Neurogenesis Markers Research Articles

Transient prenatal ruxolitinib treatment promotes neurogenesis and suppresses astrogliogenesis during embryonic mouse brain development

Ruxolitinib is a Janus kinase (JAK) inhibitor that inhibits the JAK/STAT signalling pathway by targeting JAK1 and JAK2, which are crucial for regulating astrogliogenesis. This study assessed the effect of ruxolitinib (5 and 30 mg/kg/day) on developing mouse brains by administering it to pregnant mice from E7.5 to E20.5. No adverse effects were observed in the treated mice. The brains of P1.5 pups were collected, and RNA was extracted to assess markers of neurogenesis and astrogliogenesis through RT-qPCR. The results revealed a significant decrease in Gfap expression (p<0.0001) in both ruxolitinib-treated groups compared to the control, indicating a suppression of astrogliogenesis. Additionally, S100β expression (p<0.05) was significantly reduced in the 30 mg/kg ruxolitinib-treated group. In contrast, the expression of neuronal markers vGLuT1 (p<0.01) and vGLuT2 (p<0.01) increased significantly in the 30 mg/kg treated group, suggesting enhanced neuronal differentiation. Furthermore, 5 and 30 mg/kg ruxolitinib-treated groups showed a significant increase in GAT1 expression (p<0.01) compared to the control group. A marked decrease in Nestin expression was also observed in the 5 mg/kg (p<0.001) and 30 mg/kg (p<0.0001) treated groups. These findings demonstrate that transplacental administration of ruxolitinib modulates key markers involved in neuronal differentiation and gliogenesis in the developing mouse brain, suggesting its potential use in correcting imbalances in early brain development.

ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation

AbstractEssential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer’s disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer’s disease. While autism is more prevalent in boys and Alzheimer’s disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp+/−) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.

Anxiety-like behaviors in rats exposed to the single and combined program of running exercise and environmental enrichment.

Exercise (Ex) and environmental enrichment (EE) as the nondrug solutions have positive effects on cognitive behaviors and also increase the ability to cope with anxiety, fear, and stress. In this research, we decided to investigate the simultaneous effect of Ex and EE on anxiety-like behaviors and hippocampal neurogenesis markers in healthy rats. A total of 40 male Wistar rats were divided into four treatment groups: control, EE, Ex, and EE + Ex. Animals in EE groups were housed in large cages (50 × 50 × 50 cm) equipped with toys and objects of different shapes for 3 weeks. Ex-animals were forced to run on a treadmill once a day for 3 consecutive weeks. Open field (OF) and elevated plus maze (EPM) tests were used to evaluate anxiety behaviors. The hippocampal expression of early neurogenesis markers, doublecortin, and sex determining region Y-box 2, were measured using real-time-PCR. Ex and EE animals separately did not show any significant performance in reducing anxiety levels, neither in EPM nor in OF compared with the control group. When animals were treated with EE and Ex simultaneously, they showed significantly reduced anxiety in both EPM and OF tests compared with the control as well as Ex and EE groups separately. Both treatments in combination were also more effective than individual groups in increasing the neurogenesis molecular markers within the hippocampus. This study proposes that Ex in combination with cognitive engagement is more efficient in alleviating anxiety responses and that can develop a nonpharmacological and multidomain policy that may prevent or delay psychophysiological symptoms.

Slight and hidden hearing loss in young rats is associated with impaired recognition memory and reduced myelination in the corpus callosum.

Slight and hidden hearing loss in children have been linked to cognitive and social difficulties, and yet the neurobiological mechanisms behind these issues remain poorly understood. Most animal models focus on severe hearing loss, leaving the effects of hidden or slight hearing loss largely unexplored. To uncover the neural mechanisms connecting slight/hidden hearing loss to cognitive and social challenges, we induced hearing loss in young (4-week-old) Wistar rats through noise exposure. We then examined cognitive function (object recognition test) and social behavior (juvenile play behavior and social interaction). Changes in brain anatomy were assessed using cortical thickness and hippocampal size measurements, while (immuno)histochemical staining investigated neuronal circuitry maturation (myelin basic protein, parvalbumin, and perineuronal nets) and neurogenesis (doublecortin). Noise-exposed rats displayed slight high-frequency hearing loss (around 20 dB) and hidden hearing loss at other tested frequencies. This slight/hidden hearing loss was associated with impaired object recognition but did not alter social behavior. Slight/hidden hearing loss was associated with reduced myelin basic protein expression in the corpus callosum but no other alterations in cortical thickness, hippocampal size, or other markers of maturation and neurogenesis were found. These findings show that even slight/hidden hearing loss can lead to subtle brain alterations tied to cognitive deficits. This study emphasizes the need for further research to fully understand the brain changes associated with slight/hidden hearing loss and to pinpoint the mechanisms connecting these changes to behavioral deficits. This information is crucial to develop interventions to prevent the cognitive and social consequences of hearing loss. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Divergent changes in complement pathway gene expression in schizophrenia and bipolar disorder: Links to inflammation and neurogenesis in the subependymal zone

Deficits in neurogenesis markers in the subependymal zone (SEZ) are associated with elevated inflammation in schizophrenia and bipolar disorder. However, the extent to which complement factors are also changed in the SEZ of these major psychiatric disorders and their impact on neurogenesis remains poorly understood. We extracted RNA from the SEZ of 93 brains, including controls (n = 32), schizophrenia (n = 32), and bipolar disorder (n = 29) cases. Quantitative RT-PCR measured 13 complement transcripts encoding initiators, convertases, effectors or inhibitors. Differences in abundance were analysed by diagnosis and inflammatory subgroups (high- or low-inflammation), which were previously defined by SEZ cytokine and inflammation marker expression.Complement mRNAs C1QA (p = 0.011), C1QB (p < 0.001), C1R (p = 0.027), and Factor B (p = 0.025) were increased in high-inflammation schizophrenia versus low-inflammation controls. Conversely, high-inflammation bipolar cases had decreased C1QC (p = 0.011) and C3 (p = 0.003). Complement mRNAs C1R (SCZ, p = 0.010; BD, p = 0.047), C1S (SCZ, p = 0.026; BD, p = 0.017), and Factor B (BD, p = 0.025) were decreased in low-inflammation schizophrenia and bipolar subgroups versus low-inflammation controls. Complement inhibitors varied by subgroup: Factor H was increased in high-inflammation schizophrenia (p < 0.001), and CD59 in high-inflammation bipolar disorder (p = 0.020). Complement activator and inhibitor mRNAs were positively correlated with quiescent neural stem cell marker GFAPD (q < 0.05) but negatively with immature neuron markers DLX6-AS1 (q < 0.05) and DCX (q < 0.05).These findings suggest altered complement cascade expression in the SEZ in high- and low-inflammation schizophrenia and bipolar disorder, with opposite directional changes suggesting distinct molecular pathology. Complement activation may promote stem cell quiescence and reduce differentiation or survival of newborn neurons.

New Insights on the Effects of Krill Oil Supplementation, a High-Fat Diet, and Aging on Hippocampal-Dependent Memory, Neuroinflammation, Synaptic Density, and Neurogenesis.

Krill oil (KO) has been described as having the potential to ameliorate the detrimental consequences of a high-fat diet (HFD) on the aging brain, though the magnitude and mechanism of this benefit is unclear. We thus hypothesized that dietary KO supplementation could counteract the effects of cognitive aging and an HFD on spatial learning, neuroinflammation, neurogenesis, and synaptic density in the cortex and hippocampus of aged rats. Sixteen-month-old Sprague Dawley rats were fed for 12 weeks while being divided into four groups: control (CON); control with KO supplementation (CONKO); high-fat diet (HF); and high-fat diet with KO supplementation (HFKO). We measured food consumption, body mass, spatial memory (Morris water maze), microglia, neurogenesis, cytokine concentrations, and synaptic markers (post-synaptic density-95 and synaptophysin). Predictably, an HFD did induce significant differences in body weights, with the high-fat groups gaining more weight than the low-fat controls. However, KO supplementation did not produce significant changes in the other quantified parameters. Our results demonstrate that the dietary KO dose provided in the current study does not benefit hippocampal or cortical functions in an aging model. Our results provide a benchmark for future dosing protocols that may eventually prove to be beneficial.

Spatial transcriptomic analysis of adult hippocampal neurogenesis in the human brain.

Adult hippocampal neurogenesis has been extensively characterized in rodent models, but its existence in humans remains controversial. We sought to assess the phenomenon in postmortem human hippocampal samples by combining spatial transcriptomics and multiplexed fluorescent in situ hybridization. We computationally examined the spatial expression of various canonical neurogenesis markers in postmortem dentate gyrus (DG) sections from young and middle-aged sudden-death males. We conducted in situ assessment of markers expressed in neural stem cells, proliferative cells, and immature granule neurons in postmortem DG sections from infant, adolescent, and middle-aged males. We examined frozen DG tissue from infant (n = 1, age 2 yr), adolescent (n = 1, age 16 yr), young adult (n = 2, mean age 23.5 yr), and middle-aged (n = 2, mean age 42.5 yr) males, and frozen-fixed DG tissue from middle-aged males (n = 6, mean age 43.5 yr). We detected very few cells expressing neural stem cell and proliferative markers in the human DG from childhood to middle age. However, at all ages, we observed a substantial number of DG cells expressing the immature neuronal marker DCX. Most DCX + cells displayed an inhibitory phenotype, while the remainder were non-committed or excitatory in nature. The study was limited by small sample sizes and included samples only from males. Our findings indicate very low levels of hippocampal neurogenesis throughout life and the existence of a local reserve of plasticity in the adult human hippocampus. Overall, our study provides important insight into the distribution and phenotype of cells expressing neurogenesis markers in the adult human hippocampus.

Plant Extracts and ω-3 Improve Short-Term Memory and Modulate the Microbiota–Gut–Brain Axis in D-galactose Model Mice

BackgroundAging, characterized by a slow and progressive alteration of cognitive functions, is associated with gut microbiota dysbiosis, low-grade chronic inflammation, as well as increased oxidative stress and neurofunctional alterations. Some nutrients, such as polyphenols, carotenoids, and omega (ω)-3 (n–3), are good candidates to prevent age-related cognitive decline, because of their immunomodulatory, antioxidant, and neuroprotective properties. ObjectivesThe objective of this study was to demonstrate the preventive effect of a combination of plant extracts (PE) containing Memophenol™ (grapes and blueberries polyphenols) and a patented saffron extract (saffron carotenoids and safranal) and ω-3 on cognitive function in a mouse model of accelerated aging and to understand the biological mechanisms involved. MethodsWe used an accelerated-aging model by injecting 3-mo-old male C57Bl6/J mice with D-galactose for 8 wk, during which they were fed with a balanced control diet and supplemented or not with PE and/or ω-3 (n = 15–16/group). Short-term memory was evaluated by Y-maze test, following analyses of hippocampal and intestinal RNA expressions, brain fatty acid and oxylipin amounts, and gut microbiota composition (16S rRNA gene sequencing). Statistical analyses were performed (t test, analysis of variance, and Pearson correlation). ResultsOur results showed that oral administration of PE, ω-3, or both (mix) prevented hippocampus-dependent short-term memory deficits induced by D-galactose (P < 0.05). This effect was accompanied by the modulation of gut microbiota, altered by the treatment. PE and the mix increased the expression of antioxidative and neurogenesis markers, such as catalase and doublecortin, in hippocampus (P < 0.05 for both). Moreover, ω-3 and the mix showed a higher ω-3 amounts (P < 0.05) and EPA-derived 18- hydroxyeicosapentaenoic acid (P < 0.001) in prefrontal cortex. These changes may contribute to the improvement in memory. ConclusionsThese results suggest that the mix of PE and ω-3 could be more efficient at attenuating age-related cognitive decline than individual supplementations because it targeted, in mice, the different pathways impaired with aging.

MiR-124 mediates the effects of gut microbial dysbiosis on brain function in chronic stressed mice

The gut microbiota plays a key role in the brain function impairment caused by chronic stress, yet its exact mechanism remains unclear. Many studies have revealed the important role of miR-124 in the central nervous system. Meanwhile, previous studies have indicated that miR-124 may be regulated by chronic stress and gut microbiota. Here, we aimed to explore whether miR-124 serves as a mediator for the impacts of gut microbial dysbiosis on brain function in mice subjected to chronic stress. Repeated daily restraint stress for 4 weeks was used to induce chronic stress in mice. Chronic stress resulted in gut microbial dysbiosis, abnormal behaviors, and a decrease in hippocampal miR-124 levels. Treatment with different probiotic mixtures significantly alleviated the effects of chronic stress on hippocampal miR-124 levels and mouse behaviors. Suppression of hippocampal miR-124 expression reversed the beneficial effects of probiotics on cognitive function, neurogenesis, and related molecular markers in chronically stressed mice. Bioinformatics analysis and qPCR suggested that Ptpn11 might be a target gene for miR-124 in mediating the effects of gut microbial dysbiosis on brain function in these mice. These findings suggest that miR-124 is a pivotal regulator that mediates the detrimental effects of gut microbial dysbiosis on brain function and the subsequent cognitive impairment during chronic stress.

Focused magnetic stimulation for motor recovery after stroke

Background and objectivesThe effects of noninvasive focused magnetothermal brain stimulation using magnetic nanoparticles (MNPs) on post-stroke motor deficits and metabolic dormancy in subacute ischemic injury are not well-established. This study examined if magnetothermal brain stimulation using magnetic nanoparticles (Nano-MS) enhances motor recovery after stroke. MethodsWe randomly distributed rats into Sham, Control, MNP injection only, and Nano-MS groups. We administered focused magnetic stimulation for 30 min daily following an MNP injection (15 mg/mL) into the targeted motor cortex via the carotid artery three weeks after the transient (90 min) middle cerebral artery occlusion. We assessed motor functionality via behavioral tests and conducted positron emission tomography (PET) imaging to verify cerebral metabolic activity. We assessed neuronal excitability, neuroinflammation, blood-brain barrier (BBB) integrity, and neurogenesis four weeks post-stroke. ResultsThe Nano-MS group exhibited significantly improved motor deficits and cerebral metabolic activity compared to the Control and MNP groups (p < 0.05). Focused Nano-MS modulated neuronal excitability, evident by a depolarized action potential threshold for spike initiation and reduced firing frequency post-stroke. The Nano-MS group demonstrated markedly decreased inflammatory markers, such as IL-1β, IL-6, TNF-α, MCP-1, and ICAM-1, compared to the Control and MNP groups. BBB integrity and immunofluorescence for neurogenesis markers were substantially improved in the Nano-MS group. ConclusionsFocused Nano-MS facilitates the recovery of motor deficits and metabolic inactivity in the brain by effectively modulating excitability, reducing neuroinflammation, enhancing BBB stability, and promoting neurogenesis. Nano-MS is a potential novel, noninvasive therapy for stroke rehabilitation. Further investigation is warranted.

Study of the neuroprotective properties of metformin in rats with type 2 diabetes mellitus and brain injury induced by intracerebral hemorrhage

The aim of this study was to study the effect of metformin (Met) on the formation of the conditional passive avoidance skills, markers of neurogenesis and oxidative stress in the brain of rats with acute intracerebral hemorrhage (ICH) in the setting of streptozotocin-nicotinamide-induced diabetes. Type 2 diabetes mellitus (T2DM) was induced in rats via the intraperitoneal injection of streptozotocin (STZ) and nicotinamide (NA), ICH – by microinjection of bacterial collagenase into the striatum. Rats were randomly divided into four groups: 1 – intact animals (n=8), 2 – T2DM (n=9); 3 – T2DM+ICH (n=7); 4 – T2DM+ICH+Met (n=7). The passive avoidance test was used to evaluate behavioural activity. Advanced oxidation protein products (AOPP) and lactate were measured by spectrophotometry, advanced glycation end products (AGEs) by quantitative fluorescence, level of 8-hydroxy-2-deoxyguanosine (8-OHdG) was assessed by enzyme-linked immunosorbent assay (ELISA). Histopathological examination was performed using general histological staining techniques and immunohistochemical methods for assessment of expression of endothelial NO-synthase (eNOS), Growth Associated Protein 43 (GAP43), Hypoxia-inducible factor 1-alpha (HIF-1α), neural cadherine (N-cadherine) and vascular endothelial cadherine (VE-cadherine). In this study, metformin had nootropic (anti-amnestic) activity and decreased oxidative stress markers (AGEs, AOPPs and 8-OHdG) levels by 29.1% (p&lt;0.001), 24.9% (p&lt;0.015) and 29.3% (p&lt;0.05) respectively, which indicates its positive impact on the course of free radical oxidation reactions intensified by both diabetes and intracerebral hemorrhage. The study provides additional information on neuroprotective properties of metformin and the emphasizes possibility of using metformin in diabetic patients at risk of hemorrhagic stroke. Considering the increase in VE-cadherin expression by the drug, it is possible to predict its positive effect on the function of blood-brain barrier. This study may serve as a reference for the feasibility of studying the clinical efficacy of metformin under these conditions.

Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms

BackgroundSocial affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with “profound” autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.MethodsBecause ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.ResultsAt the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.LimitationsLarger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.ConclusionsBy embryogenesis, the biological bases of two subtypes of ASD social and brain development—profound autism and mild autism—are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler’s social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.

Role of Apolipoprotein E in the Hippocampus and Its Impact following Ionizing Radiation Exposure.

Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE-/-) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE-/- females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE-/- also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.

GDF11 improves hippocampal neurogenesis and cognitive abilities in diabetic mice by reducing neural inflammation

BackgroundThe cognitive decline associated with type 2 diabetes (T2D) is often attributed to compromised hippocampal neurogenesis and exacerbated neural inflammation. This study investigates the therapeutic potential of growth differentiation factor 11 (GDF11) in reversing these neurodegenerative processes in diabetic mice. ResultWe utilized a murine model of T2D and examined the effects of GDF11 on learning, memory, neurogenesis, and neuroinflammatory markers. Our results indicate that diabetic mice exhibit significant deficits in cognitive function, mirrored by reduced hippocampal neurogenesis and increased neuroinflammation. Chronic administration of GDF11 was observed to significantly enhance cognitive abilities, as evidenced by improved performance in learning and memory tasks. Concurrently, GDF11 treatment restored neural activity and promoted the regeneration of new neurons within the hippocampus. Inflammatory profiling revealed a reduction in neuroinflammatory markers, which was further supported by reduced microglia numbers. To delineate the role of neuroinflammation, we pharmacologically depleted microglia, leading to a restoration of neurogenesis and cognitive functions in diabetic mice. ConclusionThese findings endorse the hypothesis that GDF11 exerts its beneficial effects by modulating neuroinflammatory pathways. Consequently, GDF11 represents a promising intervention to ameliorate diabetes-induced cognitive impairments and neural degeneration through its anti-inflammatory properties.

Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2–9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3′,4′-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

RNA-sequencing suggests extracellular matrix and vasculature dysregulation could impair neurogenesis in schizophrenia cases with elevated inflammation

A subgroup of schizophrenia cases with elevated inflammation have reduced neurogenesis markers and increased macrophage density in the human subependymal zone (SEZ; also termed subventricular zone or SVZ) neurogenic niche. Inflammation can impair neurogenesis; however, it is unclear which other pathways are associated with reduced neurogenesis. This research aimed to discover transcriptomic differences between inflammatory subgroups of schizophrenia in the SEZ. Total RNA sequencing was performed on SEZ tissue from schizophrenia cases, designated into low inflammation (n = 13) and high inflammation (n = 14) subgroups, based on cluster analysis of inflammation marker gene expression. 718 genes were differentially expressed in high compared to low inflammation schizophrenia (FDR p < 0.05) and were most significantly over-represented in the pathway ‘Hepatic Fibrosis/Hepatic Stellate-Cell Activation’. Genes in this pathway relate to extracellular matrix stability (including ten collagens) and vascular remodelling suggesting increased angiogenesis. Collagen-IV, a key element of the basement membrane and fractones, had elevated gene expression. Immunohistochemistry revealed novel collagen-IV+ fractone bulbs within the human SEZ hypocellular gap. Considering the extracellular matrix’s regulatory role in SEZ neurogenesis, fibrosis-related alterations in high inflammation schizophrenia may disrupt neurogenesis. Increased angiogenesis could facilitate immune cell transmigration, potentially explaining elevated macrophages in high inflammation schizophrenia. This discovery-driven analysis sheds light on how inflammation may contribute to schizophrenia neuropathology in the neurogenic niche.

Altered Hippocampal Activation in Seizure-Prone CACNA2D2 Knock-out Mice.

The voltage-gated calcium channel subunit α2δ-2 controls calcium-dependent signaling in neurons, and loss of this subunit causes epilepsy in both mice and humans. To determine whether mice without α2δ-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c-fos and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and α2δ-2 knock-out (CACNA2D2 KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-fos and ΔFosB expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1 h after handling-associated convulsions, KO mice had fewer c-fos-positive cells but dramatically increased ΔFosB expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c-fos expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of α2δ-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.

Potentiation of antidepressant effects: NPY1R agonist and ketamine synergy enhances TrkB signaling and neurogenesis in the ventral hippocampus

ABSTRACT Background Major Depressive Disorder (MDD) poses a significant challenge to global health, with current treatments often limited by efficacy and onset delays. This study explores the synergistic antidepressant-like effects of an NPY1R agonist and Ketamine, targeting their neurobiological interactions within the ventral hippocampus. Research Design and Methods Utilizing a preclinical model, this study administered Neuropeptide Y receptor 1 (NPY1R) agonist and Ketamine, both separately and in combination, through intracerebroventricular (icv) and intranasal (i.n.) routes. The Forced Swimming Test (FST) was employed to assess antidepressant-like activity, while in situ Proximity Ligation Assay and immunohistochemistry were used to examine NPY1R/TrkB heteroreceptor complexes and BDNF expression in the ventral dentate gyrus (DG), along with neurogenesis markers. Results The combined treatment significantly reduced immobility in the FST, indicative of enhanced antidepressant-like effects, correlated with increased formation of NPY1R/TrkB complex and brain-derived neurotrophic factor (BDNF) expression in the ventral DG. These molecular alterations were associated with increased neurogenesis. Conclusions The coadministration of an NPY1R agonist and Ketamine in a rodent model demonstrated potentiated antidepressant responses through synergistic neurobiological pathways, including TrkB signaling and hippocampal neurogenesis. This indicates a novel therapeutic strategy for MDD, warranting further clinical investigation to fully understand its implications.

Conditioned morphine tolerance promotes neurogenesis, dendritic remodelling and pro-plasticity molecules in the adult rat hippocampus.

Structural neuroplasticity of the hippocampus in the form of neurogenesis and dendritic remodelling underlying morphine tolerance is still less known. Therefore, in this study, we aimed to assess whether unconditioned- and conditioned-morphine tolerance can trigger structural neuroplasticity in the dorsal and ventral parts of the adult male rat hippocampus. Evaluation of the levels of neurogenesis markers (Ki67 and DCX) by immunohistochemistry shows that conditioned morphine tolerance is sufficient to increase the baseline topographic level of hippocampal neurogenesis in adult rats. Dendritic spine visualization by Golgi staining shows that the behavioural testing paradigms themselves are sufficient to trigger the hippocampus subregion-specific changes in the dendritic remodelling along the apical dendrites of hippocampal CA1 pyramidal neurons and dentate granule cells in adult rats. Quantitative reverse transcription polymerase chain reaction of Bdnf, Trkb, Rac-1 and RhoA mRNA levels as pro-plasticity molecules, shows that the conditioned morphine tolerance is effective in changing Bdnf and RhoA mRNA levels in the ventral hippocampus of adult rats. In summary, we demonstrate that the acquisition of morphine tolerance promotes adult neurogenesis, dendritic remodelling and pro-plasticity molecules such as Bdnf/Trkb in the rat hippocampus. Indeed, the structural neuroplasticity of the hippocampus may underlie the newly formed aberrant memory and could provide the initial basis for understanding the neurobiological mechanisms of morphine-tolerance plasticity in the hippocampus.

Prebiotics modulate the microbiota–gut–brain axis and ameliorate anxiety and depression-like behavior in HFD-fed mice

Previous research has demonstrated that Prebiotics can influence the composition of the gut microbiota, consequently impacting mood regulation. This study aimed to assess the effects of Prebiotics, specifically Fructooligosaccharides (FOS) and Galactooligosaccharides (GOS) on neuroinflammation, depression, and anxiety-like behavior in a mouse model fed a high-fat diet (HFD). Initially, mice were divided into two groups: a control group on a standard diet (n = 15) and a group on an HFD for 18 weeks (n = 45). By the 13th week, the HFD group was further divided into experimental groups: Control (n = 15), HFD (n = 15), HFD receiving Prebiotics (n = 15), and HFD receiving Fluoxetine (n = 15). From the 13th week onward, the HFD + Prebiotics group received both the high-fat diet and a combination of FOS and GOS, while the HFD + Fluoxetine group received Fluoxetine in their drinking water. In the 18th week, all mice underwent tests to evaluate behavior, including the Tail Suspension Test (TST), Forced Swimming Test (FST), Sucrose Preference Test (SPT), and the Plus Maze Test (PMT), after which they were euthanized. Mice on the HFD exhibited increased body weight, abdominal size, blood glucose, triglyceride levels, cholesterol, insulin, HOMA index, and higher serum IL-1β. These obese mice also displayed an increased number of microglia and astrocytes, activation of the TLR4 pathway, and elevated levels of neuroinflammatory markers like TNF-α, IL-1β, and COX-2. Moreover, obese mice showed increased activation of the IDO pathway and decreased levels of NMDA receptors. Additionally, markers of neurogenesis and synaptic plasticity, such as PSD, SAP 102, CREB-p, and BDNF, were lower. Treatment with FOS and GOS reversed symptoms of depression and anxiety in mice subjected to HD. This improvement in behavior resulted from a reduction in dysbiosis with an increase in acetate-producing bacteria (B. acidifaciens and B. dorei) and intestinal permeability, leading to a decrease in chronic peripheral and central inflammation. Furthermore, the modulation of the gut-brain axis by FOS and GOS promoted elevated acetate and GPR43 levels in the brain and a reduction in the levels of pro-inflammatory cytokines, positively impacting signaling pathways of neuronal proliferation and survival in the hippocampus and prefrontal cortex.