Hippocampal Cell Proliferation Research Articles

Neurogenesis and pesticides: news of no new neurons.

New hippocampal neurons are continuously generated in the adult human brain. Several studies have demonstrated that the proliferation of hippocampal cells is strongly influenced by a variety of stimuli, including pesticides exposure. These effects are particularly important because neurogenesis dysregulation could be associated with the decline of neuronal and cognitive functions and the possible development of neuropsychiatric disorders.

Caloric Restriction Improves Spatial Learning Deficits in Tau Mice.

Caloric restriction (CR) has been recognized for its benefits in delaying age-related diseases and extending lifespan. While its effects on amyloid pathology in Alzheimer's disease (AD) mouse models are well-documented, its effects on tauopathy, another hallmark of AD, are less explored. To assess the impact of a short-term 30% CR regimen on age-dependent spatial learning deficits and pathological features in a tauopathy mouse model. We subjected male PS19 tau P301S (hereafter PS19) and age-matched wildtype mice from two age cohorts (4.5 and 7.5 months old) to a 6-week 30% CR regimen. Spatial learning performance was assessed using the Barnes Maze test. Tau pathology, neuroinflammation, hippocampal cell proliferation, and neurogenesis were evaluated in the older cohort by immunohistochemical staining and RT-qPCR. CR mitigated age-dependent spatial learning deficits in PS19 mice but exhibited limited effects on tau pathology and the associated neuroinflammation. Additionally, we found a decrease in hippocampal cell proliferation, predominantly of Iba1+ cells. Our findings reinforce the cognitive benefits conferred by CR despite its limited modulation of disease pathology. Given the pivotal role of microglia in tau-driven pathology, the observed reduction in Iba1+ cells under CR suggests potential therapeutic implications, particularly if CR would be introduced early in disease progression.

Fluvoxamine Ameliorates the Damage to the Neuro-Behavioral Status of Rats Caused by the Administration of Valproic Acid by Preventing Cognitive Memory Deficits and Decreased Hippocampal Cellular Proliferation.

Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as itinhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.

KDM4C promotes mouse hippocampal neural stem cell proliferation through modulating ApoE expression.

KDM4C is implicated in the regulation of cell proliferation, differentiation, and maintenance in various stem cell types. However, its function in neural stem cells (NSCs) remains poorly understood. Therefore, this study aims to investigate the role and regulatory mechanism of KDM4C in NSCs. Primary hippocampal NSCs were isolated from neonatal mice, and both invivo and invitro lentivirus-mediated overexpression of KDM4C were induced in these hippocampal NSCs. Staining results revealed a significant increase in BrdU- and Ki-67-positive cells, along with an elevated number of cells in S phases due to KDM4C overexpression. Subsequently, RNA-seq was employed to analyze gene expression changes following KDM4C upregulation. GO enrichment analysis, KEGG analysis, and GSEA highlighted KDM4C-regulated genes associated with development, cell cycle, and neurogenesis. Protein-protein interaction analysis uncovered that ApoE protein interacts with several genes (top 10 upregulated and downregulated) regulated by KDM4C. Notably, knocking down ApoE mitigated the proliferative effect induced by KDM4C overexpression in NSCs. Our study demonstrates that KDM4C overexpression significantly upregulates ApoE expression, ultimately promoting proliferation in mouse hippocampal NSCs. These findings provide valuable insights into the molecular mechanisms governing neurodevelopment, with potential implications for therapeutic strategies in neurological disorders.

Evaluating the daily modulation of FADD and related molecular markers in different brain regions in male rats.

Fas-Associated protein with Death Domain (FADD), a key molecule controlling cell fate by balancing apoptotic versus non-apoptotic functions, is dysregulated in post-mortem brains of subjects with psychopathologies, in animal models capturing certain aspects of these disorders, and by several pharmacological agents. Since persistent disruptions in normal functioning of daily rhythms are linked with these conditions, oscillations over time of key biomarkers, such as FADD, could play a crucial role in balancing the clinical outcome. Therefore, we characterized the 24-h regulation of FADD (and linked molecular partners: p-ERK/t-ERK ratio, Cdk-5, p35/p25, cell proliferation) in key brain regions for FADD regulation (prefrontal cortex, striatum, hippocampus). Samples were collected during Zeitgeber time (ZT) 2, ZT5, ZT8, ZT11, ZT14, ZT17, ZT20, and ZT23 (ZT0, lights-on or inactive period; ZT12, lights-off or active period). FADD showed similar daily fluctuations in all regions analyzed, with higher values during lights off, and opposite to p-ERK/t-ERK ratios regulation. Both Cdk-5 and p35 remained stable and did not change across ZT. However, p25 increased during lights off, but exclusively in striatum. Finally, no 24-h modulation was observed for hippocampal cell proliferation, although higher values were present during lights off. These results demonstrated a clear daily modulation of FADD in several key brain regions, with a more prominent regulation during the active time of rats, and suggested a key role for FADD, and molecular partners, in the normal physiological functioning of the brain's daily rhythmicity, which if disrupted might participate in the development of certain pathologies.

Avoidance and escape conditioning adjust adult neurogenesis to conserve a fit hippocampus in adult male rodents.

In this study, the connection between cognitive behaviors and the adult rodent hippocampus was investigated. Recording field potentials at performant pathway (PP)-hippocampal dentate gyrus (DG) synapses in transverse slices from the dorsal (d), intermediate (i), and ventral (v) hippocampus showed differences in paired-pulse responses and long-term potentiation in rats. The Barnes maze (BM) and passive avoidance (PA) tests indicated a decrease in escape latency and step-through latency in both rats and mice over training days. A decrease in the use of random or sequential strategy while an increase in the use of direct strategy to search for an escape box occurred in both groups. Evaluation of the levels of neurogenesis markers (Ki67 and BrdU/NeuN) by immunofluorescence assay in the dDG, iDG, and vDG revealed a long-axis disparity in the hippocampal dentate baseline cell proliferation and exposure to the BM and PA task changed the profile of baseline cell proliferation along the DG in both rats and mice. Also, these learning experiences changed the profile of BrdU+ /NeuN+ cells along the DG of rats. Quantitation of hippocampal BDNF protein levels using ELISA exhibited no changes in BDNF levels due to learning experiences in rats. We demonstrate that PP-DG synaptic efficacy and neurogenesis are organized along a gradient. Avoidance and escape conditioning themselves are sufficient to change and calibrate adult neurogenesis along the hippocampal long axis in rodents. Further research will be required to determine the precise mechanisms underlying the role of experience-derived neuroplasticity in cognitive function and decline.

Plant Cellulose as a Substrate for 3D Neural Stem Cell Culture.

Neural stem cell (NSC)-based therapies are at the forefront of regenerative medicine strategies for various neural defects and injuries such as stroke, traumatic brain injury, and spinal cord injury. For several clinical applications, NSC therapies require biocompatible scaffolds to support cell survival and to direct differentiation. Here, we investigate decellularized plant tissue as a novel scaffold for three-dimensional (3D), in vitro culture of NSCs. Plant cellulose scaffolds were shown to support the attachment and proliferation of adult rat hippocampal neural stem cells (NSCs). Further, NSCs differentiated on the cellulose scaffold had significant increases in their expression of neuron-specific beta-III tubulin and glial fibrillary acidic protein compared to 2D culture on a polystyrene plate, indicating that the scaffold may enhance the differentiation of NSCs towards astrocytic and neuronal lineages. Our findings suggest that plant-derived cellulose scaffolds have the potential to be used in neural tissue engineering and can be harnessed to direct the differentiation of NSCs.

The Effects of Stress on Hippocampal Neurogenesis and Behavior in the Absence of Lipocalin-2.

Lipocalin-2 (LCN2) is an acute phase protein able to bind iron when complexed with bacterial siderophores. The recent identification of a mammalian siderophore also suggested a physiological role for LCN2 in the regulation of iron levels and redox state. In the central nervous system, the deletion of LCN2 induces deficits in neural stem cells proliferation and commitment, with an impact on the hippocampal-dependent contextual fear discriminative task. Additionally, stress is a well-known regulator of cell genesis and is known to decrease adult hippocampal cell proliferation and neurogenesis. Although voluntary running, another well-known regulator of neurogenesis, is sufficient to rescue the defective hippocampal neurogenesis and behavior in LCN2-null mice by promoting stem cells' cell cycle progression and maturation, the relevance of LCN2-regulated hippocampal neurogenesis in response to stress has never been explored. Here, we show a lack of response by LCN2-null mice to the effects of chronic stress exposure at the cellular and behavioral levels. Together, these findings implicate LCN2 as a relevant mediator of neuronal plasticity and brain function in the adult mammalian brain.

Electro-conductive chitosan/graphene bio-nanocomposite scaffold for tissue engineering of the central nervous system

Degenerative central nervous system (CNS) disorders and traumatic brain injuries are common nowadays. These may induce the loss of neuronal cells and delicate connections essential for optimal CNS function. The CNS tissue has restricted regeneration ability, hindering the development of effective therapies. Developing cell and tissue instructive materials may bring up new treatment possibilities. In this study, chitosan-graphene nano platelets (GNPs) composite films were developed to regenerate brain cells. This study evaluates the effects of GNP concentration (0.5, 1 and 2 wt%) and their alignment on mechanical, electrical, surface, protein adsorption and biological properties of the regenerative scaffolds. Incorporating and aligning GNPs into chitosan matrix improved all the physical and biological properties. On reinforced scaffolds, HT22 cell morphology mimics pyramidal brain cells, which are responsible for the brain's highly branched neural network. Additionally, the reinforced scaffolds supported Mesenchymal Stem like Cells growth and were biocompatible in vivo. The alignment of GNPs in the chitosan matrix offered the appropriate physicochemical and biological properties to promote adhesion, proliferation and shape morphogenesis of hippocampal HT22 neuronal cells. Overall, this study delineates the enormous potential offered by the GNP-reinforced scaffolds for regeneration of central nervous system, especially the brain.

Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.

Nanoemulsion-based piperine to enhance bioavailability for the treatment of LPS-induced depression-like behaviour in mice

In the present study, the objective was to encapsulate piperine in nanoform by solvent evaporation method and to investigate the antidepressant-like activity of nanopiperine in lipopolysaccharide (LPS) induced depression in mice. LPS-induced depression in mice was reversed by repeated treatment of nanopiperine at dosages of 5 and 10 mg/kg body weight for 14 days. After 24 h of LPS injection, the animals were exposed to a (TST) tail suspension test and (FST) forced swim test. A sequence of behaviours was measured on days 0, 7, and 14. On day 14, the animals were euthanized, and the blood was collected; biochemical analysis was performed for the measurement of inflammatory and oxidative stress markers. Within the same period, nanopiperine improved hippocampal progenitor cell proliferation and increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice subjected to LPS-induced stress. In addition, the neurotransmitter estimation by the HPLC method showed that nanopiperine increased the levels of neurotransmitters. In summary, the nanopiperine showed potent neuroprotective and antidepressant activity, and stability relating to the elevated level of hippocampal BDNF level and as compared to pure piperine, the nanopiperine showed better oral bioavailability and stability.

Beyond Motor Deficits: Environmental Enrichment Mitigates Huntington's Disease Effects in YAC128 Mice.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by motor, psychiatric, cognitive, and peripheral symptoms without effective therapy. Evidence suggests that lifestyle factors can modulate disease onset and progression, and environmental enrichment (EE) has emerged as a potential approach to mitigate the progression and severity of neurodegenerative processes. Wild-type (WT) and yeast artificial chromosome (YAC) 128 mice were exposed to different EE conditions. Animals from cohort 1 were exposed to EE between postnatal days 21 and 60, and animals from cohort 2 were exposed to EE between postnatal days 60 and 120. Motor and non-motor behavioral tests were employed to evaluate the effects of EE on HD progression. Monoamine levels, hippocampal cell proliferation, neuronal differentiation, and dendritic arborization were also assessed. Here we show that EE had an antidepressant-like effect and slowed the progression of motor deficits in HD mice. It also reduced monoamine levels, which correlated with better motor performance, particularly in the striatum. EE also modulated neuronal differentiation in the YAC128 hippocampus. These results confirm that EE can impact behavior, hippocampal neuroplasticity, and monoamine levels in YAC128 mice, suggesting this could be a therapeutic strategy to modulate neuroplasticity deficits in HD. However, further research is needed to fully understand EE's mechanisms and long-term effects as an adjuvant therapy for this debilitating condition.

CRISPR/Cas9 based gene editing of Frizzled class receptor 6 (FZD6) reveals its role in depressive symptoms through disrupting Wnt/β-catenin signaling pathway

IntroductionAs one of the common psychiatric diseases, depression poses serious threats to human health. Although many genes have been nominated for depression, few of them were investigated in details at the molecular level. ObjectivesTo demonstrate Frizzled class receptor 6 (FZD6) functions in depression through disrupting Wnt/β-catenin signal pathway. MethodsThe FZD6 edited cell line and mouse model were generated by using CRISPR/Cas9 technique. The expression of key genes and proteins in Wnt/β-catenin pathway was determined by qRT-PCR and Western blotting, respectively. Animal behavioral tests, including open field test (OFT), elevated plus maze test (EPM), forced swimming test (FST), tail suspension test (TST), and sucrose preference test (SPT), were employed to determine anxiety- and depressive-like behaviors. Immunofluorescent staining was used to assess cell proliferation in the hippocampus of mouse brain. ResultsAmong patients with depression, FZD6, one of the receptors of Wnt ligand, was significantly decreased. In CRISPR/Cas9-based FZD6 knockdown cells, we showed that FZD6 plays a significant role in regulating expression of genes involved in Wnt/β-catenin pathway. Subsequently behavioral studies on Fzd6 knockdown mice (with a 5-nucleotide deletion; Fzd6-Δ5) revealed significant changes in depressive symptoms, including increased immobility duration in FST, less preference of sucrose in SPT, reduction of distance traveled in OFT, and decreased time spent in open arms in EPM. Immunofluorescent staining showed decreased cell proliferation in the hippocampus of Fzd6-Δ5 mice with reduced number of Ki67+ and PCNA+ cells.Moreover, decreased Gsk3β mRNA expression, phosphorylated GSK3β, and cytoplasmic β-catenin in the hippocampus of Fzd6-Δ5 mice provided further evidence supporting the role of Fzd6 in depression. ConclusionTogether, above findings proved the significant role of FZD6 in depression through its effect on hippocampal cell proliferation and its ability to regulate canonical Wnt/β-catenin pathway.

Serial electroconvulsive Seizure alters dendritic complexity and promotes cellular proliferation in the mouse dentate gyrus; a role for Egr3

BackgroundDespite being one of the safest, most effective treatments for severe mood disorders, the therapeutic mechanisms of electroconvulsive therapy remain unknown. Electroconvulsive seizure (ECS) induces rapid, high-level expression of immediate early genes (IEGs) and brain-derived neurotrophic factor (BDNF), in addition to stimulation of neurogenesis and dendritic remodeling of dentate gyrus (DG) neurons. We have previously shown that this upregulation of BDNF fails to occur in the hippocampus of mice lacking the IEG Egr3. Since BDNF influences neurogenesis and dendritic remodeling, we hypothesized that Egr3−/− mice will exhibit deficits in neurogenesis and dendritic remodeling in response to ECS. ObjectiveTo test this hypothesis, we examined dendritic remodeling and cellular proliferation in the DG of Egr3−/− and wild-type mice following repeated ECS. MethodsMice received 10 daily ECSs. Dendritic morphology was examined in Golgi-Cox-stained tissue and cellular proliferation was analyzed through bromodeoxyuridine (BrdU) immunohistochemistry and confocal imaging. ResultsSerial ECS in mice results in dendritic remodeling, increased spine density, and cellular proliferation in the DG. Loss of Egr3 alters the dendritic remodeling induced by serial ECS but does not change the number of dendritic spines or cellular proliferation consequences of ECS. ConclusionEgr3 influences the dendritic remodeling induced by ECS but is not required for ECS-induced proliferation of hippocampal DG cells.

Chronic Mycobacterium avium infection differentially affects the cytokine expression profile of three mouse strains, but has no effect on behavior

One of the most remarkable findings in the immunology and neuroscience fields was the discovery of the bidirectional interaction between the immune and the central nervous systems. This interplay is tightly regulated to maintain homeostasis in physiological conditions. Disruption in this interplay has been suggested to be associated with several neuropsychiatric disorders. Most studies addressing the impact of an immune system disruption on behavioral alterations focus on acute pro-inflammatory responses. However, chronic infections are highly prevalent and associated with an altered cytokine milieu that persists over time. Studies addressing the potential effect of mycobacterial infections on mood behavior originated discordant results and this relationship needs to be further addressed. To increase our understanding on the effect of chronic infections on the central nervous system, we evaluated the role of Mycobacterium avium infection. A model of peripheral chronic infection with M. avium in female from three mouse strains (Balb/c, C57BL/6, and CD-1) was used. The effect of the infection was evaluated in the cytokine expression profile (spleen and hippocampus), hippocampal cell proliferation, neuronal plasticity, serum corticosterone production and mood behavior. The results show that M. avium peripheral chronic infection induces alterations not just in the peripheral immune system but also in the central nervous system, namely in the hippocampus. Interestingly, the cytokine expression profile alterations vary between mouse strains, and are not accompanied by hippocampal cell proliferation or neuronal plasticity changes. Accordingly, no differences were observed in locomotor, anxious and depressive-like behaviors, in any of the mouse strains used. We conclude that the M. avium 2447 infection-induced alterations in the cytokine expression profile, both in the periphery and the hippocampus, are insufficient to alter hippocampal plasticity and behavior.

Lama2 And Samsn1 Mediate the Effects of Brn4 on Hippocampal Neural Stem Cell Proliferation and Differentiation.

The transcription factor Brn4 exhibits vital roles in the embryonic development of the neural tube, inner ear, pancreas islet, and neural stem cell differentiation. Our previous studies have shown that Brn4 promotes neuronal differentiation of hippocampal neural stem cells (NSCs). However, its mechanism is still unclear. Here, starting from the overlapping genes between RNA-seq and ChIP-seq results, we explored the downstream target genes that mediate Brn4-induced hippocampal neurogenesis. There were 16 genes at the intersection of RNA-seq and ChIP-seq, among which the Lama2 and Samsn1 levels can be upregulated by Brn4, and the combination between their promoters and Brn4 was further determined using ChIP and dual luciferase reporter gene assays. EdU incorporation, cell cycle analysis, and CCK-8 assay indicated that Lama2 and Samsn1 mediated the inhibitory effect of Brn4 on the proliferation of hippocampal NSCs. Immunofluorescence staining, RT-qPCR, and Western blot suggested that Lama2 and Samsn1 mediated the promoting effect of Brn4 on the differentiation of hippocampal NSCs into neurons. In conclusion, our study demonstrates that Brn4 binds to the promoters of Lama2 and Samsn1, and they partially mediate the regulation of Brn4 on the proliferation inhibition and neuronal differentiation promotion of hippocampal NSCs.

MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice.

Hippocampal neural stem cell (NSC) proliferation is known to decline with age, which is closely linked to learning and memory impairments. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes. The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.

Sex differences in the antidepressant-like response and molecular events induced by the imidazoline-2 receptor agonist CR4056 in rats

In searching for novel targets to design antidepressants, among the characterized imidazoline receptors (IR), I2 receptors are an innovative therapeutical approach since they are dysregulated in major depressive disorder and by classical antidepressant treatments. In fact, several I2 agonists have been characterized for their antidepressant-like potential, but the results in terms of efficacy were mixed and exclusively reported in male rodents. Since there are well-known sex differences in antidepressant-like efficacy, this study characterized the potential effects induced by two I2 drugs, CR4056 (i.e., most promising drug already in phase II clinical trial for its analgesic properties) and B06 (a compound from a new family of bicyclic α-iminophosphonates) under the stress of the forced-swim test in male and female rats exposed to early-life stress. Moreover, some hippocampal neuroplasticity markers related to the potential effects observed were also evaluated (i.e., FADD, p-ERK/ERK, mBDNF, cell proliferation: Ki-67 + cells). The main results replicated the only prior study reporting the efficacy of CR4056 in male rats, while providing new data on its efficacy in females, which was clearly dependent on prior early-life stress exposure. Moreover, B06 showed no antidepressant-like effects in male or female rats. Finally, CR4056 increased FADD content and decreased cell proliferation in hippocampus, without affecting p-ERK/t-ERK ratio and/or mBDNF content. Interestingly, these effects were exclusively observed in female rats, and independently of early-life conditions, suggesting some distinctive molecular underpinnings participating in the therapeutic response of CR4056 for both sexes. In conjunction, these results present CR4056 with an antidepressant-like potential, especially in female rats exposed to stress early in life, together with some neuronal correlates described in the context of these behavioral changes in females.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model

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.