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Experimental Neurology Aug 2024Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive...
OBJECTIVE
Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis.
METHODS
Monoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3-4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout.
RESULTS
Mice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9-11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3-4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8-10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation.
SIGNIFICANCE
These findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant.
Topics: Animals; Humans; Male; Mice; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoantibodies; Disease Models, Animal; Doublecortin Protein; Hippocampus; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Neurogenesis; Receptors, N-Methyl-D-Aspartate
PubMed: 38801989
DOI: 10.1016/j.expneurol.2024.114838 -
Biochemical Pharmacology Jul 2024TMP269, a class IIA histone deacetylase inhibitor with selectivity, that has a protective effect on the central nervous system, yet its specific mechanism of action...
TMP269, a class IIA histone deacetylase inhibitor with selectivity, that has a protective effect on the central nervous system, yet its specific mechanism of action remains ambiguous. Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that histone deacetylase 5 plays a key role in the pathological process of depression and the fact that preclinical studies have shown HDAC5 to be a potential antidepressant target, the search for natural drugs or small molecule compounds that can target HDAC5 may be a potential therapeutic strategy for the treatment of depression. In addition, we examined the role of the Brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for neuronal survival and growth, as a potential downstream target of HDAC5. We found downward revision of HDAC5 levels in the hippocampus ameliorated depressive-like behavior in LH (Learned helplessness) mice. Furthermore, injection of HDAC5 overexpressing adenoviral vectors in the hippocampal dentate gyrus of wild-type mice produced a somewhat depressive-like phenotype. Pharmacological, immunofluorescence and biochemical experiments showed that TMP269 could produce antidepressant effects by inhibiting mouse hippocampal HDAC5 and thus modulating its downstream BDNF. Over all, TMP269 mitigated LH-induced depressive-like behaviors and abnormalities in synapse formation and neurogenesis within the hippocampus. These findings suggest potential beneficial effects of TMP269 on depression.
Topics: Animals; Antidepressive Agents; Mice; Male; Depression; Mice, Inbred C57BL; Stress, Psychological; Hippocampus; Histone Deacetylases; Brain-Derived Neurotrophic Factor; Histone Deacetylase Inhibitors; Behavior, Animal
PubMed: 38801927
DOI: 10.1016/j.bcp.2024.116320 -
Progress in Neuro-psychopharmacology &... May 2024Chronic neuropathic pain (NP) is commonly associated with cognitive and emotional impairments. Cannabidiol (CBD) presents a broad spectrum of action with a potential...
BACKGROUND AND PURPOSE
Chronic neuropathic pain (NP) is commonly associated with cognitive and emotional impairments. Cannabidiol (CBD) presents a broad spectrum of action with a potential analgesic effect. This work investigates the CBD effect on comorbidity between chronic NP, depression, and memory impairment.
EXPERIMENTAL APPROACH
The connection between the neocortex and the hippocampus was investigated with biotinylated dextran amine (BDA) deposits in the prelimbic cortex (PrL). Wistar rats were submitted to chronic constriction injury (CCI) of the sciatic nerve and CA treatment with CBD (15, 30, 60 nmol).
KEY RESULTS
BDA-labeled perikarya and terminal buttons were found in CA and dentate gyrus. CCI-induced mechanical and cold allodynia increased c-Fos protein expression in the PrL and CA. The number of astrocytes in PrL and CA increased, and the number of neuroblasts decreased in CA. Animals submitted to CCI procedure showed increasing depressive-like behaviors, such as memory impairment. CBD (60 nmol) treatment decreased mechanical and cold allodynia, attenuated depressive-associated behaviors, and improved memory performance. Cobalt chloride (CoCl: 1 nM), WAY-100635 (0.37 nmol), and AM251 (100 nmol) intra-PrL reversed the effect of CA treatment with CBD (60 nmol) on nociceptive, cognitive, and depressive behaviors.
CONCLUSION
CBD represents a promising therapeutic perspective in the pharmacological treatment of chronic NP and associated comorbidities such as depression and memory impairments. The CBD effects possibly recruit the CA-PrL pathway, inducing neuroplasticity. CBD acute treatment into the CA produces functional and molecular morphological improvements.
PubMed: 38797491
DOI: 10.1016/j.pnpbp.2024.111039 -
International Journal of Developmental... May 2024Modulation of in vivo adult neurogenesis (AN) is an evolving concept in managing neurodegenerative diseases. CDRI-08, a bacoside-enriched fraction of Bacopa monnieri,...
Restoration of hippocampal adult neurogenesis by CDRI-08 (Bacopa monnieri extract) relates with the recovery of BDNF-TrkB levels in male rats with moderate grade hepatic encephalopathy.
Modulation of in vivo adult neurogenesis (AN) is an evolving concept in managing neurodegenerative diseases. CDRI-08, a bacoside-enriched fraction of Bacopa monnieri, has been demonstrated for its neuroprotective actions, but its effect on AN remains unexplored. This article describes the status of AN by monitoring neuronal stem cells (NSCs) proliferation, differentiation/maturation markers and BDNF-TrkB levels (NSCs signalling players) vs. the level of neurodegeneration and their modulations by CDRI-08 in the hippocampal dentate gyrus (DG) of male rats with moderate grade hepatic encephalopathy (MoHE). For NSC proliferation, 10 mg/kg b.w. 5-bromo-2'-deoxyuridine (BrdU) was administered i.p. during the last 3 days, and for the NSC differentiation study, it was given during the first 3 days to the control, the MoHE (developed by 100 mg/kg b.w. of thioacetamide i.p. up to 10 days) and to the MoHE male rats co-treated with 350 mg/kg b.w. CDRI-08. Compared with the control rats, the hippocampus DG region of MoHE rats showed significant decreases in the number of Nestin/BrdU and SOX2/BrdU (proliferating) and DCX/BrdU and NeuN/BrdU (differentiating) NSCs. This was consistent with a similar decline in BDNF/TrkB NSCs. However, all these NSC marker positive cells were observed to be recovered to their control levels, with a concordant restoration of total cell numbers in the DG of the CDRI-08-treated MoHE rats. The findings suggest that the restoration of hippocampal AN by CDRI-08 is consistent with the recovery of BDNF-TrkB-expressing NSCs in the MoHE rat model of neurodegeneration.
PubMed: 38795011
DOI: 10.1002/jdn.10350 -
International Journal of Molecular... May 2024Adult neurogenesis in the dentate gyrus (DG) is impaired during Alzheimer's disease (AD) progression. Curcumin has been reported to reduce cell apoptosis and stimulate...
Adult neurogenesis in the dentate gyrus (DG) is impaired during Alzheimer's disease (AD) progression. Curcumin has been reported to reduce cell apoptosis and stimulate neurogenesis. This study aimed to investigate the influence of curcumin on adult neurogenesis in AD mice and its potential mechanism. Two-month-old male C57BL/6J mice were injected with soluble β-amyloid (Aβ) using lateral ventricle stereolocalization to establish AD models. An immunofluorescence assay, including bromodeoxyuridine (BrdU), doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), was used to detect hippocampal neurogenesis. Western blot and an enzyme-linked immunosorbent assay (ELISA) were used to test the expression of related proteins and the secretion of brain-derived neurotrophic factor (BDNF). A Morris water maze was used to detect the cognitive function of the mice. Our results showed that curcumin administration (100 mg/kg) rescued the impaired neurogenesis of Aβ mice, shown as enhanced BrdU/DCX and BrdU/NeuN cells in DG. In addition, curcumin regulated the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) -mediated glycogen synthase kinase-3β (GSK3β) /Wingless/Integrated (Wnt)/β-catenin pathway and cyclic adenosine monophosphate response element-binding protein (CREB)/BDNF in Aβ mice. Inhibiting Wnt/β-catenin and depriving BDNF could reverse both the upregulated neurogenesis and cognitive function of curcumin-treated Aβ mice. In conclusion, our study indicates that curcumin, through targeting PI3K/Akt, regulates GSK3β/Wnt/β-catenin and CREB/BDNF pathways, improving the adult neurogenesis of AD mice.
Topics: Animals; Male; Mice; Alzheimer Disease; Amyloid beta-Peptides; beta Catenin; Brain-Derived Neurotrophic Factor; Curcumin; Disease Models, Animal; Doublecortin Protein; Hippocampus; Mice, Inbred C57BL; Neurogenesis; Proto-Oncogene Proteins c-akt; Up-Regulation; Wnt Signaling Pathway
PubMed: 38791161
DOI: 10.3390/ijms25105123 -
Brain Sciences May 2024This study explores the multifaceted influence of litter size, maternal care, exercise, and aging on rats' neurobehavioral plasticity and dentate gyrus microglia...
This study explores the multifaceted influence of litter size, maternal care, exercise, and aging on rats' neurobehavioral plasticity and dentate gyrus microglia dynamics. Body weight evolution revealed a progressive increase until maturity, followed by a decline during aging, with larger litters exhibiting lower weights initially. Notably, exercised rats from smaller litters displayed higher body weights during the mature and aged stages. The dentate gyrus volumes showed no significant differences among groups, except for aged sedentary rats from smaller litters, which exhibited a reduction. Maternal care varied significantly based on litter size, with large litter dams showing lower frequencies of caregiving behaviors. Behavioral assays highlighted the detrimental impact of a sedentary lifestyle and reduced maternal care/large litters on spatial memory, mitigated by exercise in aged rats from smaller litters. The microglial dynamics in the layers of dentate gyrus revealed age-related changes modulated by litter size and exercise. Exercise interventions mitigated microgliosis associated with aging, particularly in aged rats. These findings underscore the complex interplay between early-life experiences, exercise, microglial dynamics, and neurobehavioral outcomes during aging.
PubMed: 38790475
DOI: 10.3390/brainsci14050497 -
Brain Sciences Apr 2024Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence...
Previous studies demonstrate that ethanol dependence induced by repeating cycles of chronic intermittent ethanol vapor exposure (CIE) followed by protracted abstinence produces significant gray matter damage via myelin dysfunction in the rodent medial prefrontal cortex (mPFC) and alterations in neuronal excitability in the mPFC and the dentate gyrus (DG) of the hippocampus. Specifically, abstinence-induced neuroadaptations have been associated with persistent elevated relapse to drinking. The current study evaluated the effects of forced abstinence for 1 day (d), 7 d, 21 d, and 42 d following seven weeks of CIE on synaptic plasticity proteins in the mPFC and DG. Immunoblotting revealed reduced expression of CaMKII in the mPFC and enhanced expression of GABA and CaMKII in the DG at the 21 d time point, and the expression of the ratio of GluN2A/2B subunits did not change at any of the time points studied. Furthermore, cognitive performance via Pavlovian trace fear conditioning (TFC) was evaluated in 3 d abstinent rats, as this time point is associated with negative affect. In addition, the expression of the ratio of GluN2A/2B subunits and a 3D structural analysis of neurons in the mPFC and DG were evaluated in 3 d abstinent rats. Behavioral analysis revealed faster acquisition of fear responses and reduced retrieval of fear memories in CIE rats compared to controls. TFC produced hyperplasticity of pyramidal neurons in the mPFC under control conditions and this effect was not evident or blunted in abstinent rats. Neurons in the DG were unaltered. TFC enhanced the GluN2A/2B ratio in the mPFC and reduced the ratio in the DG and was not altered by abstinence. These findings indicate that forced abstinence from CIE produces distinct and divergent alterations in plasticity proteins in the mPFC and DG. Fear learning-induced changes in structural plasticity and proteins contributing to it were more profound in the mPFC during forced abstinence.
PubMed: 38790410
DOI: 10.3390/brainsci14050431 -
Genes May 2024Schizophrenia symptomatology includes negative symptoms and cognitive impairment. Several studies have linked schizophrenia with the PDE4 family of enzymes due to their... (Meta-Analysis)
Meta-Analysis
Schizophrenia symptomatology includes negative symptoms and cognitive impairment. Several studies have linked schizophrenia with the PDE4 family of enzymes due to their genetic association and function in cognitive processes such as long-term potentiation. We conducted a systematic gene expression meta-analysis of four PDE4 genes (PDE4A-D) in 10 brain sample datasets (437 samples) and three blood sample datasets (300 samples). Subsequently, we measured mRNA levels in iPSC-derived hippocampal dentate gyrus neurons generated from fibroblasts of three groups: healthy controls, healthy monozygotic twins (MZ), and their MZ siblings with schizophrenia. We found downregulation of PDE4B in brain tissues, further validated by independent data of the CommonMind consortium (515 samples). Interestingly, the downregulation signal was present in a subgroup of the patients, while the others showed no differential expression or even upregulation. Notably, PDE4A, PDE4B, and PDE4D exhibited upregulation in iPSC-derived neurons compared to healthy controls, whereas in blood samples, PDE4B was found to be upregulated while PDE4A was downregulated. While the precise mechanism and direction of altered PDE4 expression necessitate further investigation, the observed multilevel differential expression across the brain, blood, and iPSC-derived neurons compellingly suggests the involvement of PDE4 genes in the pathophysiology of schizophrenia.
Topics: Schizophrenia; Humans; Cyclic Nucleotide Phosphodiesterases, Type 4; Induced Pluripotent Stem Cells; Neurons; Brain; Male; Female; Adult
PubMed: 38790238
DOI: 10.3390/genes15050609 -
Alcohol, Clinical & Experimental... May 2024Cannabis is increasingly being legalized and socially accepted around the world and is often used with alcohol in social settings. We recently showed that in utero...
BACKGROUND
Cannabis is increasingly being legalized and socially accepted around the world and is often used with alcohol in social settings. We recently showed that in utero exposure to both substances can alter the density of parvalbumin-expressing interneurons in the hippocampus. Here we investigate the effects of in utero alcohol and cannabis exposure, alone or in combination, on somatostatin- and neuropeptide Y-positive (NPY) interneurons. These are separate classes of interneurons important for network synchrony and inhibition in the hippocampus.
METHODS
A 2 (Ethanol, Air) × 2 (tetrahydrocannabinol [THC], Vehicle) design was used to expose pregnant Sprague-Dawley rats to either ethanol or air, in addition to either THC or the inhalant vehicle solution, during gestational days 5-20. Immunohistochemistry for somatostatin- and NPY-positive interneurons was performed in 50 μm tissue sections obtained at postnatal day 70.
RESULTS
Exposure to THC in utero had region-specific and sex-specific effects on the density of somatostatin-positive interneurons in the adult rat hippocampus. A female-specific decrease in NPY interneuron cell density was observed in the CA1 region following THC exposure. Combined exposure to alcohol and THC reduced NPY neurons selectively in the ventral dentate gyrus hippocampal subfield. However, overall, co-exposure to alcohol and cannabis had neither additive nor synergistic effects on interneuron populations in other areas of the hippocampus.
CONCLUSIONS
These results illustrate how alcohol and cannabis exposure in utero may affect hippocampal function by altering inhibitory processes in a sex-specific manner.
PubMed: 38789401
DOI: 10.1111/acer.15350 -
Peptides Aug 2024The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but...
The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but their specific roles remain unclear. This study utilized behavioral and molecular approaches to investigate the effects of putatively reversible blockade of RXFP3 in the ventral dentate gyrus (vDG) of the hippocampus on spatial and fear memory formation in rats. Male Wistar rats received bilateral vDG cannula implantation and injections of the RXFP3 antagonist, R3(BΔ23-27)R/I5 (400 ng/0.5 μL per side), or vehicle at specific time points before acquisition, consolidation, or retrieval phases of the Morris water maze and passive avoidance learning tasks. RXFP3 inhibition impaired acquisition in the passive avoidance task but not the spatial learning task. However, both memory consolidation and retrieval were disrupted in both tasks following RXFP3 antagonism. Ventral hippocampal levels of the consolidation-related kinase p70-S6 kinase (p70S6K) were reduced RXFP3 blockade. These findings highlight a key role for ventral hippocampal RXFP3 signaling in the acquisition, consolidation, and retrieval of spatial and emotional memories, extending previous work implicating this neuropeptide system in hippocampal memory processing.
Topics: Animals; Dentate Gyrus; Rats; Receptors, G-Protein-Coupled; Male; Fear; Rats, Wistar; Avoidance Learning; Memory; Relaxin; Spatial Memory; Maze Learning; Hippocampus; Receptors, Peptide
PubMed: 38788901
DOI: 10.1016/j.peptides.2024.171244