR1 and 5αR2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Downregulation of 5αR2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5αR2 knockout rats. Notably, 5αR1 regulated baseline AP synthesis, while 5αR2 enabled AP production under stress. Acute AP administration restored stress response in 5αR2 knockdown rats. Single-nucleus transcriptomics showed that 5αR2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5αR2 in mediating sex-specific differences in acute stress reactivity.

Exploring persistence in animal models: The sinking platform test

Journal of Neuroscience Methods · 2024-12-15