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CNS Neuroscience & Therapeutics Jun 2024Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the...
BACKGROUND
Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the relationship among mitochondrial dynamics, neurogenesis, and spatial memory during normal development remains unclear. This study aims to elucidate the role of mitophagy in spatial memory mediated by neurogenesis during development.
METHODS
Adolescent and adult male mice were used to assess spatial memory performance. Immunofluorescence staining was employed to evaluate levels of neurogenesis, and mitochondrial dynamics were assessed through western blotting and transmission electron microscopy. Pharmacological interventions further validated the causal relationship among mitophagy, neurogenesis, and behavioral performance during development.
RESULTS
The study revealed differences in spatial memory between adolescent and adult mice. Diminished neurogenesis, accompanied by reduced mitophagy, was observed in the hippocampus of adult mice compared to adolescent subjects. Pharmacological induction of mitophagy in adult mice with UMI-77 resulted in enhanced neurogenesis and prolonged spatial memory retention. Conversely, inhibition of mitophagy with Mdivi-1 in adolescent mice led to reduced hippocampal neurogenesis and impaired spatial memory.
CONCLUSION
The observed decline in spatial memory in adult mice is associated with decreased mitophagy, which affects neurogenesis in the dentate gyrus. This underscores the therapeutic potential of enhancing mitophagy to counteract age- or disease-related cognitive decline.
Topics: Animals; Neurogenesis; Mitophagy; Spatial Memory; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mitochondrial Dynamics; Quinazolinones
PubMed: 38887162
DOI: 10.1111/cns.14800 -
Neural Regeneration Research Mar 2025JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal...
JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/β-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
PubMed: 38886955
DOI: 10.4103/NRR.NRR-D-23-01446 -
Molecular Neurobiology Jun 2024To validate that treadmill exercise promotes neurofunctional recovery post ischemic stroke and to specifically explore the role of the CX3CL1/CX3CR1 signaling pathway in...
To validate that treadmill exercise promotes neurofunctional recovery post ischemic stroke and to specifically explore the role of the CX3CL1/CX3CR1 signaling pathway in this treadmill-mediated recovery process. C57BL/6 J mice were used to establish a middle cerebral artery occlusion (MCAO) model. From days 5 to 28 post-stroke, the experimental group did 10-min treadmill sessions twice daily at 12 r/min; the control group remained inactive. On day 6 post-stroke, mice received three intraperitoneal injections of Bromodeoxyuridine (BrdU) or PBS. On days 1, 3, and 5 post-stroke, mice received intracerebroventricular injections of exogenous recombinant CX3CL1, CX3CL1 antagonist, or PBS. The modified neurological severity score (mNSS) and the corner test were used to assess sensorimotor function, and the morris water maze (MWM) test was employed to evaluate cognitive function. Western blot detected CX3CL1 and CX3CR1 protein expression, while immunofluorescence observed these proteins, neurogenesis in the subventricular zone (SVZ), rostral migratory stream (RMS), and dentate gyrus (DG), along with Iba1 and CD68 co-expression. ELISA quantified IL-1β, IL-4, and IL-10 levels. Treadmill exercise significantly improved neurofunctional recovery in MCAO mice, enhanced neurogenesis in the RMS and SVZ, and increased the expression of CX3CL1 and CX3CR1. The CX3CL1/CX3CR1 axis enhanced the impact of treadmill exercise on neurofunctional recovery, promoting neurogenesis in the RMS and SVZ, and reducing inflammation. Additionally, this axis also enhanced neurogenesis and suppressed microglial activation in the DG induced by treadmill exercise. This study demonstrates the CX3CL1/CX3CR1 pathway as critical for treadmill-induced post-stroke recovery, indicating its potential target for exercise mimetics in rehabilitation.
PubMed: 38886327
DOI: 10.1007/s12035-024-04287-1 -
British Journal of Pharmacology Jun 2024Alzheimer's disease (AD) is associated with gradual memory loss and anxiety which affects ~75% of AD patients. This study investigated whether AD-associated anxiety...
BACKGROUND
Alzheimer's disease (AD) is associated with gradual memory loss and anxiety which affects ~75% of AD patients. This study investigated whether AD-associated anxiety correlated with modulation of extrasynaptic δ-subunit-containing GABA receptors (δ-GABARs) in experimental mouse models of AD.
EXPERIMENTAL APPROACH
We combined behavioural experimental paradigms to measure cognition performance, and anxiety with neuroanatomy and molecular biology, using familial knock-in (KI) mouse models of AD that harbour β-amyloid (Aβ) precursor protein App (App) with or without humanized microtubule-associated protein tau (MAPT), age-matched to wild-type control mice at three different age windows.
RESULTS
App KI and App/MAPT AD models showed a similar magnitude of cognitive decline and elevated magnitude of anxiety correlated with neuroinflammatory hallmarks, including triggering receptor expressed on myeloid cells 2 (TREM2), reactive astrocytes and activated microglia consistent with accumulation of Aβ, tau and down-regulation of Wnt/β-catenin signalling compared to aged-matched WT controls. In both the CA1 region of the hippocampus and dentate gyrus, there was an age-dependent decline in the expression of δ-GABARs selectively expressed in parvalbumin (PV)-expressing interneurons, encapsulated by perineuronal nets (PNNs) in the AD mouse models compared to WT mice. In vivo positive allosteric modulation of the δ-GABARs, using a δ-selective-compound DS2, decreased the level of anxiety in the AD mouse models, which was correlated with reduced hallmarks of neuroinflammation, and 'normalisation' of the expression of δ-GABARs.
CONCLUSIONS
Our data show that the δ-GABARs could potentially be targeted for alleviating symptoms of anxiety, which would greatly improve the quality of life of AD individuals.
PubMed: 38886118
DOI: 10.1111/bph.16441 -
Neuropsychopharmacology : Official... Jun 2024Contextual fear conditioning has been shown to activate a set of "fear ensemble" cells in the hippocampal dentate gyrus (DG) whose reactivation is necessary and...
Contextual fear conditioning has been shown to activate a set of "fear ensemble" cells in the hippocampal dentate gyrus (DG) whose reactivation is necessary and sufficient for expression of contextual fear. We previously demonstrated that extinction learning suppresses reactivation of these fear ensemble cells and activates a competing set of DG cells-the "extinction ensemble." Here, we tested whether extinction was sufficient to suppress reactivation in other regions and used single nucleus RNA sequencing (snRNA-seq) of cells in the dorsal dentate gyrus to examine how extinction affects the transcriptomic activity of fear ensemble and fear recall-activated cells. Our results confirm the suppressive effects of extinction in the dorsal and ventral dentate gyrus and demonstrate that this same effect extends to fear ensemble cells located in the dorsal CA1. Interestingly, the extinction-induced suppression of fear ensemble activity was not detected in ventral CA1. Our snRNA-seq analysis demonstrates that extinction training markedly changes transcription patterns in fear ensemble cells and that cells activated during recall of fear and recall of extinction have distinct transcriptomic profiles. Together, our results indicate that extinction training suppresses a broad portion of the fear ensemble in the hippocampus, and this suppression is accompanied by changes in the transcriptomes of fear ensemble cells and the emergence of a transcriptionally unique extinction ensemble.
PubMed: 38877180
DOI: 10.1038/s41386-024-01897-0 -
Advanced Science (Weinheim,... Jun 2024Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input-output function and is...
Intrinsic plasticity, a fundamental process enabling neurons to modify their intrinsic properties, plays a crucial role in shaping neuronal input-output function and is implicated in various neurological and psychiatric disorders. Despite its importance, the underlying molecular mechanisms of intrinsic plasticity remain poorly understood. In this study, a new ubiquitin ligase adaptor, protein tyrosine phosphatase receptor type N (PTPRN), is identified as a regulator of intrinsic neuronal excitability in the context of temporal lobe epilepsy. PTPRN recruits the NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) to Na1.2 sodium channels, facilitating NEDD4L-mediated ubiquitination, and endocytosis of Na1.2. Knockout of PTPRN in hippocampal granule cells leads to augmented Na1.2-mediated sodium currents and higher intrinsic excitability, resulting in increased seizure susceptibility in transgenic mice. Conversely, adeno-associated virus-mediated delivery of PTPRN in the dentate gyrus region decreases intrinsic excitability and reduces seizure susceptibility. Moreover, the present findings indicate that PTPRN exerts a selective modulation effect on voltage-gated sodium channels. Collectively, PTPRN plays a significant role in regulating intrinsic excitability and seizure susceptibility, suggesting a potential strategy for precise modulation of Na1.2 channels' function.
PubMed: 38874331
DOI: 10.1002/advs.202400560 -
Frontiers in Neuroscience 2024Abnormal hippocampal neurodevelopment, particularly in the dentate gyrus region, may be a key mechanism of attention-deficit/hyperactivity disorder (ADHD). In this...
OBJECTIVES
Abnormal hippocampal neurodevelopment, particularly in the dentate gyrus region, may be a key mechanism of attention-deficit/hyperactivity disorder (ADHD). In this study, we investigate the effect of the most commonly used Chinese herb for the treatment of ADHD, Rehmanniae Radix Preparata (RRP), on behavior and hippocampal neurodevelopment in spontaneously hypertensive rats (SHR).
METHODS
Behavior tests, including Morris water maze (MWM) test, open field test (OFT) and elevated plus maze (EPM) test were performed to assess the effect of RRP on hyperactive and impulsive behavior. Hippocampal neurodevelopment was characterized by transmission electron microscopy, immunofluorescence, Golgi staining and Nissl staining approaches. Regulatory proteins such as Trkb, CDK5, FGF2/FGFR1 were examined by Western blot analysis.
RESULTS
The results showed that RRP could effectively control the impulsive and spontaneous behavior and improve the spatial learning and memory ability. RRP significantly reduced neuronal loss and increased the number of hippocampal stem cells, and promoted synaptic plasticity. In addition, FGF/FGFR signaling was upregulated after RRP treatment.
CONCLUSION
RRP can effectively reduce impulsive and spontaneous behavior and ameliorate hippocampal neurodevelopmental abnormalities in ADHD rat model.
PubMed: 38872946
DOI: 10.3389/fnins.2024.1402056 -
ENeuro Jun 2024Glutamatergic synapses exhibit significant molecular diversity but circuit-specific mechanisms that underlie synaptic regulation are not well characterized. Prior...
Glutamatergic synapses exhibit significant molecular diversity but circuit-specific mechanisms that underlie synaptic regulation are not well characterized. Prior reports show that RhoGEF Tiam1 regulates perforant path-dentate gyrus (DG) granule neuron synapses. In the present study, we report Tiam1's homolog Tiam2 is implicated in glutamatergic neurotransmission at CA1 pyramidal neurons. We find that Tiam2 regulates evoked excitatory glutamatergic currents via a post-synaptic mechanism mediated by the catalytic Dbl-homology domain. Overall, we present evidence for RhoGEF Tiam2's role in glutamatergic synapse function at Schaffer-collateral-CA1 pyramidal neuron synapses. Glutamatergic synapses are known to vary in composition and function but how this heterogeneity is established to create input-specific synaptic diversity is not well understood. In the present study we show Tiam2 regulates glutamatergic neurotransmission at Schaffer-collateral-CA1 pyramidal neuron synapses. We find that this function is dependent on its catalytic domain. By contrast we did not observe a role for Tiam2 in synaptic transmission at perforant path-DG granule neuron synapses. We also find that Tiam1 and Tiam2 are individually dispensable for functional synaptic plasticity in CA1 pyramidal neurons. To our knowledge, this is the first evidence of the RhoGEF Tiam2's role in regulating glutamatergic synapses.
PubMed: 38871458
DOI: 10.1523/ENEURO.0500-21.2024 -
Biotechnic & Histochemistry : Official... Jun 2024Hypoxic-ischemic encephalopathy (HIE) is a cause of serious morbidity and mortality in newborns. Dexpanthenol, which is metabolized into D-pantothenic acid, has...
Hypoxic-ischemic encephalopathy (HIE) is a cause of serious morbidity and mortality in newborns. Dexpanthenol, which is metabolized into D-pantothenic acid, has antioxidant and other potentially therapeutic properties. We examined some effects of dexpanthenol on the brains of week-old rat pups with HIE induced by obstruction of the right carotid artery followed by keeping in 8% O for 2 hours. Dexpanthenol (500 mg/kg) was administered intraperitoneally to 16 of 32 pups with HIE. Protein, DNA, and lipid oxidation degradation products were assayed and hippocampal and cortical cell apoptosis and neuronal cell numbers were evaluated in stained sections. Dexpanthenol application reduced oxidative stress and inflammation. TNF-α and IL-6 cytokine levels in HIE also decreased with dexpanthenol treatment. The numbers of caspase-3 positive cells in the dentate gyrus and CA1/CA2/CA3 regions of the hippocampus was lower, and apoptosis was decreased in the dexpanthenol-treated animals. These findings suggest possible clinical applications of dexpanthenol in human HIE.
PubMed: 38869860
DOI: 10.1080/10520295.2024.2365231 -
Metabolic Brain Disease Jun 2024Monosodium glutamate (MSG) is the sodium compound derived from glutamic acid. Excessive daily ingestion of MSG leads to elevated amounts of glutamic acid in the...
Monosodium glutamate (MSG) is the sodium compound derived from glutamic acid. Excessive daily ingestion of MSG leads to elevated amounts of glutamic acid in the bloodstream, which can be detrimental to brain structures. Camellia sinensis, often known as green tea (GT), is a rich source of essential hexogen antioxidants that are necessary for the body. Thirty-two adult male albino rats were divided into four groups (n = 8). Group 1 served as a control -ve group. Group 2 was given GT (1.5 ml/rat/day). Group 3 was given MSG (600 mg/kg/day). Group 4 was given MSG (600 mg/kg/day) and GT (1.5 ml/rat/day). All treatments were given orally for 28 days. MSG administration resulted in significant neurotoxicity in rats that was revealed by the significant reduction of serum concentration of glutathione peroxidase (GPx) and nitric oxide (NO), and the significant elevation of total antioxidant capacity (TAC) accompanied by the significant reduction of levels of serum monoamines (dopamine, serotonin, and norepinephrine) and histological changes in the hippocampus area CA1, dentate gyrus, and cerebellar cortex and positive immunohistochemical staining of glial fibrillary acidic proteins (GFAP) and calretinin. Administration of GT with MSG counteracted the MSG-mediated oxidative stress by significantly increasing serum concentrations of GP and NO and significantly decreasing concentrations of TAC. Furthermore, GT significantly increased levels of serum monoamines (dopamine, serotonin, and norepinephrine). Moreover, it ameliorated the histological changes, GFAP, and calretinin immunostaining in brain tissues. It is envisaged that GT will serve as a viable protective choice for the inclusion of the neurotoxicity treatment procedure.
PubMed: 38869783
DOI: 10.1007/s11011-024-01365-0