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Cells Apr 2024This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on...
This study investigates the combined effects of the neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31-Pro34]NPY at a dose of 132 µg and Ketamine at 10 mg/Kg on cognitive functions and neuronal proliferation, against a backdrop where neurodegenerative diseases present an escalating challenge to global health systems. Utilizing male rats in a physiological model, this research employed a single-dose administration of these compounds and assessed their impact 24 h after treatment on object-in-place memory tasks, alongside cellular proliferation within the dorsal hippocampus dentate gyrus. Methods such as the in situ proximity ligation assay and immunohistochemistry for proliferating a cell nuclear antigen (PCNA) and doublecortin (DCX) were utilized. The results demonstrated that co-administration significantly enhanced memory consolidation and increased neuronal proliferation, specifically neuroblasts, without affecting quiescent neural progenitors and astrocytes. These effects were mediated by the potential formation of NPY1R-TrkB heteroreceptor complexes, as suggested by receptor co-localization studies, although further investigation is required to conclusively prove this interaction. The findings also highlighted the pivotal role of brain-derived neurotrophic factor (BDNF) in mediating these effects. In conclusion, this study presents a promising avenue for enhancing cognitive functions and neuronal proliferation through the synergistic action of the NPY1R agonist and Ketamine, potentially via NPY1R-TrkB heteroreceptor complex formation, offering new insights into therapeutic strategies for neurodegenerative diseases.
Topics: Animals; Male; Doublecortin Protein; Ketamine; Cognition; Rats, Sprague-Dawley; Rats; Receptors, Neuropeptide Y; Neurons; Cell Proliferation; Receptor, trkB; Brain-Derived Neurotrophic Factor; Dentate Gyrus; Neurogenesis; Receptors, Neuropeptide; Receptors, G-Protein-Coupled
PubMed: 38667284
DOI: 10.3390/cells13080669 -
BioRxiv : the Preprint Server For... Apr 2024Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term...
The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: implications for deep space missions, female crews, and potential antioxidant countermeasures.
Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment is lacking. Here we asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received the antioxidant CDDO-EA (400 µg/g of food) or a control diet (vehicle, Veh) for 5 days and either Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: 1) location discrimination reversal (which tests behavior pattern separation and cognitive flexibility, two abilities reliant on the dentate gyrus) and 2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment end (14.25-month post-IRR), neurogenesis was assessed (doublecortin-immunoreactive [DCX+] dentate gyrus neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. Notably, one radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had worse stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice show normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change in neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew's longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks.
PubMed: 38659963
DOI: 10.1101/2024.04.12.588768 -
BioRxiv : the Preprint Server For... Apr 2024Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the ( ) gene. RTT patients experience a myriad of debilitating...
Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by loss-of-function mutations in the ( ) gene. RTT patients experience a myriad of debilitating symptoms, which include respiratory phenotypes that are often associated with lethality. Our previous work established that expression of the M muscarinic acetylcholine receptor (mAchR) is decreased in RTT autopsy samples, and that potentiation of the M receptor improves apneas in a mouse model of RTT; however, the population of neurons driving this rescue is unclear. Loss of Mecp2 correlates with excessive neuronal activity in cardiorespiratory nuclei. Since M is found on cholinergic interneurons, we hypothesized that M -potentiating compounds decrease apnea frequency by tempering brainstem hyperactivity. To test this, and mice were screened for apneas before and after administration of the M positive allosteric modulator (PAM) VU0453595 (VU595). Brains from the same mice were then imaged for c-Fos, ChAT, and Syto16 using whole-brain light-sheet microscopy to establish genotype and drug-dependent activation patterns that could be correlated with VU595's efficacy on apneas. The vehicle-treated brain exhibited broad hyperactivity when coupled with the phenotypic prescreen, which was significantly decreased by administration of VU595, particularly in regions known to modulate the activity of respiratory nuclei (i.e. hippocampus and striatum). Further, the extent of apnea rescue in each mouse showed a significant positive correlation with c-Fos expression in non-cholinergic neurons in the striatum, thalamus, dentate gyrus, and within the cholinergic neurons of the brainstem. These results indicate that mice are prone to hyperactivity in brain regions that regulate respiration, which can be normalized through M potentiation.
PubMed: 38659804
DOI: 10.1101/2024.04.15.586099 -
Heliyon Apr 2024Addressing the treatment of depression is crucial; nevertheless, the etiology and pathogenesis remain unelucidated. Therefore, this study investigated the effects of...
Addressing the treatment of depression is crucial; nevertheless, the etiology and pathogenesis remain unelucidated. Therefore, this study investigated the effects of teriflunomide (TF) on corticosterone (CORT)-induced depression-like behaviors in mice. Notably, TF administration resulted in a substantial amelioration of anxiety and depression-like behaviors observed in CORT-treated mice. This was evidenced by behavioral assessments conducted via the sucrose preference test (SPT), open-field test (OFT), novelty-suppressed feeding test (NSFT), forced swimming test (FST), and tail suspension test (TST). The administration of CORT inflicts damage upon oligodendrocytes and neurons within the hippocampus. Our findings indicate that TF offers significant protective effects on oligodendrocytes, mitigating apoptosis both and . Additionally, TF was found to counteract the CORT-induced neuronal loss and synaptic damage, as demonstrated by an increase in Nissl-positive cells across hippocampal regions CA1, CA3, and the dentate gyrus (DG) alongside elevated levels of synapse-related proteins including PSD-95 and synaptophysin. Additionally, TF treatment facilitated a reduction in the levels of apoptosis-related proteins while simultaneously augmenting the levels of Bcl2. Our findings indicate that TF administration effectively mitigates CORT-induced depression-like behaviors and reverses damage to oligodendrocytes and neurons in the hippocampus, suggesting TF as a promising candidate for depression.
PubMed: 38655332
DOI: 10.1016/j.heliyon.2024.e29481 -
Journal of Neuroinflammation Apr 2024Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as...
BACKGROUND
Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice.
METHODS
A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated.
RESULTS
Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1β and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1β and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway.
CONCLUSIONS
Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.
Topics: Animals; NF-E2-Related Factor 2; Male; Mice; Mice, Inbred C57BL; Neurogenesis; Gastrointestinal Microbiome; Postoperative Cognitive Complications; Neuroinflammatory Diseases; Succinates; Brain; Cognitive Dysfunction; Anesthesia
PubMed: 38649932
DOI: 10.1186/s12974-024-03103-w -
Data on electroconvulsive seizure in mice, effects of anesthesia on immediate early gene expression.Data in Brief Jun 2024Although electroconvulsive therapy (ECT) is one of the most effective treatments for severe mood and psychotic disorders, the mechanisms underlying its therapeutic...
Although electroconvulsive therapy (ECT) is one of the most effective treatments for severe mood and psychotic disorders, the mechanisms underlying its therapeutic effects remain unknown. Electroconvulsive stimulation (ECS), the animal model for ECT, can be used to investigate the potential therapeutic mechanisms of ECT in rodents. ECS produces numerous effects in the brain, such as increasing levels of growth factors, inducing dendritic sprouting, and stimulating neurogenesis. It also induces high-level expression of immediate early genes (IEGs) that have been implicated in the pathogenesis of schizophrenia, such as early growth response 3 () and activity-regulated cytoskeleton-associated protein (), a validated downstream target of [1-3]. However, the effect of isoflurane anesthesia preceding ECS on IEG response in mice has not been well characterized. This article provides immunofluorescent data of the activity responsive IEG ARC in the dorsal and ventral dentate gyrus of wildtype (WT) mice following ECS with or without anesthesia, as well as following sham ECS. The data in this article relate to a published article that employed serial ECS in mice to investigate the requirement of in the neurobiological effects of this model of ECT [4]. The ability to study the effects of serial ECS has been limited in mice due to high rates of mortality during seizure. Administration of isoflurane anesthesia prior to ECS significantly reduces rodent mortality, irrespective of the number of times ECS is applied [5]. Since general anesthesia is administered to patients prior to ECT, use of isoflurane prior to ECS also more closely models the clinical use of ECT [6].
PubMed: 38646190
DOI: 10.1016/j.dib.2024.110365 -
Neuro-oncology Advances 2024Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy...
BACKGROUND
Changes in the hippocampus after brain metastases radiotherapy can significantly impact neurocognitive functions. Numerous studies document hippocampal atrophy correlating with the radiation dose. This study aims to elucidate volumetric changes in patients undergoing whole-brain radiotherapy (WBRT) or targeted stereotactic radiotherapy (SRT) and to explore volumetric changes in the individual subregions of the hippocampus.
METHOD
Ten patients indicated to WBRT and 18 to SRT underwent brain magnetic resonance before radiotherapy and after 4 months. A structural T1-weighted sequence was used for volumetric analysis, and the software FreeSurfer was employed as the tool for the volumetry evaluation of 19 individual hippocampal subregions.
RESULTS
The volume of the whole hippocampus, segmented by the software, was larger than the volume outlined by the radiation oncologist. No significant differences in volume changes were observed in the right hippocampus. In the left hippocampus, the only subregion with a smaller volume after WBRT was the granular cells and molecular layers of the dentate gyrus (GC-ML-DG) region (median change -5 mm, median volume 137 vs. 135 mm; = .027), the region of the presumed location of neuronal progenitors.
CONCLUSIONS
Our study enriches the theory that the loss of neural stem cells is involved in cognitive decline after radiotherapy, contributes to the understanding of cognitive impairment, and advocates for the need for SRT whenever possible to preserve cognitive functions in patients undergoing brain radiotherapy.
PubMed: 38645488
DOI: 10.1093/noajnl/vdae040 -
BioRxiv : the Preprint Server For... Apr 2024Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation...
Activation of hypoactive parvalbumin-positive fast-spiking interneuron restores dentate inhibition to prevent epileptiform activity in the mouse intrahippocampal kainate model of temporal lobe epilepsy.
UNLABELLED
Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed PV immunostaining and whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. We found that the number of dentate PV+ cells was reduced in IHK treated mice. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) Spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) The amplitude of evoked IPSCs in DGCs by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous epileptiform activity in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished the epileptiform activity. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy.
HIGHLIGHTS
Reduced number of dentate PV+ interneurons in TLE micePersistently reduced action potential firing rates of dentate PV+ interneurons in TLE miceEnhanced amplitude but decreased frequency of spontaneous IPSCs in the dentate gyrus in TLE miceIncreased amplitude of evoked IPSCs mediated by dentate PV+ interneurons in TLE miceChemogenetic activation of PV+ interneurons prevents epileptiform activity in TLE mice.
PubMed: 38645248
DOI: 10.1101/2024.04.05.588316 -
BioRxiv : the Preprint Server For... Feb 2024Hyperexcitability in Alzheimer's disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We...
INTRODUCTION
Hyperexcitability in Alzheimer's disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We hypothesized that mossy cells (MCs), regulators of DG excitability, contribute to early hyperexcitability in AD. Indeed, MCs generate hyperexcitability in epilepsy.
METHODS
Using the Tg2576 model and WT mice (∼1month-old), we compared MCs electrophysiologically, assessed c-Fos activity marker, Aβ expression and mice performance in a hippocampal-dependent memory task.
RESULTS
Tg2576 MCs exhibit increased spontaneous excitatory events and decreased inhibitory currents, increasing the charge transfer excitation/inhibition ratio. Tg2576 MC intrinsic excitability was enhanced, and showed higher c-Fos, intracellular Aβ expression, and axon sprouting. Granule cells only showed changes in synaptic properties, without intrinsic changes. The effects occurred before a memory task is affected.
DISCUSSION
Early electrophysiological and morphological alterations in Tg2576 MCs are consistent with enhanced excitability, suggesting an early role in DG hyperexcitability and AD pathophysiology.
HIGHLIGHTS
∘ MCs from 1 month-old Tg2576 mice had increased spontaneous excitatory synaptic input. ∘ Tg2576 MCs had reduced spontaneous inhibitory synaptic input. ∘ Several intrinsic properties were abnormal in Tg2576 MCs. ∘ Tg2576 GCs had enhanced synaptic excitation but no changes in intrinsic properties. ∘ Tg2576 MCs exhibited high c-Fos expression, soluble Aβ and axonal sprouting.
PubMed: 38645244
DOI: 10.1101/2024.02.09.579729 -
Frontiers in Molecular Neuroscience 2024Cognitive aging widely varies among individuals due to different stress experiences throughout the lifespan and vulnerability of neurocognitive mechanisms. To understand...
Cognitive aging widely varies among individuals due to different stress experiences throughout the lifespan and vulnerability of neurocognitive mechanisms. To understand the heterogeneity of cognitive aging, we investigated the effect of early adulthood stress (EAS) on three different hippocampus-dependent memory tasks: the novel object recognition test (assessing recognition memory: RM), the paired association test (assessing episodic-like memory: EM), and trace fear conditioning (assessing trace memory: TM). Two-month-old rats were exposed to chronic mild stress for 6 weeks and underwent behavioral testing either 2 weeks or 20 months later. The results show that stress and aging impaired different types of memory tasks to varying degrees. RM is affected by combined effect of stress and aging. EM became less precise in EAS animals. TM, especially the contextual memory, showed impairment in aging although EAS attenuated the aging effect, perhaps due to its engagement in emotional memory systems. To further explore the neural underpinnings of these multi-faceted effects, we measured long-term potentiation (LTP), neural density, and synaptic density in the dentate gyrus (DG). Both stress and aging reduced LTP. Additionally, the synaptic density per neuron showed a further reduction in the stress aged group. In summary, EAS modulates different forms of memory functions perhaps due to their substantial or partial dependence on the functional integrity of the hippocampus. The current results suggest that lasting alterations in hippocampal circuits following EAS could potentially generate remote effects on individual variability in cognitive aging, as demonstrated by performance in multiple types of memory.
PubMed: 38638601
DOI: 10.3389/fnmol.2024.1344141