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Journal of Cellular and Molecular... Apr 2024Bergamot essential oil (BEO) is an extract of the bergamot fruit with significant neuroprotective effect. This study was to investigate the effects and the underlying...
Bergamot essential oil (BEO) is an extract of the bergamot fruit with significant neuroprotective effect. This study was to investigate the effects and the underlying mechanism of BEO in mitigating depression. GC-MS were used to identify its constituents. Antidepressive properties of BEO were evaluated by sucrose preference test (SPT), force swimming test (FST) and open field test (OFT). Nissl staining was used to determine the number of Nissl bodies in hippocampus (HIPP) of rats. Changes in HIPP dendritic length and dendritic spine density were detected by Golgi-Cox staining. Immunohistochemistry and Western blot were used to detect the postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the HIPP of rats. The enzyme-linked immunosorbent assay was used to determine the 5-hydroxytryptamine (5-HT), insulin-like growth factor 1 (IGF-1) and interleukin-1β (IL-1β) in the HIPP, serum and cerebrospinal fluid (CSF) of rats. Inhaled BEO significantly improved depressive behaviour in chronic unpredictable mild stress (CUMS) rats. BEO increased Nissl bodies, dendritic length and spine density, PSD-95 and SYP protein in the HIPP. Additionally, BEO upregulated serum 5-HT, serum and CSF IGF-1, while downregulating serum IL-1β. Collectively, inhaled BEO mitigates depression by protecting the plasticity of hippocampal neurons, hence, providing novel insights into treatment of depression.
Topics: Rats; Animals; Depression; Oils, Volatile; Insulin-Like Growth Factor I; Serotonin; Hippocampus; Disks Large Homolog 4 Protein; Neurons; Stress, Psychological; Disease Models, Animal; Behavior, Animal
PubMed: 38553964
DOI: 10.1111/jcmm.18178 -
Brain Sciences Feb 2024Previous studies have shown that Lindl. alkaloids (DNLAs) have neuroprotective effects in several Alzheimer's disease (AD) models. Dendrobine (DDB) is one of the...
Previous studies have shown that Lindl. alkaloids (DNLAs) have neuroprotective effects in several Alzheimer's disease (AD) models. Dendrobine (DDB) is one of the monomer components with the highest content in DNLAs. However, the effects of DDB on cognitive impairments in AD remain unknown. In this study, we investigated the efficacy of DDB in 3 × Tg-AD mice to determine whether DDB was a key component of the anti-AD effect of DNLAs. Five-month mice were intragastrically administrated with DDB (10 and 20 mg/kg/d) or DNLAs (20 mg/kg/d) for seven consecutive months, and the effects of DDB and DNLAs were evaluated at twelve months. The results revealed that 3 × Tg-AD mice treated with DDB showed enhanced nesting ability. DDB also effectively rescued spatial learning and memory deficits in 3 × Tg-AD mice. Meanwhile, DDB treatment prevented the loss of dendritic spine density, with increased expression levels of synaptophysin, PSD95, and NCAM in the hippocampus. Finally, DDB ameliorated the increase in APP, sAPPβ, CTF-β, and β-amyloid peptides, accompanied by the promotion of GSK phosphorylation at the Ser9 site, thereby reducing hyperphosphorylated tau levels. As the active component of DNLA, DDB can preserve cognitive function, alleviate neuronal and synaptic defects, and improve APP/tau pathology in 3 × Tg-AD mice.
PubMed: 38539620
DOI: 10.3390/brainsci14030231 -
Nature Communications Mar 2024Long noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity...
Long noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity impacts the transcriptional regulation of lncRNAs, or if this leads to synapse-related changes and contributes to the formation of long-term memories. Here, we report the identification of a lncRNA, SLAMR, which becomes enriched in CA1-hippocampal neurons upon contextual fear conditioning but not in CA3 neurons. SLAMR is transported along dendrites via the molecular motor KIF5C and is recruited to the synapse upon stimulation. Loss of function of SLAMR reduces dendritic complexity and impairs activity-dependent changes in spine structural plasticity and translation. Gain of function of SLAMR, in contrast, enhances dendritic complexity, spine density, and translation. Analyses of the SLAMR interactome reveal its association with CaMKIIα protein through a 220-nucleotide element also involved in SLAMR transport. A CaMKII reporter reveals a basal reduction in CaMKII activity with SLAMR loss-of-function. Furthermore, the selective loss of SLAMR function in CA1 disrupts the consolidation of fear memory in male mice, without affecting their acquisition, recall, or extinction, or spatial memory. Together, these results provide new molecular and functional insight into activity-dependent changes at the synapse and consolidation of contextual fear.
Topics: Mice; Male; Animals; RNA, Long Noncoding; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Neurons; Hippocampus; Mental Recall; Neuronal Plasticity; Mice, Inbred C57BL
PubMed: 38538603
DOI: 10.1038/s41467-024-46972-8 -
Journal of Integrative Neuroscience Mar 2024Tanshinone IIA (TSIIA) is an element of the effective ingredients of Bunge (Labiatae), exhibits a significant therapeutic effect in brain neuroprotection. The focus of...
BACKGROUND
Tanshinone IIA (TSIIA) is an element of the effective ingredients of Bunge (Labiatae), exhibits a significant therapeutic effect in brain neuroprotection. The focus of this study was the examination of synaptic plasticity of in Mg2+-free-induced epileptic hippocampus neurons and how TSIIA protects against it.
METHODS
The purity of the primary hippocampal neurons extracted from Sprague Dawley rats was assessed within 24 hours by microtubule-associated protein (MAP2) immunofluorescence staining. A hippocampal neuron model for Mg2+-free-induced spontaneous recurrent epileptiform discharge was developed, five experimental groups were then randomized: blank (Blank), model (Model), TSIIA (TSIIA, 20 µM), LY294002 (LY294002, 25 µM), and TSIIA+LY294002 (TSIIA+LY294002, 20 µM+25 µM). FIJI software was used to examine variations of neurite complexity, total length of hippocampal neurons, number of primary dendrites and density of dendritic spines. Developmental regulation brain protein (Drebrin) and brain-derived neurotrophic factor (BDNF) expression was evaluated using immunofluorescence staining and the relative expression of phospho-protein kinase B (p-Akt)/Akt, BDNF, synaptophysin (SYN) and postsynaptic density 95 (PSD-95) determined by Western blot.
RESULTS
In contrast to the model group, TSIIA drastically reduced damage to synaptic plasticity of hippocampal neurons caused by epilepsy ( < 0.05). The TSIIA group showed a significant increase in the relative expression of PSD-95, SYN, BDNF, and p-Akt/Akt ( < 0.01).
CONCLUSIONS
TSIIA was effective in reducing harm to the synaptic plasticity of hippocampal neurons induced by persistent status epilepticus, with the possible mechanism being regulation of the phosphatidylinositol 3-kinase 56 (PI3K)/Akt signaling pathway.
Topics: Animals; Rats; Abietanes; Brain-Derived Neurotrophic Factor; Disks Large Homolog 4 Protein; Epilepsy; Hippocampus; Neuronal Plasticity; Neurons; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction
PubMed: 38538223
DOI: 10.31083/j.jin2303061 -
Current Issues in Molecular Biology Feb 2024Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy...
Autism spectrum disorder (ASD) is thought to result from susceptibility genotypes and environmental risk factors. The offspring of women who experience pregnancy infection have an increased risk for autism. Maternal immune activation (MIA) in pregnant animals produces offspring with autistic behaviors, making MIA a useful model for autism. However, how MIA causes autistic behaviors in offspring is not fully understood. Here, we show that NKCC1 is critical for mediating autistic behaviors in MIA offspring. We confirmed that MIA induced by poly(I:C) infection during pregnancy leads to autistic behaviors in offspring. We further demonstrated that MIA offspring showed significant microglia activation, excessive dendritic spines, and narrow postsynaptic density (PSD) in their prefrontal cortex (PFC). Then, we discovered that these abnormalities may be caused by overexpression of NKCC1 in MIA offspring's PFCs. Finally, we ameliorated the autistic behaviors using PFC microinjection of NKCC1 inhibitor bumetanide (BTN) in MIA offspring. Our findings may shed new light on the pathological mechanisms for autism caused by pregnancy infection.
PubMed: 38534737
DOI: 10.3390/cimb46030121 -
Scientific Reports Mar 2024This study aimed to investigate structural synaptic plasticity in the medial prefrontal cortex of rats under treadmill exercise pretreatment or naive conditions in a...
Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in vascular dementia rat and improved recognition memory.
This study aimed to investigate structural synaptic plasticity in the medial prefrontal cortex of rats under treadmill exercise pretreatment or naive conditions in a vascular dementia model, followed by recognition memory performance in a novel object recognition task. In this study, 24 Sprague-Dawley rats were obtained and randomly assigned into 4 groups as follows: control group (Con group, n = 6), vascular dementia (VD group, n = 6), exercise and vascular dementia group (Exe + VD group, n = 6), and exercise group (Exe group, n = 6). Initially, 4 weeks of treadmill exercise intervention was administered to the rats in the Exe + VD and Exe groups. Then, to establish the vascular dementia model, the rats both in the VD and Exe + VD groups were subjected to bilateral common carotids arteries surgery. One week later, open-field task and novel recognition memory task were adopted to evaluate anxiety-like behavior and recognition memory in each group. Then, immunofluorescence and Golgi staining were used to evaluate neuronal number and spine density in the rat medial prefrontal cortex. Transmission electron microscopy was used to observe the synaptic ultrastructure. Finally, microdialysis coupled with high-performance liquid chromatography was used to assess the levels of 5-HT and dopamine in the medial prefrontal cortex. The behavior results showed that 4 weeks of treadmill exercise pretreatment significantly alleviated recognition memory impairment and anxiety-like behavior in VD rats (P < 0.01), while the rats in VD group exhibited impaired recognition memory and anxiety-like behavior when compared with the Con group (P < 0.001). Additionally, NeuN immunostaining results revealed a significant decrease of NeuN-marked neuron in the VD group compared to Con group (P < 0.01), but a significantly increase in this molecular marker was found in the Exe + VD group compared to the Con group (P < 0.01). Golgi staining results showed that the medial prefrontal cortex neurons in the VD group displayed fewer dendritic spines than those in the Con group (P < 0.01), and there were more spines on the dendrites of medial prefrontal cortex cells in Exe + VD rats than in VD rats (P < 0.01). Transmission electron microscopy further revealed that there was a significant reduction of synapses intensity in the medial prefrontal cortex of rats in the VD group when compared with the Con group(P < 0.01), but physical exercise was found to significantly increased synapses intensity in the VD model (P < 0.01). Lastly, the levels of dopamine and 5-HT in the medial prefrontal cortex of rats in the VD group was significantly lower compared to the Con group (P < 0.01), and treadmill exercise was shown to significantly increased the levels of dopamine and 5-HT in the VD rats (P < 0.05). Treadmill exercise pretreatment ameliorated structural synaptic plasticity impairments of medial prefrontal cortex in VD rat and improved recognition memory.
Topics: Rats; Animals; Rats, Sprague-Dawley; Dopamine; Serotonin; Dementia, Vascular; Neuronal Plasticity; Memory Disorders; Prefrontal Cortex; Hippocampus
PubMed: 38531892
DOI: 10.1038/s41598-024-57080-4 -
NeuroImage May 2024Memory is closely associated with neuronal activity and dendritic spine formation. Low-intensity transcranial ultrasound stimulation (TUS) improves the memory of...
Memory is closely associated with neuronal activity and dendritic spine formation. Low-intensity transcranial ultrasound stimulation (TUS) improves the memory of individuals with vascular dementia (VD). However, it is unclear whether neuronal activity and dendritic spine formation under ultrasound stimulation are involved in memory improvement in VD. In this study, we found that seven days of TUS improved memory in VD model while simultaneously increasing pyramidal neuron activity, promoting dendritic spine formation, and reducing dendritic spine elimination. These effects lasted for 7 days but disappeared on 14 d after TUS. Neuronal activity and dendritic spine formation strongly corresponded to improvements in memory behavior over time. In addition, we also found that the memory, neuronal activity and dendritic spine of VD mice cannot be restored again by TUS of 7 days after 28 d. Collectively, these findings suggest that TUS increases neuronal activity and promotes dendritic spine formation and is thus important for improving memory in patients with VD.
Topics: Mice; Humans; Animals; Dementia, Vascular; Neurons; Pyramidal Cells; Ultrasonography
PubMed: 38522806
DOI: 10.1016/j.neuroimage.2024.120584 -
Nature Methods May 2024cAMP is a universal second messenger regulated by various upstream pathways including Ca and G-protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we...
cAMP is a universal second messenger regulated by various upstream pathways including Ca and G-protein-coupled receptors (GPCRs). To decipher in vivo cAMP dynamics, we rationally designed cAMPinG1, a sensitive genetically encoded green cAMP indicator that outperformed its predecessors in both dynamic range and cAMP affinity. Two-photon cAMPinG1 imaging detected cAMP transients in the somata and dendritic spines of neurons in the mouse visual cortex on the order of tens of seconds. In addition, multicolor imaging with a sensitive red Ca indicator RCaMP3 allowed simultaneous measurement of population patterns in Ca and cAMP in hundreds of neurons. We found Ca-related cAMP responses that represented specific information, such as direction selectivity in vision and locomotion, as well as GPCR-related cAMP responses. Overall, our multicolor suite will facilitate analysis of the interaction between the Ca, GPCR and cAMP signaling at single-cell resolution both in vitro and in vivo.
Topics: Animals; Cyclic AMP; Calcium; Mice; Visual Cortex; Neurons; Receptors, G-Protein-Coupled; Humans; Mice, Inbred C57BL; Calcium Signaling; HEK293 Cells
PubMed: 38514778
DOI: 10.1038/s41592-024-02222-9 -
IScience Apr 2024Fragile X syndrome (FXS) is caused by the loss of fragile X messenger ribonucleoprotein (FMRP), a translational regulator that binds the transcripts of proteins involved...
Fragile X syndrome (FXS) is caused by the loss of fragile X messenger ribonucleoprotein (FMRP), a translational regulator that binds the transcripts of proteins involved in synaptic function and plasticity. Dysregulated protein synthesis is a central effect of FMRP loss, however, direct translational modulation has not been leveraged in the treatment of FXS. Thus, we examined the effect of the translational modulator integrated stress response inhibitor (ISRIB) in treating synaptic and behavioral symptoms of FXS. We show that FMRP loss dysregulates synaptic protein abundance, stabilizing dendritic spines through increased PSD-95 levels while preventing spine maturation through reduced glutamate receptor accumulation, thus leading to the formation of dense, immature dendritic spines, characteristic of FXS patients and knockout (KO) mice. ISRIB rescues these deficits and improves social recognition in KO mice. These findings highlight the therapeutic potential of targeting core translational mechanisms in FXS and neurodevelopmental disorders more broadly.
PubMed: 38510125
DOI: 10.1016/j.isci.2024.109259 -
Experimental Neurology Jun 2024Overexpression of the Ube3a gene and the resulting increase in Ube3a protein are linked to autism spectrum disorder (ASD). However, the cellular and molecular processes...
Overexpression of the Ube3a gene and the resulting increase in Ube3a protein are linked to autism spectrum disorder (ASD). However, the cellular and molecular processes underlying Ube3a-dependent ASD remain unclear. Using both male and female mice, we find that neurons in the somatosensory cortex of the Ube3a 2× Tg ASD mouse model display reduced dendritic spine density and increased immature filopodia density. Importantly, the increased gene dosage of Ube3a in astrocytes alone is sufficient to confer alterations in neurons as immature dendritic protrusions, as observed in primary hippocampal neuron cultures. We show that Ube3a overexpression in astrocytes leads to a loss of astrocyte-derived spinogenic protein, thrombospondin-2 (TSP2), due to a suppression of TSP2 gene transcription. By neonatal intraventricular injection of astrocyte-specific virus, we demonstrate that Ube3a overexpression in astrocytes in vivo results in a reduction in dendritic spine maturation in prelimbic cortical neurons, accompanied with autistic-like behaviors in mice. These findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels. SIGNIFICANCE STATEMENT: Increased gene dosage of Ube3a is tied to autism spectrum disorders (ASDs), yet cellular and molecular alterations underlying autistic phenotypes remain unclear. We show that Ube3a overexpression leads to impaired dendritic spine maturation, resulting in reduced spine density and increased filopodia density. We find that dysregulation of spine development is not neuron autonomous, rather, it is mediated by an astrocytic mechanism. Increased gene dosage of Ube3a in astrocytes leads to reduced production of the spinogenic glycoprotein thrombospondin-2 (TSP2), leading to abnormalities in spines. Astrocyte-specific Ube3a overexpression in the brain in vivo confers dysregulated spine maturation concomitant with autistic-like behaviors in mice. These findings indicate the importance of astrocytes in aberrant neurodevelopment and brain function in Ube3a-depdendent ASD.
Topics: Animals; Mice; Astrocytes; Autism Spectrum Disorder; Cells, Cultured; Dendritic Spines; Hippocampus; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Neuroglia; Neurons; Somatosensory Cortex; Thrombospondins; Ubiquitin-Protein Ligases
PubMed: 38508482
DOI: 10.1016/j.expneurol.2024.114756