Children with attention-deficit/hyperactivity disorder (ADHD) often struggle with impaired executive function, temporal processing, and visuospatial memory, hallmarks of the predominantly inattentive presentation (ADHD-PI), subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structures to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal dentate gyri tissues from thyroid hormone-responsive protein overexpressing (THRSP OE) mice with defining characteristics of ADHD-PI were utilized in proteomics. Integrated proteomics and network analysis revealed an altered protein network involved in Wnt signaling. Compared with THRSP knockout (KO) mice, THRSP OE mice showed impaired attention and memory, accompanied by dysregulated Wnt signaling affecting hippocampal dentate gyrus cell proliferation and expression of markers for neural stem cell (NSC) activity. Also, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity. These findings show new markers specific to the ADHD-PI presentation, converging with the ancient and evolutionary Wnt signaling pathways crucial for cell fate determination, migration, polarity, and neural patterning during neurodevelopment. These findings from THRSP OE mice support the role of Wnt signaling in neurological disorders, particularly ADHD-PI presentation.
Background
Cognitive impairment is a commonly reported symptom with increasing life spans. Numerous studies have focused on identifying precise targets to relieve or reduce cognitive impairment; however, its underlying mechanism remains elusive. Most patients or animals exposed to addictive drugs exhibit cognitive impairment. Accordingly, the present review discusses the molecular changes induced by addictive drugs to clarify potential mechanisms that mediate cognitive impairments.
Main body
We investigated changes in cognitive function using four drugs: cannabinoids, ketamine, methamphetamine, and cocaine. Chronic administration of most addictive drugs reduces overall cognitive functions, such as working, spatial, and long-term recognition memories. Levels of several transcription factors involved in neuronal differentiation, as well as functional components of neurotransmitter receptors in neuronal cells, are reportedly altered. In addition, inflammatory factors showed a generally increasing trend. These impairments could be mediated by neuroinflammation, synaptic activity, and neuronal plasticity.
Conclusion
This review outlines the effects of acute or chronic drug use and potential molecular alterations in the central nervous system. In the central nervous system, addictive drug-induced changes in molecular pathways associated with cognitive function might play a pivotal role in elucidating the pathogenesis of cognitive impairment.
Despite the predominance and high heritability of attention-deficit/hyperactivity disorder (ADHD), its etiology remains unclear. Preclinical and clinical evidence partially implicates impaired limbic system function, particularly in the hippocampus (HPC). Children diagnosed with ADHD often struggle with deficits in executive function, temporal processing, and visuospatial memory, the defining hallmarks of the predominantly inattentive presentation (ADHD-PI), which is subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structure to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal tissues from a mouse model overexpressing (OE) thyroid hormone-responsive protein (THRSP) with defining characteristics of ADHD-PI were utilized for proteomic analyses. Integrated proteomics and network analysis revealed altered protein network involved in Wnt signaling. Compared with THRSP knockout (KO) mice, THRSP OE mice showed impaired attention and memory, accompanied by dysregulated Wnt signaling affecting hippocampal cell proliferation (BrdU) and neurogenic marker expression (i.e., NEU-N, GFAP), markers of neural stem cell (NSC) activity. In addition, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity.
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