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Behavioural Pharmacology Jun 2024Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing...
D2-like dopamine receptors blockade within the dentate gyrus shows a greater effect on stress-induced analgesia in the tail-flick test compared to D1-like dopamine receptors.
INTRODUCTION
Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain.
METHODS
Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals.
RESULTS
The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test.
DISCUSSION
Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.
PubMed: 38869040
DOI: 10.1097/FBP.0000000000000782 -
Heliyon Jun 2024Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated with a long range of adverse effects, of which...
Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated with a long range of adverse effects, of which cognitive deficits stand out. The present study aimed to assess the neurologic adverse outcome pathways of two clinically relevant cumulative doses of DOX. Adult male CD-1 mice received biweekly intraperitoneal administrations for 3 weeks until reaching cumulative doses of 9 mg/kg (DOX9) or 18 mg/kg (DOX18). Animals were euthanized one week after the last administration, and biomarkers of oxidative stress and brain metabolism were evaluated in the whole brain. Coronal sections of fixed brains were used for specific determinations of the prefrontal cortex (PFC) and hippocampal formation (HF). In the whole brain, DOX18 tended to disrupt the antioxidant defences, affecting glutathione levels and manganese superoxide dismutase expression. Considering the regional analysis, DOX18 increased the volume of all brain areas evaluated, while GFAP-immunoreactive astrocytes decreased in the dentate gyrus (DG) and increased in the CA3 region of HF, both in a dose-dependent manner. Concerning the apoptosis pathway, whereas Bax increased in the DOX9 group, it decreased in the DOX18 group. Only in the latter group did Bcl-2 levels also decrease. While p53 only increased in the CA3 region of the DOX9 group, AIF increased in the PFC and DG of DOX18. Finally, phosphorylation of Tau decreased with the highest DOX dose in DG and CA3, while TNF-α levels increased in CA1 of DOX18. Our results indicate new pathways not yet described that could be responsible for the cognitive impairments observed in treated patients.
PubMed: 38868005
DOI: 10.1016/j.heliyon.2024.e31608 -
Annals of Neurology Jun 2024The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can...
OBJECTIVE
The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown.
METHODS
Human-derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP).
RESULTS
We showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin-1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD-related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti-inflammatory miRNA, inhibited astrocyte activation in vitro and in vivo, and the mechanism was related to regulation of CD4 Th1 cells mediated tumor necrosis factor (TNF) pathway.
INTERPRETATION
Taken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti-inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024.
PubMed: 38860520
DOI: 10.1002/ana.27001 -
The European Journal of Neuroscience Jun 2024Animal studies and clinical trials suggest that maintenance of gamma-aminobutyric acid (GABA)-ergic activity may be crucial in coping with stressful conditions, anxiety...
Animal studies and clinical trials suggest that maintenance of gamma-aminobutyric acid (GABA)-ergic activity may be crucial in coping with stressful conditions, anxiety and mood disorders. Drugs highly efficient in promoting anxiolysis were shown to activate this system, particularly via the α2-subunit of type A receptors (GABAA α2). Given the high expression of GABAA α2 in the dentate gyrus (DG) sub-field of the hippocampus, we sought to examine whether manipulation of the α2 subunit in this area will evoke changes in emotional behaviour, memory and learning as well as in synaptic plasticity. We found that knockdown of GABAAα2 receptor specifically in the dorsal DG of rats caused increased anxiety without affecting locomotor activity. Spatial memory and learning in the Morris water maze were also impaired in GABAAα2 receptor knocked down rats, an effect accompanied by alterations in synaptic plasticity, as assessed by long-term potentiation in the DG. Our findings provide further support to the notion that emotional information processing in the hippocampus may be controlled, at least in part, via the inhibitory GABAA α2 receptor subunit, opening a potential avenue for early interventions from pre- puberty into adulthood, as a strategy for controlling anxiety-related psychopathology.
PubMed: 38858171
DOI: 10.1111/ejn.16441 -
BioRxiv : the Preprint Server For... May 2024Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example,...
Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with electrophysiological and optical imaging tools during sleep-wake cycles. We found that the activity of major glutamatergic cell populations in the DG is organized into in-fraslow oscillations (0.01 - 0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep. Further experiments revealed that the infraslow oscillation in the DG is modulated by rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by 5-HT1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
PubMed: 38854102
DOI: 10.1101/2023.05.12.540575 -
BioRxiv : the Preprint Server For... May 2024Astrocytes use Ca signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and...
Astrocytes use Ca signals to regulate multiple aspects of normal and pathological brain function. Astrocytes display context-specific diversity in their functions, and in their response to noxious stimuli between brain regions. Indeed, astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on their ATP generation and Ca buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca signaling in astrocytes, the extent of this regulation into the rich diversity of astrocytes in different brain regions remains largely unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for proper astrocyte function, however, few insights into possible diverse responses to this noxious stimulus from astrocytes in different brain areas were reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI, which expresses the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two distinct brain regions, the dorsolateral striatum, and the hippocampal dentate gyrus, and we show that Mito-PstI can induce astrocytic mtDNA loss , but with remarkable brain-region-dependent differences on mitochondrial dynamics, spontaneous Ca fluxes and astrocytic as well as microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca signaling in a brain-region-selective manner.
PubMed: 38853966
DOI: 10.1101/2024.05.29.596517 -
Adiponectin rescues synaptic plasticity in the dentate gyrus of a mouse model of Fragile X Syndrome.Philosophical Transactions of the Royal... Jul 2024Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients...
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Fragile X Syndrome; Dentate Gyrus; Mice; Neuronal Plasticity; Mice, Knockout; Disease Models, Animal; Fragile X Mental Retardation Protein; Adiponectin; Long-Term Potentiation; Male; Receptors, AMPA
PubMed: 38853554
DOI: 10.1098/rstb.2023.0221 -
Philosophical Transactions of the Royal... Jul 2024Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different... (Review)
Review
Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different experiments. However, this is clearly not the case. We illustrate the point by comparing LTP in the CA3 projections to CA1 with the different forms of potentiation in the dentate gyrus. These studies lead to the hypothesis that specialized properties of CA1-LTP are adaptations for encoding unsupervised learning and episodic memory, whereas the dentate gyrus variants subserve learning that requires multiple trials and separation of overlapping bodies of information. Recent work has added sex as a second and somewhat surprising dimension along which LTP is also differentiated. Triggering events for CA1-LTP differ between the sexes and the adult induction threshold is significantly higher in females; these findings help explain why males have an advantage in spatial learning. Remarkably, the converse is true before puberty: Females have the lower LTP threshold and are better at spatial memory problems. A mechanism has been identified for the loss-of-function in females but not for the gain-of-function in males. We propose that the many and disparate demands of natural environments, with different processing requirements across ages and between sexes, led to the emergence of multiple LTPs. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Female; Humans; Male; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Long-Term Potentiation; Memory; Sex Factors
PubMed: 38853551
DOI: 10.1098/rstb.2023.0223 -
Phytomedicine : International Journal... Aug 2024Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of...
Zexieyin formula alleviates Alzheimer's disease via post-synaptic CaMKII modulating AMPA receptor: Involved in promoting neurogenesis to strengthen synaptic plasticity in mice hippocampus.
BACKGROUND
Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD.
PURPOSE
The study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action.
METHODS
We used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD.
RESULTS
The results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells.
CONCLUSION
ZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.
Topics: Animals; Alzheimer Disease; Receptors, AMPA; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Drugs, Chinese Herbal; Hippocampus; Neurogenesis; Disease Models, Animal; Mice; Male; Neuronal Plasticity; Scopolamine; Mice, Transgenic; Maze Learning; Donepezil; Cyclic AMP Response Element-Binding Protein; Memory; Mice, Inbred C57BL
PubMed: 38852473
DOI: 10.1016/j.phymed.2024.155802 -
Cell Reports Jun 2024Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC...
Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC hallmark, little is known about the process, milestones, and mechanisms underlying the transition of developmental NSCs to an adult NSC state. Here, we performed targeted single-cell RNA-seq analysis to reveal the molecular cascade underlying NSC development in the early postnatal mouse dentate gyrus. We identified two sequential steps, first a transition to quiescence followed by further maturation, each of which involved distinct changes in metabolic gene expression. Direct metabolic analysis uncovered distinct milestones, including an autophagy burst before NSC quiescence acquisition and cellular reactive oxygen species level elevation along NSC maturation. Functionally, autophagy is important for the NSC transition to quiescence during early postnatal development. Together, our study reveals a multi-step process with defined milestones underlying establishment of the adult NSC pool in the mammalian brain.
PubMed: 38852158
DOI: 10.1016/j.celrep.2024.114339