Search Results (177)

Mice rely heavily on their sense of smell to provide crucial environmental information. The intricate organization of neural circuits within the olfactory bulb (OB) and the communication across the OB-hippocampus network in mice underpin their ability to discriminate and adapt to odors and perform odor-guided behaviors. Wnt/β-catenin signaling has been shown to regulate neural stem cell proliferation and migration during embryogenesis and adult neurogenesis. However, the potential role of β-catenin in adult OB and hippocampus in olfaction, odor-guided behavior and working memory is not known. Here, we report the unexpected expression of collagen, type X, alpha 1 (Col10a1), in the postnatal mouse OB and the hippocampus starting at approximately postnatal day 14. We exploited this finding to generate OB and hippocampus conditional Ctnnb1 knockout (Ctnnb1^cKO) mice. We found Ctnnb1^cKO mice displayed impaired odor habituation and discrimination abilities, whereas food foraging ability was unaffected. Surprisingly, Ctnnb1^cKO mice displayed modestly improved working memory in the Radial Arm Maze test. Together, these findings identify behavioral phenotypes associated with Col10a1-Cre-driven Ctnnb1 deletion and establish this mouse line as a useful tool for studying β-catenin function in adult OB–hippocampal circuits. Full article

Cancer-related cognitive impairment (CRCI) is often attributed to chemotherapy, yet cognitive deficits are detectable in some patients before systemic treatment begins. This review examines a proposed two-hit framework in which cancer-related psychological and physiological stress contributes to pretreatment neural vulnerability, followed by superimposed chemotherapy-associated neurotoxicity. The review focuses on adults with non-central nervous system cancers. This narrative review synthesizes epidemiologic, neuroendocrine, neuroimaging, neuroimmune, autonomic, preclinical, and clinical evidence addressing chronic stress biology, pretreatment cognitive and brain changes, chemotherapy-related neurotoxicity, hypothalamic–pituitary–adrenal (HPA) axis interactions, and potential interventions. Pretreatment cognitive impairment has been reported in approximately one-quarter of patients, accompanied by elevated inflammatory cytokines, altered neurotrophic signaling, and changes in amygdala–hippocampal connectivity. The first hit may reflect interacting cancer- and host-related factors, including systemic inflammation, distress, sleep disruption, fatigue, pain, and HPA-axis/circadian dysregulation. The second hit occurs when chemotherapy inflicts superimposed neurotoxic injury, including white matter degradation, suppressed hippocampal neurogenesis, and blood–brain barrier disruption. The relationship may also be bidirectional: chemotherapy can perturb HPA-axis function, while glucocorticoid signaling may influence treatment response and antitumor immunity. Behavioral, autonomic, and circadian interventions are mechanistically promising, although neuroprotective efficacy remains uncertain. CRCI is likely multifactorial and may begin before chemotherapy. The two-hit framework integrates pretreatment stress-related vulnerability with treatment-associated neurotoxicity but remains hypothesis-generating rather than causally established. Prospective studies beginning at diagnosis and incorporating serial cognitive, psychological, endocrine, inflammatory, autonomic, and neuroimaging measures are needed to test this model and identify patients at greatest risk. Full article

Post-stroke cognitive impairment (PSCI) is a frequent and disabling consequence of stroke that limits long-term recovery and quality of life. Disruption of the hippocampal neurogenic niche may impair adult hippocampal neurogenesis (AHN), while exercise is increasingly recognized as a promising non-pharmacological strategy for cognitive rehabilitation. This review synthesizes evidence that exercise may shift the post-stroke hippocampal niche from a hostile to a permissive state through coordinated regulation of neuroinflammation, neurovascular integrity, and mitochondrial homeostasis. We distinguish increased progenitor proliferation from productive neurogenesis, defined by the survival, maturation, appropriate positioning, and functional integration of newborn neurons. Exercise may attenuate inflammatory signaling, support angiogenesis and blood–brain barrier repair, and improve mitochondrial biogenesis and quality control; however, much of the mechanistic evidence remains preclinical, and increases in early neurogenic markers do not by themselves establish functional neuronal integration or causality. Current clinical evidence supports cognitive benefits of exercise more strongly than it supports AHN as the indispensable mediator of those benefits. A productive-neurogenesis framework therefore provides a more rigorous basis for interpreting existing studies and designing future experiments that combine lineage tracing, temporally controlled neurogenesis ablation, circuit-level analysis, and domain-specific cognitive outcomes. Full article

Adult hippocampal neurogenesis is involved in hippocampal plasticity and can be enhanced by voluntary physical activity, which also elevates “brain-derived neurotrophic factor” (BDNF) levels and improves memory performance. BDNF might either be essential for the maintenance of neurogenesis, or be necessary for mediating activity-dependent increases in neurogenesis. In order to get more insight on this, we examined male heterozygous BDNF-deficient (BDNF +/−) mice with or without access to a running wheel. Only males were analyzed, since sex steroids can interact with BDNF signaling pathways. Although male BDNF +/− mice exhibited a higher body weight as compared to age-matched controls (BDNF +/+), they did not differ in distance traveled, running time or running speed. We then analyzed whether changes in adult hippocampal neurogenesis can be observed. Under housing conditions without running wheels, the rates of basal adult hippocampal neurogenesis were not altered between genotypes. Interestingly, voluntary wheel running significantly increased neurogenesis in both groups; however, the magnitude was attenuated in BDNF +/− mice. These results indicate that, in adult male mice, reduced BDNF availability does not impair basal adult hippocampal neurogenesis, but limits the plasticity-related enhancement of neurogenesis induced by physical activity. Full article

Objectives: Alzheimer’s disease (AD) is associated with impaired adult hippocampal neurogenesis (AHN). This study aimed to establish an in vitro model of Aβ_1–42 oligomer-damaged neural stem cells (NSCs) and to employ the 5×FAD mouse model of AD in vivo, and to evaluate the therapeutic effects of brain-derived neurotrophic factor-loaded hyaluronic acid hydrogel (BDNF-HA gel) on AHN. Methods: In vitro, BDNF-HA gel was co-cultured with Aβ_1–42 oligomer-impaired NSC spheres and evaluate NSC proliferation, migration, and differentiation. In vivo, BDNF-HA gel was infused intracerebroventricularly into 5×FAD mice. Using BrdU labeling, immunofluorescence, anterograde transsynaptic viral tracing, and behavioral tests, we assessed the effects of BDNF-HA gel on adult neurogenesis, newborn neuron integration into memory circuits, and cognitive function. Results: In vitro, BDNF-HA gel attenuated Aβ_1–42-induced NSC apoptosis, restored proliferation and migration, promoted differentiation into neuroblasts, newborn neurons, and oligodendrocytes, and alleviated mitochondrial depolarization and loss of mitochondrial mass. In vivo, despite the absence of significant Aβ plaques reduction in 5×FAD mice, BDNF-HA gel markedly enhanced NSC proliferation and neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ). Behavioral tests further revealed significant improvements in object recognition, spatial working memory, and spatial reference memory. Conclusions: BDNF-HA gel can effectively counteract the toxic microenvironment induced by Aβ oligomers, promoting NSC proliferation, migration, and differentiation into neurons. Without altering the Aβ burden, it significantly enhances adult neurogenesis and rescues cognitive deficits in AD mice. Full article

Temporal lobe epilepsy (TLE) is a common drug-resistant epilepsy characterized by recurrent seizures, cognitive impairment, aberrant adult hippocampal neurogenesis, inhibitory circuit disruption, and persistent inflammatory remodeling. Current anti-seizure medications primarily offer symptomatic control and do not target the progressive structural and functional deterioration of epileptic hippocampal networks. Here, we investigated whether local nerve growth factor (NGF)-hydrogel delivery during the latent phase after status epilepticus could mitigate hippocampal pathological remodeling and improve long-term outcomes in a kainic acid (KA)-induced mouse model (utilizing C57BL/6J and Nestin-CreERT2 mice). Animals were randomly assigned to three groups: the saline control group, the untreated KA epilepsy group, and the KA + NGF-hydrogel treatment group. NGF-hydrogel was administered into hippocampal Cornu Ammonis 1 (CA1) beginning 3 days post-kainic acid and repeated every 15 days. Histological, immunofluorescence, circuit-tracing, electrophysiology, electroencephalography (EEG), and behavioral assessments were used to evaluate neurogenesis, microenvironment, circuit readouts, seizure burden, and cognition. NGF-hydrogel treatment was associated with preserved dentate gyrus neural stem cell populations, improved newborn granule cell localization and maturation, attenuated neuroinflammation and gliosis, and partial recovery of inhibitory interneuron markers. These changes were accompanied by improved hippocampal circuit readouts, reduced chronic spontaneous seizure burden, and enhanced recognition and spatial memory. Our findings indicate that local NGF-hydrogel delivery following status epilepticus is associated with improved hippocampal remodeling and functional outcomes, and suggest that biomaterial-based neurotrophic support may be a promising strategy for providing targeted neuroprotection and facilitating excitatory/inhibitory (E/I) balance reconstruction in the epileptic hippocampus. Full article

Adult hippocampal neurogenesis persists throughout the human lifespan, yet declines in Alzheimer’s disease and major depression, associated in part with reduced brain-derived neurotrophic factor (BDNF) levels. For rodents, environmental enrichment, dichotomised primarily as physical activity and spatial complexity, robustly promotes adult hippocampal neurogenesis, but no framework has translated these findings to human environments. This review is the first to synthesise evidence across the full translational pathway, arguing that spatial complexity and physically active navigation in neighbourhoods and buildings constitute a humanised form of environmental enrichment. It proposes that standard indoor environments may represent a functionally impoverished condition for the human hippocampus, paralleling standard laboratory caging. An applied model is presented, mapping built environment features onto the neurobiological mechanisms regulating adult hippocampal neurogenesis, with BDNF as the central translatable biomarker linking environmental exposures to neurogenic outcomes. A methodological roadmap for future empirical validation is also outlined. This framework repositions the built environment as a modifiable determinant of adult hippocampal neurogenesis in humans, with implications for mitigating the risk of depression, cognitive impairment, and Alzheimer’s disease. Full article

Prenatal exposure to ionizing radiation is a known risk factor for neurodevelopmental deficits; however, the molecular mechanisms linking chronic embryonic insult to abnormal brain development remain poorly understood. This study investigated the long-term consequences of chronic prenatal gamma irradiation throughout gestation in C57BL/6 mice. Behavioural analysis of adult offspring revealed a specific increase in depression-like behaviours, with no significant alterations in anxiety or general exploratory activity. Immunohistochemical assessment demonstrated a significant reduction in adult hippocampal neurogenesis, marked by decreased doublecortin (DCX)-positive newborn neurons in the subgranular zone and fewer NeuN-positive mature neurons in the dentate gyrus hilus. Integrated RNA-seq, qPCR, and Western blot analyses implicated the upregulation of the Mef2c/Egr1 signalling pathway in this neurogenic deficit. Furthermore, miRNA sequencing identified a pronounced decrease in miR-1843a-3p, which was subsequently validated to directly target Mef2c. Collectively, these findings suggest that prenatal gamma irradiation disrupts neurogenic processes and adult brain function, leading to specific behavioral abnormalities. This long-term impairment is associated with, and may be at least partially mediated by, dysregulation of the miR-1843a-3p/Mef2c/Egr1 pathway. Full article

Fragile X Syndrome (FXS) is an inherited cause of intellectual disability and autism, arising from silencing of the Fmr1 gene and loss of Fragile X Messenger Ribonucleoprotein 1 (FMRP). FMRP is an RNA-binding protein critically involved in neurodevelopmental processes, including neurogenesis. We examined the proliferation and maturation of adult-born dentate granule cells (abDGCs) and glial populations in Fmr1 knockout (KO) and wild-type (WT) mice at 4, 12, and 24 weeks of age under control and early-life stress (ELS) conditions. Based on prior findings, we hypothesized that KO mice would exhibit increased neurogenesis and atypical responses to ELS compared with WT mice. Using immunohistochemistry, we quantified multiple stages of neurogenesis in the dentate gyrus, including proliferating (Ki67+), immature (doublecortin [DCX]+), and apoptotic (cleaved caspase-3 [CC3]+) cells. We also assessed glia using Iba1 (microglia) and GFAP (astrocytes) immunoreactivity. KO mice displayed significantly increased Ki67+ proliferating and reduced CC3+ apoptotic cells across ages, accompanied by increased Iba1+ and GFAP+ glial densities. However, KO mice exhibited fewer DCX+ neuroblasts at later time points. When reared in ELS conditions, KO mice show blunted or no changes in neurogenesis and glial populations relative to WT mice reared in ELS conditions or KO mice in control conditions. These results indicate that FMRP loss disrupts hippocampal neurogenesis by increasing cell proliferation while limiting neuronal maturation and expanding glial populations. Moreover, the absence of neurogenic and glial responses to ELS in KO mice highlights a gene–environment interaction that may influence FXS-related neuropathology by limiting the adaptive capacity of the hippocampal neurogenic niche. Full article

The brain has a higher energy demand per unit weight than any other organ in the body; however, links between metabolism, diet and neurological function have historically been underexplored. This partly stems from early assumptions that brain metabolism is primarily dependent on glucose and ketone bodies, whereas more recent evidence indicates broader metabolic flexibility and complex cell-type specialisation. In the past few decades, brain metabolism has become increasingly recognised as relevant to neurological and mental health, and many neurodegenerative disorders are accompanied by changes in brain energy utilisation. In parallel, epidemiological studies associate hypercaloric dietary patterns and metabolic disorders—particularly type-2 diabetes mellitus—with increased risk of later cognitive decline and sporadic Alzheimer’s disease, although causal pathways remain difficult to establish in humans. In this narrative review, we summarise selected findings linking “unhealthy” diets to synaptic function, focusing on synaptic plasticity, neuroinflammation and adult hippocampal neurogenesis, and we distinguish between evidence from human observational studies and mechanistic insights from animal and cellular models. We also discuss candidate mechanisms—including insulin resistance-linked signalling changes, lipid-driven inflammatory amplification, oxidative stress, and altered lipid handling—that may contribute to synaptic vulnerability. Finally, we outline translational considerations and key knowledge gaps (including physiological exposure levels and heterogeneity of experimental paradigms) that currently limit inference from preclinical models to clinical intervention. Full article

Chronic stress is among the most pervasive health challenges of contemporary urban life, yet its persistence is not simply a matter of external pressure. When adult hippocampal neurogenesis is impaired, the brain loses its capacity to regulate the hypothalamic–pituitary–adrenal (HPA) axis and distinguish new threats from familiar ones through dentate gyrus pattern separation, rendering stress self-perpetuating. Physical activity is widely recognised as a promoter of neurogenesis through brain-derived neurotrophic factor (BDNF), yet the built environments in which most people spend approximately 90% of their time simultaneously suppress BDNF through chronic stress and deny sufficient physical activity intensity to restore it, a condition known as type 2 allostatic overload sustained by architectural impoverishment. This paper proposes architectural enrichment as a theoretical framework designed to resolve this problem at its root through two independent but synergistic mechanisms: architecturally mediated voluntary stair use to elevate peripheral BDNF via metabolic pathways, and neurobiophilic design based on the Neurobiophilia Index to attenuate cortisol and passively support BDNF and neurogenesis. Twelve hypothesised neurobiological profiles are derived in a framework that advances the concept of hippocampal neurosustainability, proposing that buildings can be designed not merely to avoid harming the brain but to actively sustain its capacity for resilience amid the stressors of modern urban living. Full article

A reliable isolation of the dentate gyrus (DG) is a critical pre-analytical step for region-specific neurobiological assays, yet DG microdissection practices vary widely and are rarely compared quantitatively under standardized conditions. In addition, long-term paraformaldehyde-fixed archival brain tissue is commonly regarded as unsuitable for microdissection because of reduced pliability and poor anatomical contrast, limiting its use for training and protocol development. Here, we quantitatively compare two commonly used DG microdissection strategies, a medial (intact-block) approach and a coronal (slice-guided) approach across fresh, fixed, and softened-fixed rat brain hemispheres under matched conditions. To enable the use of archival material, fixed hemispheres were subjected to a simple 15-day slow-running tap water softening protocol to improve tissue handling and landmark visibility. Dissection duration and anatomical specificity were evaluated, the latter quantified by measuring residual cornu ammonis (CA)1–3 area on hematoxylin–eosin-stained coronal sections following DG removal. In fresh tissue, the medial approach enabled significantly faster DG isolation than the coronal approach, while both strategies achieved comparable anatomical specificity. In softened-fixed tissue, dissection times increased for both approaches, but the same relative performance ranking was preserved. Softening markedly improved tissue pliability and boundary visualization, particularly benefiting the coronal, stepwise dissection strategy. Residual CA1–3 areas did not differ significantly between approaches or tissue states. This study provides a validated, training-oriented DG microdissection workflow that supports methodological standardization, reproducibility, and 3R-aligned use of archival tissue, strengthening the pre-analytical foundation for downstream region-specific neuroscience assays. Full article

Adult neurogenesis, the process of generating new, functional neurons in the mature central nervous system, represents a key mechanism of brain plasticity and a potential source of regeneration. This process occurs primarily within specialised neurogenic niches: the subgranular zone of the hippocampal dentate gyrus (SGZ) and the subependymal zone (SEZ). It is regulated by a complex network of endogenous factors (e.g., hormones, neurotrophins, growth factors) and exogenous factors (environment, stress, diet, physical activity). Impairments in neurogenesis are linked to the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In their course, chronic inflammation, mitochondrial dysfunction, oxidative stress, and the accumulation of pathological proteins (β-amyloid, Tau protein, α-synuclein) create a microenvironment that inhibits the proliferation, differentiation, and survival of new neurons. This results in the exacerbation of cognitive and memory deficits. A review of the literature indicates that modulating neurogenesis through non-pharmacological interventions (e.g., a diet rich in anti-inflammatory compounds, physical exercise) and targeted therapeutic strategies represents a promising, albeit complex, research avenue. The primary challenge remains not only stimulating neuron generation but also ensuring their proper maturation, survival, and functional integration into existing neuronal circuits. A deeper understanding of the molecular and environmental mechanisms regulating adult neurogenesis may open new therapeutic possibilities for slowing the progression of neurodegenerative diseases. Full article

Affective disorders, such as major depressive disorder and anxiety disorders, represent a major global health burden, with current treatments proving inadequate for a substantial proportion of patients. Emerging research highlights the microbiota–gut–brain (MGB) axis as a crucial bidirectional communication system influencing brain function and neuroplasticity through neural, endocrine, immune, and metabolic pathways. This narrative review examines probiotics—live beneficial microorganisms—as modulators of adult neurogenesis and synaptic plasticity, two processes fundamentally implicated in the pathophysiology of affective disorders. Preclinical evidence demonstrates that specific strains, particularly from the Lactobacillus and Bifidobacterium genera, promote hippocampal neurogenesis and synaptic function through epigenetic regulation via short-chain fatty acids (SCFAs), notably butyrate-mediated histone deacetylase inhibition, modulation of neuroinflammatory pathways, regulation of neurotransmitter receptor expression across glutamatergic, GABAergic, and monoaminergic systems, and production of neuroactive peptides. Clinical evidence from randomized controlled trials and recent meta-analyses indicates that probiotic supplementation produces significant reductions in depressive and anxiety symptoms, with effects correlating to changes in gut microbiota composition and peripheral neuroplasticity biomarkers, particularly brain-derived neurotrophic factor (BDNF). However, significant methodological limitations persist, including small sample sizes, lack of standardization in probiotic strains and dosages, inconsistent outcome measures, and considerable interindividual variability. While the mechanistic and clinical evidence is biologically plausible and directionally promising, it is not yet sufficient to support definitive therapeutic recommendations. Future research must prioritize adequately powered clinical trials with standardized consortia, comprehensive multi-omics biomarker panels, and precision psychobiotic strategies guided by microbiome-defined patient stratification. Full article

Adult neurogenesis is a regulated form of brain plasticity shaped by interactions between hormonal systems and environmental context. Social experience has been identified as an important modulator of neuronal proliferation, differentiation, and survival across the lifespan, although effects vary across species, developmental stages, and experimental paradigms. This review synthesizes evidence indicating that diverse social behaviors—including isolation, social hierarchy, parenting, sexual interaction, social buffering, and social learning—engage neuroendocrine, neurochemical, and stress-related pathways that are associated with modulation of hippocampal and olfactory neurogenesis. Affiliative and reproductive contexts have been linked in multiple models to enhanced neurogenic indices via gonadal hormones, oxytocinergic and vasopressinergic signaling, and neurotrophic mechanisms, whereas chronic isolation or social defeat has frequently been associated with reduced neurogenic markers, particularly within stress-sensitive regions of the ventral dentate gyrus. Sex differences further shape these patterns, reflecting both biological regulation and uneven sampling across paradigms. Comparative findings in prairie voles, eusocial mole-rats, nonhuman primates, songbirds, and teleost fish indicate that social organization can be accompanied by either increased or constrained neurogenic activity, depending on ecological pressures and life-history strategies. Collectively, the available evidence suggests that adult neurogenesis represents a context-dependent plastic process embedded within vertebrate social systems, while underscoring the need for integrative and evidence-graded interpretations. Full article