bims-adhine 2026-07-05 papers

Issue of 2026–07–05
three papers selected by
Tamara J. Buijs, Universiteit van Amsterdam

J Appl Toxicol. 2026 Jul 02.

Chronic Low-Dose Cadmium Exposure Impairs Adult Hippocampal Neurogenesis by Suppressing Noncanonical Wnt5a Signaling.

Xutong Qin, Yuwei Zhang, Qiuyun Gu, Yaxin Han, Longfei Feng, Jinglin Wang, Jiming Zhang, Zhijun Zhou, Xiuli Chang.

Cadmium (Cd) is a pervasive environmental heavy metal associated with impaired hippocampal neurogenesis, yet the molecular mechanisms linking chronic low-dose exposure to disrupted neuronal differentiation remain incompletely understood. In particular, whether noncanonical Wnt5a signaling, a pathway implicated in neural stem cell (NSC) lineage commitment and neuronal maturation, contributes to Cd-induced neurogenic deficits remains not fully elucidated. Here, using primary mouse NSCs derived from the subgranular zone (SGZ) and a chronic low-dose Cd-exposed mouse model, we investigated the effects of Cd on noncanonical Wnt5a signaling and adult hippocampal neurogenesis (AHN). We found that long-term Cd exposure suppresses multiple components of the noncanonical Wnt5a signaling cascade, including Wnt5a, its receptors Fzd2/3, the coreceptor Ror2, and downstream effectors RhoA, PKC, and JNK. This suppression was accompanied by reduced differentiation of NSCs into DCX+ immature neurons and decreased neuronal structural complexity both in vitro and in vivo. Functional rescue experiments further demonstrated that recombinant Wnt5a treatment partially restored neuronal differentiation and morphological complexity, whereas lentiviral-mediated Wnt5a overexpression more effectively reversed Cd-induced deficits and reactivated downstream signaling. Together, these results provide converging evidence that disruption of noncanonical Wnt5a signaling contributes to impaired SGZ-derived NSC differentiation under chronic Cd exposure. This study offers mechanistic insight into Cd-induced neurotoxicity and identifies Wnt5a signaling as a potential molecular target for mitigating environmentally relevant Cd-associated neurogenic dysfunction.

Keywords: cadmium; differentiation defects; hippocampal neurogenesis; neural stem cells; neurotoxicity; noncanonical Wnt5a pathway

DOI: https://doi.org/10.1002/jat.70325

Transl Psychiatry. 2026 Jul 03.

Kappa-opioid receptor activation promotes depression-like behaviors by suppressing Pax6-dependent adult hippocampal neurogenesis.

Hui-Sheng Peng, Ruo-Song Chen, Ru-Feng Ye, Cai-Yu Zhai, Xing-Cong Jiang, Pei-Pei Li, Jia-Yu Ye, Man-Man Han, Qian-Qian Fu, Yi-Quan Shen, Jing-Gen Liu, Chi Xu.

Accumulating evidence indicates that adult hippocampal neurogenesis (AHN) undergoes heterogeneous alterations in depression, yet the underlying mechanisms remain incompletely understood. In this study, we established a corticosterone (CORT)-induced mouse model of depression and combined pharmacological, molecular biological, and genetic approaches to investigate the mechanisms through which CORT suppresses AHN and induces depressive-like behaviors. Our results demonstrated that chronic CORT treatment led to depressive-like phenotypes in mice, including decreased sucrose preference and behavioral despair, accompanied by impaired AHN, manifested by a reduction in immature neurons (DCX⁺BrdU⁺) but an increase in proliferating cells (Ki67⁺). Further mechanistic studies revealed that CORT upregulates dynorphin A in the dentate gyrus (DG), leading to overactivation of the κ-opioid receptor (KOR). This subsequently inhibits the expression of Pax6 and its downstream targets Neurog2 and NeuroD1, thereby obstructing neuronal differentiation. The KOR antagonist nor-BNI effectively reversed both the depressive-like behaviors and AHN abnormalities induced by CORT. Moreover, overexpression of Pax6 alleviated depressive behaviors and restored neurogenesis, whereas knockdown of Pax6 was sufficient to induce depressive phenotypes and impair AHN. Our study unveils a central role of the KOR/Pax6 signaling axis in AHN suppression and depression pathogenesis, providing a theoretical foundation for antidepressant strategies targeting KOR or Pax6.

DOI: https://doi.org/10.1038/s41398-026-04230-z

Neurochem Res. 2026 Jun 29. pii: 205. [Epub ahead of print]51(4):

Microglia-Dependent BDNF Signaling in the Dentate Gyrus Underlies the Antidepressant Effects of Gardiquimod, a Toll-Like Receptor 7 Agonist, in Chronically Stressed Mice.

Jing Gu, Jin Hong, Xu Lu, Nan Liu, Hao Lu, Lijuan Tong, Huijun Liu, Yi Zhang, Chao Huang.

Accumulating evidence suggests that pharmacological restoration of microglial homeostasis in the hippocampus may be a promising strategy for treating depression. In this study, we evaluated whether gardiquimod (GDQ), a selective Toll-like receptor 7 (TLR7) agonist, produces antidepressant effects in mice subjected to chronic unpredictable stress (CUS). A single intraperitoneal injection of GDQ at 1 or 1.5 mg/kg, but not 0.5 mg/kg, improved depression-related behaviors within 5 h of administration. Time-course analyses showed that the antidepressant efficacy of GDQ (1.5 mg/kg) appeared between 5 and 8 h, persisted for up to 7 days, and diminished by 14 days after a single dose. Notably, a second GDQ injection at 14 days restored the behavioral improvements, indicating sustained responsiveness to the drug. Mechanistically, the antidepressant effects of GDQ were abolished by both pharmacological inhibition (minocycline) and genetic depletion (PLX3397) of microglia, highlighting the necessity of these cells. Furthermore, GDQ reversed the CUS-induced reduction in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus in a microglia-dependent manner. The critical role of BDNF signaling was confirmed by three complementary approaches: intra-hippocampal infusion of a BDNF-neutralizing antibody, genetic disruption of activity-dependent BDNF release via the Val68Met knock-in mutation, and pharmacological blockade of the TrkB receptor with K252a. Each intervention abolished the behavioral effects of GDQ. Together, these findings identify GDQ as a promising candidate for antidepressant development and highlight the restoration of microglia-supported BDNF signaling in the dentate gyrus as a key mechanism underlying TLR7-mediated mood regulation.

Keywords: Dentate gyrus; Depression; Gardiquimod; Microglia; TLR7

DOI: https://doi.org/10.1007/s11064-026-04813-8