Search Results (383)

Background: A high-fat diet has been shown to have an impact on metabolism resulting in changes in arterial wall thickness and degeneration of surviving neural cells of the hippocampus. The present review focuses on the various animal models used to induce high-fat diet conditions for studying obesity-induced atherosclerosis, along with the associated changes observed in surviving neural cells of the hippocampus. It also highlights the limitations of rodent models and discusses their implications for human research. Methods: The sources for the literature search were Scopus, PubMed, Medline and Google Scholar. Both animal and human studies published were considered and are cited. Results: High-fat-diet-induced vascular changes, mainly in the tunica media, has been shown to have more impact on medium-sized arteries and on the Cornu Ammonis three subregions and outer dentatae gyrus of the hippocampus. Conclusions: High-fat-diet-induced neurovascular changes have been studied radically in animal models, and more supporting studies representing preclinical research should be advanced to humans. Full article

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

Neuroinflammation is a key feature of Alzheimer’s disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm². Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

(1) Background: Evidence from non-human animal and spaceflight analog studies have suggested that traveling to outer space could have a significant impact on the structural properties of the hippocampus, a brain region within the medial temporal lobe that is critical for learning and memory. Here, we tested this hypothesis in a group of astronauts who participated in a six-month mission in the International Space Station (ISS). (2) Methods: We collected magnetic resonance imaging (MRI) scans from a sample of 17 (9 males, 8 females) astronauts before and after the ISS mission, and calculated percent gray matter volume changes in the whole hippocampus and its (anterior, body, and posterior) subregions in both hemispheres. (3) Following the six-month mission in the ISS, we found a significantly decreased volume in the whole left hippocampus; in addition, when looking at subregions separately, we detected a significantly decreased volume in the anterior subregion of the left hippocampus and the body subregion of the right hippocampus. We also found a significantly decreased volume in the whole right hippocampus of male astronauts as compared to female astronauts. (4) Conclusions: This study, providing the very first evidence of hippocampal volumetric changes in astronauts following a six-month mission to the ISS, could have significant implications for cognitive performance during future long-duration spaceflights. Full article

Dysregulated inflammatory processes contribute to depression, and gene–environment interactions may influence an individual’s risk and resilience. Reduced brain-derived neurotrophic factor (BDNF) expression increases susceptibility for developing depressive symptoms, and the Val66Met (rs6265) single-nucleotide polymorphism (SNP) on the BDNF gene is linked to mood disorders. However, whether Val66Met confers increased vulnerability to inflammation-induced depressive tendencies is unknown. Here, we tested the hypothesis that the Val66Met SNP increases vulnerability to inflammation-induced depressive symptoms in a mouse model of lipopolysaccharide (LPS)-induced depression-like behavior. Behavior and neuroinflammation, following a 24 h LPS challenge, were measured in mice expressing the human BDNF Val66Met gene variant or Val66Val littermates (control). The Val66Met genotype did not affect the peripheral inflammatory response, acute neuroinflammation, or the acute sickness behavior response. Val66Met mice exhibited anhedonia-like behavioral responses following LPS challenge, and we found increased mRNA expression of IL-1β and TNFα in the cerebrum compared to controls. The mRNA expression of IL-1β and TNFα in the hippocampus and the nucleus accumbens of Val66Met mice was increased following LPS, and a significant genotype × LPS interaction was detected for CD68 expression in the nucleus accumbens. In summary, these data suggest that immune activation in Val66Met mice increased susceptibility to anhedonic behavior and dysregulated negative regulation of inflammation. Full article

In the freshwater snail L. stagnalis, two hours of shallow water crawling exercise are accompanied by the formation of memory, metabolic, neuronal, and behavioral changes, such as faster orientation in a novel environment. Interestingly, rest following exercise enhances serotonin and dopamine metabolism linked to the formation of memory and adaptation to novel conditions. However, the underlying transcriptional responses are not characterized. In this paper, we show that, while two hours of forced crawling exercise in L. stagnalis produce significant changes in nervous system gene expression, the subsequent rest induces a completely distinct transcriptional program. Chromatin-modifying, vesicle transport, and cell cycle genes were induced, whereas neurodevelopmental, behavioral, synaptic, and hormone response genes were preferentially repressed immediately after two hours of exercise. These changes were normalized after two hours of the subsequent rest. In turn, rest induced the expression of genes functioning in neuron differentiation and synapse structure/activity, while mitotic, translational, and protein degradation genes were repressed. Our findings are likely relevant to the physiology of exercise, rest, and learning in other species. For example, chronic voluntary exercise training in mice affects the expression of many homologous genes in the hippocampus. Moreover, in humans, homologous genes are pivotal for normal development and complex neurological functions, and their mutations are associated with behavioral, learning, and neurodevelopmental abnormalities. Full article

Industrial development has increased environmental dioxin concentrations, sparking concern about human health impacts. Examining dioxin neurotoxicity has highlighted associations with cognitive impairment and behavioral abnormality. Dioxins are ligands of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor; it is speculated that dioxin-induced AHR activation is pivotal for toxic effects. Accurate AHR-expressing cell identification is therefore indispensable for understanding the molecular and cellular mechanisms of dioxin toxicity. Herein, current knowledge regarding AHR expression in the mammalian brain is summarized, and dioxin neurotoxicity mechanisms are discussed. Histological studies show AHR-expressing neurons in multiple brain regions, including the hippocampus and cerebral cortex. Dopaminergic and noradrenergic neurons exhibit AHR expression, suggesting possible roles in the monoaminergic system. AHR overactivation evokes dendritic arborization atrophy, whereas its deficiency increases complexity, implying that AHR-mediated signaling is crucial for neuronal growth and maturation. AHR is also involved in neurogenesis and neuronal precursor migration. Collectively, these findings support the notion that dioxin-induced AHR overactivation in individual neurons disrupts neural circuit structure, ultimately leading to impaired brain function. However, as AHR downstream signaling is intertwined with various molecules and pathways, the precise mechanisms remain unclear. Further studies on the expression, signaling, and roles of AHR are needed to clarify dioxin neurotoxicity. Full article

The substantia nigra (SN) has historically been regarded as a pivotal element of the brain’s motor circuits, notably within the context of the nigrostriatal pathway and Parkinson’s disease. However, recent advancements in neuroimaging techniques, particularly tractography, have facilitated the delineation of its anatomical projections. These techniques have revealed the involvement of the SN in a more extensive array of functional networks encompassing cognitive, emotional, and motivational domains. This paper reviews the current knowledge on the structural connectivity of the SN in humans based on diffusion tensor imaging and tractography. It summarizes the main projection pathways, including classical and newly described connections, such as the direct SN pars compacta connections to the thalamus, cortico–neural inputs, and connections to limbic regions and the hippocampus. Furthermore, the text delves into the distinctions between the SN pars compacta and SN pars reticulata subregions, exploring their parcellation based on connectivity. The paper demonstrates that the SN is a functionally diversified nucleus, the implications of which are significant for the understanding of both motor and neuropsychiatric disorders. The present study addresses the paucity of comprehensive treatment in this area and provides a framework for further research on dopaminergic circuits. Full article

Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer’s disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ_25–35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau¹⁸¹, Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau¹⁸¹ in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD. Full article

PDE11A is a little-studied phosphodiesterase sub-family that breaks down cAMP/cGMP, with the PDE11A4 isoform enriched in the memory-related hippocampal formation. Age-related increases in PDE11A expression occur in human and rodent hippocampus and cause age-related cognitive decline of social memories. Interestingly, age-related increases in PDE11A4 protein ectopically accumulate in spherical clusters that group together in the brain to form linear filamentous patterns termed “PDE11A4 ghost axons”. The biophysical/physiochemical mechanisms underlying this age-related clustering are not known. Here, we determine if age-related clustering of PDE11A4 reflects liquid–liquid phase separation (LLPS; biomolecular condensation), and if PDE11A inhibitors can reverse this LLPS. We show human and mouse PDE11A4 exhibit several LLPS-promoting sequence features, including intrinsically disordered regions, non-covalent pi–pi interactions, and prion-like domains that were particularly enriched in the N-terminal regulatory region. Further, multiple bioinformatic tools predict PDE11A4 undergoes LLPS. Consistent with these predictions, aging-like PDE11A4 clusters in HT22 hippocampal neuronal cells were membraneless spherical droplets that progressively fuse over time in a concentration-dependent manner. Deletion of the N-terminal intrinsically disordered region prevented PDE11A4 LLPS despite equal protein expression between WT and mutant constructs. 1,6-hexanediol, along with tadalafil and BC11-38 that inhibit PDE11A4, reversed PDE11A4 LLPS in HT22 hippocampal neuronal cells. Interestingly, PDE11A4 inhibitors reverse PDE11A4 LLPS independently of increasing cAMP/cGMP levels via catalytic inhibition. Importantly, orally dosed tadalafil reduced PDE11A4 ghost axons in old mouse ventral hippocampus by 50%. Thus, PDE11A4 exhibits the four defining criteria of LLPS, and PDE11A inhibitors reverse this age-related phenotype both in vitro and in vivo. Full article

Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, utilizing SSRIs and SNRIs, with Esketamine emerging as a supplementary option in recent times. Nevertheless, there is a growing focus on exploring the relationship between inflammation and depression, revealing a strong correlation between the two. This insight prompts consideration of the anti-inflammatory properties of current antidepressants in their therapeutic application. Methods: A systematic literature search was conducted using the PubMed database to identify randomized controlled trials (RCTs) and clinical trials (CTs) that assessed the in vivo anti-inflammatory effects of SSRIs (fluoxetine, escitalopram, sertraline, and paroxetine), the SNRI venlafaxine, and esketamine/ketamine in human subjects undergoing treatment for depression. The included studies were evaluated based on changes in levels of pro-inflammatory and anti-inflammatory markers in response to the antidepressant treatments. Results: SSRIs, SNRIs, esketamine, and ketamine (a racemic mixture of S- and R-ketamine not formally approved for the treatment of depression) exhibit anti-inflammatory effects through diverse mechanisms, such as reducing pro-inflammatory cytokines or enhancing anti-inflammatory cytokines in serum or within specific brain regions like the hippocampus and prefrontal cortex. These actions are mediated through various inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome, the glutamatergic system, the gut–brain axis, the hypothalamic–pituitary axis, impaired neuroplasticity, and the kynurenine pathway. Conclusions: In summary, SSRIs, SNRIs, esketamine, and ketamine exert an anti-inflammatory role alongside their antidepressant effects via these intricate mechanisms. Full article

Brain ischemia-reperfusion (IR) injury is a critical pathological process that leads to extensive neuronal death, with hippocampal pyramidal cells, particularly those in the cornu Ammonis 1 (CA1) subfield, being highly vulnerable. Until now, human olfactory mitral cell resistance to IR injury has not been directly studied, but olfactory dysfunction in humans is frequently reported in systemic vascular conditions such as ischemic heart failure and may serve as an early clinical marker of neurological or cardiovascular disease. Mitral cells, the principal neurons of the olfactory bulb (OB), exhibit remarkable resistance to IR injury, suggesting the presence of unique molecular adaptations that support their survival under ischemic stress. Several factors may contribute to the resilience of mitral cells. They have a lower susceptibility to excitotoxicity, mitigating the harmful effects of excessive glutamate signaling. Additionally, they maintain efficient calcium homeostasis, preventing calcium overload—a major trigger for cell death in vulnerable neurons. Mitral cells may also express high baseline levels of antioxidant enzymes and their activities, counteracting oxidative stress. Their robust mitochondrial function enhances energy production and reduces susceptibility to metabolic failure. Furthermore, neuroprotective signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated antioxidative responses, further bolster their resistance. In addition to these intrinsic mechanisms, the unique microvascular architecture and metabolic support within the olfactory bulb provide an extra layer of protection. By comparing mitral cells to ischemia-sensitive neurons, key vulnerabilities—such as oxidative stress, excitotoxicity, calcium dysregulation, and mitochondrial dysfunction—can be identified and potentially mitigated in other brain regions. Understanding these molecular determinants of neuronal survival may offer valuable insights for developing novel neuroprotective strategies to combat IR injury in highly vulnerable areas, such as the hippocampus and cortex. Full article

The composition of genomic mediators of glucocorticoid actions in the brain remains elusive because of low-statistical-power experiments and the associated transcriptomic data with very low consistency. The problem is further exaggerated by the underrepresentation of chronic experiments and the interpretation of differentially expressed genes without understanding their contribution to the total transcriptomic activity. To fill existing gaps in knowledge, we have performed a large transcriptomic experiment, testing the effects of prolonged treatment with corticosterone on the hippocampal transcriptome (RNA sequencing). The experiment showed that prolonged treatment with corticosterone induced a set of transcriptomic effects that were replicable across treatment durations, including genes relevant for human PTSD (Opalin, Pllp, Ttyh2, Lpar1) and prolonged stress in animals (Cnp, Fam163a, Fcrls, Tmem125). Some of the affected genes are specific for oligodendrocytes, neurons, astrocytes, immune cells, the vascular system, and brain ventricles, indicating that glucocorticoids may affect all central nervous system components. The data also showed that the largest changes in expression of corticosterone-responsive genes are restricted to genes with a relatively low expression level and small contribution to the overall pool of mRNAs in the hippocampus. As a result, even a large change in the number of affected genes leads to a small change in the number of newly synthesized mRNA copies. This means, in turn, that the transcriptomic changes induced by corticosterone have low-cost effects on the brain. This specificity of transcriptomic responses also poses a challenge for the interpretation of data and constitutes a potential source of reporting bias in past studies. Therefore, there is a need for further research on products of gene expression, both at the transcriptomic and proteomic levels, during stress conditions. Full article

While the greatest risk factor for Alzheimer’s disease (AD) is aging, women are disproportionately affected by the disease. Interestingly, the hippocampus and cerebellum exhibit gender-specific cytoarchitecture differences, which are associated with AD, despite the absence of a role in animal reproductive behavior or hormonal signaling. This study investigates the potential association of sex differences associated with AD by interrogating cerebellar and hippocampal volume in preclinical (MCI) as well as clinical phases of AD compared to cognitively normal patients (CN) and in an animal model of AD, the streptozotocin (STZ)-induced sporadic AD model. In order to investigate putative changes in cerebellum and hippocampus in a rat model of AD, we used a STZ-induced sporadic AD model at three different time points (2, 4, and 8 weeks) after surgery in male and female rats. Previous studies have reported hippocampal-dependent changes as well as sex-dependent behavioral and signaling effects in the STZ animal model of sporadic AD while our current study showed involvement of cerebellum-mediated changes. To interrogate the role of cerebellar volume in AD progression within the human context, we analyzed data available through the Alzheimer’s Disease Neuroimaging Initiative (ADNI). In a cross-sectional analysis, we observed that levels of peripheral Glial Acidic Fibrillary Protein (GFAP) (astrocytic protein) were associated negatively with cerebellar and hippocampal volumes (β = −0.002, p-value = 0.04; β = −6.721, p-value < 0.0001) and were associated with sex specific differences in males. Our analysis identified that the effect on hippocampal volume was earlier in disease stage, reinforcing the relevance of longitudinal alterations of cerebellum and hippocampus volume over time. The STZ animal model of sporadic AD, corroborated the progressive changes in hippocampal volume and more minor and temporally delayed involvement of the cerebellum volume changes which were dependent on sex. This suggests that cerebellar involvement may be secondary to hippocampal neurodegeneration, and both regional differences were dependent on sex. Due to the association with GFAP, our findings may be due to network astrocyte connection spread regardless of primary pathology. Overall, our study uncovers a novel role for cerebellum in AD in a model and in the human context. Full article