Showing papers on "Dentate gyrus published in 2023"
TL;DR: In this article , the genome-wide m6A epitranscriptome in the healthy and diseased brains of mice and humans was described, and it was shown that a substantial amount of m6As transcripts are conserved.
Abstract: Significance The precise role of m6A RNA methylation in the adult brain is not well understood. In our study, we describe the genome-wide m6A epitranscriptome in the healthy and diseased brains of mice and humans. Our data demonstrate that a substantial amount of m6A transcripts are conserved. These transcripts are linked to the regulation of synaptic processes and are localized to synapses. We detected decreased m6A RNA methylation in brain tissue from an AD mice model and in human brain tissue from the cingulate gyrus in individuals with Alzheimer’s disease. At the mechanistic level, we provide evidence that supports that reduced m6A-modified transcripts are linked to impaired synaptic protein synthesis.
5 citations
TL;DR: In this paper , the authors used immunohistochemistry to characterize the staining patterns of commonly used CA2 markers along the dorsal-ventral hippocampal axis and determine how these markers align along the proximodistal axis.
Abstract: Hippocampal area CA2 is a molecularly and functionally distinct region of the hippocampus that has classically been defined as the area with large pyramidal neurons lacking input from the dentate gyrus and the thorny excrescences (TEs) characteristic of CA3 neurons. A modern definition of CA2, however, makes use of the expression of several molecular markers that distinguish it from neighboring CA3 and CA1. Using immunohistochemistry, we sought to characterize the staining patterns of commonly used CA2 markers along the dorsal–ventral hippocampal axis and determine how these markers align along the proximodistal axis. We used a region of CA2 that stained for both Regulator of G‐protein Signaling 14 (RGS14) and Purkinje Cell Protein 4 (PCP4; “double‐labeled zone” [DLZ]) as a reference. Here, we report that certain commonly used CA2 molecular markers may be better suited for drawing distinct boundaries between CA2/3 and CA2/1. For example, RGS14+ and STEP+ neurons showed minimal to no extension into area CA1 while areas stained with VGluT2 and Wisteria Floribunda agglutinin were consistently smaller than the DLZ/CA2 borders by ~100 μ on the CA1 or CA3 sides respectively. In addition, these patterns are dependent on position along the dorsal–ventral hippocampal axis such that PCP4 labeling often extended beyond the distal border of the DLZ into CA1. Finally, we found that, consistent with previous findings, mossy fibers innervate a subset of RGS14 positive neurons (~65%–70%) and that mossy fiber bouton number and relative size in CA2 are less than that of boutons in CA3. Unexpectedly, we did find evidence of some complex spines on apical dendrites in CA2, though much fewer in number than in CA3. Our results indicate that certain molecular markers may be better suited than others when defining the proximal and distal borders of area CA2 and that the presence or absence of complex spines alone may not be suitable as a distinguishing feature differentiating CA3 from CA2 neurons.
5 citations
TL;DR: In this paper , the authors showed that early placement in an enriched environment after a stroke lesion markedly increased neurogenesis and flexible learning but not the formation of aberrant neurons, indicating that rehabilitative training, as a combination of running wheel training and enriched environment housing, improved functional and structural outcomes after stroke.
Abstract: Ischemic lesions stimulate adult neurogenesis in the dentate gyrus, however, this is not associated with better cognitive function. Furthermore, increased neurogenesis is associated with the formation of aberrant neurons. In a previous study, we showed that a running task after a stroke not only increases neurogenesis but also the number of aberrant neurons without improving general performance. Here, we determined whether stimulation in an enriched environment after a lesion could increase neurogenesis and cognitive function without enhancing the number of aberrant neurons. After an ischemic stroke induced by MCAO, animals were transferred to an enriched environment containing a running wheel, tunnels and nest materials. A GFP-retroviral vector was delivered on day 3 post-stroke and a modified water maze test was performed 6 weeks after the lesion. We found that the enriched environment significantly increased the number of new neurons compared with the unstimulated stroke group but not the number of aberrant cells after a lesion. Increased neurogenesis after environmental enrichment was associated with improved cognitive function. Our study showed that early placement in an enriched environment after a stroke lesion markedly increased neurogenesis and flexible learning but not the formation of aberrant neurons, indicating that rehabilitative training, as a combination of running wheel training and enriched environment housing, improved functional and structural outcomes after a stroke.
5 citations
TL;DR: In this paper , Nacetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats.
Abstract: Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.
2 citations
TL;DR: In this article , the role of thyroid hormone-responsive protein overexpressing (THRSP OE) mice with defining characteristics of ADHD-PI were utilized in proteomics.
Abstract: Abstract Children with attention-deficit/hyperactivity disorder (ADHD) often struggle with impaired executive function, temporal processing, and visuospatial memory, hallmarks of the predominantly inattentive presentation (ADHD-PI), subserved by the hippocampus. However, the specific genes/proteins involved and how they shape hippocampal structures to influence ADHD behavior remain poorly understood. As an exploratory tool, hippocampal dentate gyri tissues from thyroid hormone-responsive protein overexpressing (THRSP OE) mice with defining characteristics of ADHD-PI were utilized in proteomics. Integrated proteomics and network analysis revealed an altered protein network involved in Wnt signaling. Compared with THRSP knockout (KO) mice, THRSP OE mice showed impaired attention and memory, accompanied by dysregulated Wnt signaling affecting hippocampal dentate gyrus cell proliferation and expression of markers for neural stem cell (NSC) activity. Also, combined exposure to an enriched environment and treadmill exercise could improve behavioral deficits in THRSP OE mice and Wnt signaling and NSC activity. These findings show new markers specific to the ADHD-PI presentation, converging with the ancient and evolutionary Wnt signaling pathways crucial for cell fate determination, migration, polarity, and neural patterning during neurodevelopment. These findings from THRSP OE mice support the role of Wnt signaling in neurological disorders, particularly ADHD-PI presentation.
2 citations
TL;DR: In this article , the expression level of miR•181a•5p was decreased in the hippocampal NSCs of aged mice and exogenous overexpression promoted NSC proliferation without affecting the differentiation into neurons and astrocytes.
Abstract: Hippocampal neural stem cell (NSC) proliferation is known to decline with age, which is closely linked to learning and memory impairments. In the current study, we found that the expression level of miR‐181a‐5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR‐181a‐5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes. The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR‐181a‐5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR‐181a‐5p levels. Moreover, overexpression of miR‐181a‐5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR‐181a‐5p played a functional role in NSC proliferation and aging‐related, hippocampus‐dependent learning and memory impairments.
2 citations
TL;DR: In this article , the effect of adiponectin signaling on METH-induced conditioned place preference (CPP) was investigated in a male C57/BL6J mice model.
Abstract: Methamphetamine (METH) is a highly addictive psychostimulant. The adipocyte-derived hormone adiponectin has a broad spectrum of functions in the brain. However, limited research has been conducted on the effect of adiponectin signaling on METH-induced conditioned place preference (CPP) and knowledge of the underlying neural mechanisms is scarce. The METH induced adult male C57/BL6J mice model were used for testing the therapeutic activities of intraperitoneal injection of AdipoR agonist AdipoRon and peroxisome proliferator-activated receptor gamma (PPARγ)-selective agonist rosiglitazone, adiponectin receptor 1 (AdipoR1) overexpression in hippocampal dentate gyrus (DG), and chemogenetic inhibiting the neural activity of DG, and the changes of neurotrophic factors, synaptic molecules, glutamate receptors, and inflammatory cytokines were also measured. We found that adiponectin expression was significantly reduced in METH addicted patients and mice. Our findings also showed that injection of AdipoRon or rosiglitazone alleviated the METH-induced CPP behavior. Moreover, the expression of AdipoR1 in the hippocampus was also reduced, and AdipoR1 overexpression blocked the development of METH-induced CPP behavior through regulatory effects on neurotrophic factors, synaptic molecules, and glutamate receptors. The observed inhibitory neural activity of the hippocampal dentate gyrus (DG) induced via a chemogenetic approach produced a therapeutic effect on the METH-induced CPP behavior. Finally, we identified an abnormal expression of some key inflammatory cytokines through the PPARγ/Adiponectin/AdipoR1 axis. This study demonstrates that adiponectin signaling is a promising diagnostic and therapeutic target for METH addiction.
2 citations
TL;DR: In this paper , the authors identify putative changes in cortico-hippocampal signaling mechanisms that could lead to learning and memory deficits in a clinically relevant developmental pathophysiological rodent model, Febrile status epilepticus (FSE).
Abstract: How the development and function of neural circuits governing learning and memory are affected by insults in early life remains poorly understood. The goal of this study was to identify putative changes in cortico‐hippocampal signaling mechanisms that could lead to learning and memory deficits in a clinically relevant developmental pathophysiological rodent model, Febrile status epilepticus (FSE). FSE in both pediatric cases and the experimental animal model, is associated with enduring physiological alterations of the hippocampal circuit and cognitive impairment. Here, we deconstruct hippocampal circuit throughput by inducing slow theta oscillations in rats under urethane anesthesia and isolating the dendritic compartments of CA1 and dentate gyrus subfields, their reception of medial and lateral entorhinal cortex inputs, and the efficacy of signal propagation to each somatic cell layer. We identify FSE‐induced theta‐gamma decoupling at cortical synaptic input pathways and altered signal phase coherence along the CA1 and dentate gyrus somatodendritic axes. Moreover, increased DG synaptic activity levels are predictive of poor cognitive outcomes. We propose that these alterations in cortico‐hippocampal coordination interfere with the ability of hippocampal dendrites to receive, decode and propagate neocortical inputs. If this frequency‐specific syntax is necessary for cortico‐hippocampal coordination and spatial learning and memory, its loss could be a mechanism for FSE cognitive comorbidities.
2 citations
TL;DR: In this paper , the authors used an in vitro cellular model of human hippocampal neurogenesis and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE.
Abstract: Hippocampal neurogenesis (HN) is considered an important mechanism underlying lifelong brain plasticity, and alterations in this process have been implicated in early Alzheimer's disease progression. APOE polymorphism is the most common genetic risk factor for late‐onset Alzheimer's disease where the ε4 genotype is associated with a significantly earlier disease onset compared to the neutral ε3 allele. Recently, APOE has been shown to play an important role in the regulation of HN. However, the time‐dependent impact of its polymorphism in humans remains elusive, partially due to the difficulties of studying human HN in vivo. To bridge this gap of knowledge, we used an in vitro cellular model of human HN and performed a time course characterization on isogenic induced pluripotent stem cells with different genotypes of APOE. We found that APOE itself was more highly expressed in ε4 at the stem cell stage, while the divergence of differential gene expression phenotype between ε4 and ε3 became prominent at the neuronal stage of differentiation. This divergence was not associated with the differential capacity to generate dentate gyrus granule cell‐like neurons, as its level was comparable between ε4 and ε3. Transcriptomic profiling across different stages of neurogenesis indicated a clear “maturation of functional neurons” phenotype in ε3 neural progenitors and neurons, while genes differentially expressed only in ε4 neurons suggested potential alterations in “metabolism and mitochondrial function.” Taken together, our in vitro investigation suggests that APOE ε4 allele can exert a transcriptome‐wide effect at the later stages of HN, without altering the overall level of neurogenesis per se.
2 citations
TL;DR: In this paper , the authors show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-h oscillation that controls spiking probability, which is mediated by antiphase G-protein regulation of potassium and sodium currents that reduce excitability during the Light phase.
2 citations
TL;DR: In this article , the authors argue that immature neurons contribute a unique form of transience on the dentate gyrus that complements synaptic plasticity to help animals flexibly adapt to changing environments.
Abstract: Although most neurons are generated embryonically, neurogenesis is maintained at low rates in specific brain areas throughout adulthood, including the dentate gyrus of the mammalian hippocampus. Episodic-like memories encoded in the hippocampus require the dentate gyrus to decorrelate similar experiences by generating distinct neuronal representations from overlapping inputs (pattern separation). Adult-born neurons integrating into the dentate gyrus circuit compete with resident mature cells for neuronal inputs and outputs, and recruit inhibitory circuits to limit hippocampal activity. They display transient hyperexcitability and hyperplasticity during maturation, making them more likely to be recruited by any given experience. Behavioral evidence suggests that adult-born neurons support pattern separation in the rodent dentate gyrus during encoding, and they have been proposed to provide a temporal stamp to memories encoded in close succession. The constant addition of neurons gradually degrades old connections, promoting generalization and ultimately forgetting of remote memories in the hippocampus. This makes space for new memories, preventing saturation and interference. Overall, a small population of adult-born neurons appears to make a unique contribution to hippocampal information encoding and removal. Although several inconsistencies regarding the functional relevance of neurogenesis remain, in this review we argue that immature neurons confer a unique form of transience on the dentate gyrus that complements synaptic plasticity to help animals flexibly adapt to changing environments.
TL;DR: In this article , the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour was investigated in wild-type and standard housing conditions (SH) or an enriched environment (EE).
Abstract: Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus.
TL;DR: In this paper , the authors found that acute and chronic corticosterone (CS) elevations after traumatic brain injury (TBI) may be involved in distant hippocampal damage and the development of late posttraumatic behavioral pathology.
Abstract: Acute and chronic corticosterone (CS) elevations after traumatic brain injury (TBI) may be involved in distant hippocampal damage and the development of late posttraumatic behavioral pathology. CS-dependent behavioral and morphological changes were studied 3 months after TBI induced by lateral fluid percussion in 51 male Sprague–Dawley rats. CS was measured in the background 3 and 7 days and 1, 2 and 3 months after TBI. Tests including open field, elevated plus maze, object location, new object recognition tests (NORT) and Barnes maze with reversal learning were used to assess behavioral changes in acute and late TBI periods. The elevation of CS on day 3 after TBI was accompanied by early CS-dependent objective memory impairments detected in NORT. Blood CS levels > 860 nmol/L predicted delayed mortality with an accuracy of 0.947. Ipsilateral neuronal loss in the hippocampal dentate gyrus, microgliosis in the contralateral dentate gyrus and bilateral thinning of hippocampal cell layers as well as delayed spatial memory deficits in the Barnes maze were revealed 3 months after TBI. Because only animals with moderate but not severe posttraumatic CS elevation survived, we suggest that moderate late posttraumatic morphological and behavioral deficits may be at least partially masked by CS-dependent survivorship bias.
TL;DR: In this article , the authors conducted a network meta-analysis to estimate and contrast alterations in subfield volumes in patients with schizophrenia and major depressive disorder (MDD) compared to healthy controls.
Abstract: Background: Hippocampal disturbances are important in the pathophysiology of both schizophrenia and major depressive disorder (MDD). Imaging studies have shown selective volume deficits across hippocampal subfields in both disorders. We aimed to investigate whether these volumetric alterations in hippocampal subfields are shared or divergent across disorders. Methods: We searched PubMed and Embase from database inception to May 8, 2021. We identified MRI studies in patients with schizophrenia, MDD or both, in which hippocampal subfield volumes were measured. We excluded nonoriginal, animal or postmortem studies, and studies that used other imaging modalities or overlapping data. We conducted a network meta-analysis to estimate and contrast alterations in subfield volumes in the 2 disorders. Results: We identified 45 studies that met the initial criteria for systematic review, of which 15 were eligible for network metaanalysis. Compared to healthy controls, patients with schizophrenia had reduced volumes in the bilateral cornu ammonis (CA) 1, granule cell layer of the dentate gyrus, subiculum, parasubiculum, molecular layer, hippocampal tail and hippocampus–amygdala transition area (HATA); in the left CA4 and presubiculum; and in the right fimbria. Patients with MDD had decreased volumes in the left CA3 and CA4 and increased volumes in the right HATA compared to healthy controls. The bilateral parasubiculum and right HATA were smaller in patients with schizophrenia than in patients with MDD. Limitations: We did not investigate medication effects because of limited information. Study heterogeneity was noteworthy in direct comparisons between patients with MDD and healthy controls. Conclusion: The volumes of multiple hippocampal subfields are selectively altered in patients with schizophrenia and MDD, with overlap and differentiation in subfield alterations across disorders. Rigorous head-to-head studies are needed to validate our findings.
TL;DR: In this paper , the role of the hippocampus in impulsive and drug seeking behaviors was investigated in adolescent and adult male rats by means of a delay discounting task (DDT) by evaluating preference and seeking motivation for alcohol consumption, and analyzing CB1R expression in CA1, CA3 and the dentate gyrus of the HPP as well as in the medial prefrontal cortex (mPFC).
Abstract: There are a few studies suggesting that the hippocampus is involved in the regulation of impulsivity, and which attempt to explain drug seeking behavior in addiction. In addition, cannabinoid receptor 1 (CB1R) is highly expressed in the hippocampus (HPP). To further understand the potential role of the hippocampal CB1R in impulsive and drug seeking behaviors, we characterized impulsivity in adolescent and adult male rats, by means of a delay discounting task (DDT) by evaluating preference and seeking motivation for alcohol (10 % v/v) consumption, and analyzing CB1R expression in CA1, CA3 and the dentate gyrus (DG) of the HPP as well as in the medial prefrontal cortex (mPFC). Our results show that adolescent rats display more impulsive choices than adult rats in the DDT. The k value is statistically higher in adolescents, further supporting that they are more impulsive. Besides, adolescent rats have higher forced and voluntary alcohol consumption and display a higher alcohol conditioned place preference (CPP) vs. adult rats. In addition, CB1R expression in CA3 and the DG is higher in adolescent vs. adult rats. Our data further support the role of the hippocampus in impulsivity with the potential involvement of the endocannabinoid system, considering that CB1R in CA3 and DG is higher in adolescents, who display impulsivity and alcohol seeking and consumption.
TL;DR: Zhang et al. as discussed by the authors constructed active and passive immunization mouse models of anti-NMDAR encephalitis, and used single-nucleus RNA sequencing to investigate the diverse expression profile of neuronal populations isolated from different hippocampal regions.
Abstract: Anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease with variable clinical manifestations caused by NMDAR autoantibody. The underlying molecular underpinnings of this disease are rarely characterized on a genomic scale. Anti‐NMDAR encephalitis mainly affects the hippocampus, however, its effect on gene expression in hippocampal neurons is unclear at present. Here, we construct the active and passive immunization mouse models of anti‐NMDAR encephalitis, and use single‐nucleus RNA sequencing to investigate the diverse expression profile of neuronal populations isolated from different hippocampal regions. Dramatic changes in cell proportions and differentially expressed genes were observed in excitatory neurons of the dentate gyrus (DG) subregion. In addition, we found that ATP metabolism and biosynthetic regulators related genes in excitatory neurons of DG subregion were significantly affected. Kcnq1ot1 in inhibitory neurons and Meg3 in interneurons also changed. Notably, the latter two molecules exhibited opposite changes in different models. Therefore, the above genes were used as potential targets for further research on the pathological process of anti‐NMDAR encephalitis. These data involve various hippocampal neurons, which delineate a framework for understanding the hippocampal neuronal circuit and the potential molecular mechanisms of anti‐NMDAR encephalitis.
06 Apr 2023
TL;DR: In this paper , the authors investigated the CBD effect on comorbidity between chronic neuropathic pain, depression, and memory impairment, and found that CBD treatment decreased mechanical and cold allodynia, attenuated depressiveassociated behaviors, and improved memory performance.
Abstract: Abstract 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 1 -treatment with CBD (15, 30, 60 nmol). Key Results BDA-labeled were found in CA 1 and dentate gyrus. CCI-induced mechanical and cold allodynia increased c-Fos protein expression in the PrL and CA 1 . The number of astrocytes in PrL and CA 1 increased, and the number of neuroblasts decreased in CA 1 . The CCI animals 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 2 : 1 nM), WAY-100635 (0.37 nmol), and AM251 (100 nmol) intra-PrL reversed the CBD (60 nmol) effect intra-CA 1 , both in 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 1 -PrL pathway, inducing neuroplasticity. CBD acute treatment into the PrL cortex produces functional, molecular, and morphological improvements.
TL;DR: In this article , the brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation, and selective silencing of MS cholinergic neurons selectively would reduce IIS.
Abstract: Interictal spikes (IIS) are a common type of abnormal electrical activity in animal models of Alzheimer’s disease (AD) and AD patients. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked where IIS are largest along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the medial septohippocampal cholinergic neurons selectively would reduce IIS. We used 3 models of AD, Tg2576 mice, presenilin 2 knockout mice, and the Ts65Dn mouse model of Down’s syndrome. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with ChAT-Cre mice and offspring mice were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs. We recorded EEG along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and were primarily during REM sleep. In all 3 models, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS frequency during REM sleep without affecting the overall duration or number of REM sleep bouts. Maximal IIS amplitude in the DG of 3 AD mouse models suggests that the DG could be one of the areas that contribute to IIS generation. Selectively reducing MS cholinergic tone could be a new strategy to reduce IIS in AD.
31 Jan 2023
TL;DR: This paper showed that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan, and provided a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
Abstract: Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
TL;DR: In this paper , the authors used cyclin D2 knockout mice with constitutively extremely low levels of adult hippocampal neurogenesis and their wild-type littermates in a shared enriched environment (ENR) paradigm.
Abstract: There is still limited mechanistic insight into how the interaction of individuals with their environment results in the emergence of individuality in behavior and brain structure. Nevertheless, the idea that personal activity shapes the brain is implicit in strategies for healthy cognitive aging as well as in the idea that individuality is reflected in the brain's connectome. We have shown that even isogenic mice kept in a shared enriched environment (ENR) developed divergent and stable social and exploratory trajectories. As these trajectories—measured as roaming entropy (RE)—positively correlated with adult hippocampal neurogenesis, we hypothesized that a feedback between behavioral activity and adult hippocampal neurogenesis might be a causal factor in brain individualization. We used cyclin D2 knockout mice with constitutively extremely low levels of adult hippocampal neurogenesis and their wild‐type littermates. We housed them for 3 months in a novel ENR paradigm, consisting of 70 connected cages equipped with radio frequency identification antennae for longitudinal tracking. Cognitive performance was evaluated in the Morris Water Maze task (MWM). With immunohistochemistry we confirmed that adult neurogenesis correlated with RE in both genotypes and that D2 knockout mice had the expected impaired performance in the reversal phase of the MWM. But whereas the wild‐type animals developed stable exploratory trajectories with increasing variance, correlating with adult neurogenesis, this individualizing phenotype was absent in D2 knockout mice. Here the behaviors started out more random and revealed less habituation and low variance. Together, these findings suggest that adult neurogenesis contributes to experience‐dependent brain individualization.
TL;DR: In this paper , a single prolonged stress protocol was used to model PTSD in long-inbred C57BL/6 and wild-derived (house) female mice, and the susceptibility of mice to single- prolonged stress was assessed by behavior phenotyping in the Open Field and Elevated Plus Maze, the level of neuroinflammation in the hippocampus was estimated by real-time PCR to TNFα, IL-1β, IL-, IL-6 and IL-10, Iba1 and GFAP, as well as immunohistochemical analysis of microglial morphology.
Abstract: Many people experience traumatic events during their lives, but not all of them develop severe mental pathologies, characterized by high levels of anxiety that persists for more than a month after psychological trauma, such as posttraumatic stress disorder (PTSD). We used a single prolonged stress protocol in order to model PTSD in long-inbred C57BL/6 and wild-derived (house) female mice. The susceptibility of mice to single prolonged stress was assessed by behavior phenotyping in the Open Field and Elevated Plus Maze, the level of neuroinflammation in the hippocampus was estimated by real-time PCR to TNFα, IL-1β, IL-6, IL-10, Iba1 and GFAP, as well as immunohistochemical analysis of microglial morphology and mean fluorescence intensity for GFAP+ cells. The level of neurogenesis was analyzed by real-time PCR to Ki67, Sox2 and DCX as well as immunohistochemistry to Ki67. We showed that long-inbread C57BL/6 mice are more susceptible to a single prolonged stress protocol compared to wild-derived (house) mice. Stressed C57BL/6 mice demonstrated elevated expression levels of proinflammatory cytokines TNFα, IL-1β, and IL-6 in the hippocampus, while in house mice no differences in cytokine expression were detected. Expression levels of Iba1 in the hippocampus did not change significantly after single prolonged stress, however GFAP expression increased substantially in stressed C57BL/6 mice. The number of Iba+ cells in the dentate gyrus also did not change after stress, but the morphology of Iba+ microglia in C57BL/6 animals allowed us to suggest that it was activated; house mice also had significantly more microglia than C57BL/6 animals. We suppose that decreased microglia levels in the hippocampus of C57BL/6 compared to house mice might be one of the reasons for their sensitivity to a single prolonged stress. Single prolonged stress reduced the number of Ki67+ proliferating cells in the dentate gyrus of the hippocampus but only in C57BL/6 mice, not in house mice, with the majority of cells detected in the dorsal (septal) hippocampus in both. The increase in the expression level of DCX might be a compensatory reaction to stress; however, it does not necessarily mean that these immature neurons will be functionally integrated, and this issue needs to be investigated further.
TL;DR: In this article , the authors found that mice that were previously housed in an enriched environment, which triggers an increase in neurogenesis, had increased spatial information encoding in the hippocampal dentate gyrus during novel context exposure.
Abstract: Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we found that mice that were previously housed in an enriched environment, which triggers an increase in neurogenesis, had increased spatial information encoding in the hippocampal dentate gyrus during novel context exposure. Ablating adult neurogenesis by prior focal irradiation of the hippocampus blocked the effect of enrichment and lowered spatial information content, as did the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreased the calcium activity rates of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast to previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves neural representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory.
TL;DR: In this article , the authors characterized various cellular and molecular signatures of parity (nulliparous, prim-parous, biparous) in the hippocampus, an important area for cognitive and emotional regulation, and in plasma.
Abstract: Pregnancy is marked by brain changes to volume, structure, connectivity, some of which are long-lasting. Few studies have examined possible mechanisms of these changes or the effects of multiple pregnancies. Here, we characterized various cellular and molecular signatures of parity (nulliparous, primiparous, biparous) in the hippocampus, an important area for cognitive and emotional regulation, and in plasma. We investigated density of neural stems cells (Sox2) and microglia (Iba-1), and levels of the postsynaptic density protein (PSD-95), cell signalling pathways, hippocampal and peripheral inflammation and the tryptophan-kynurenine (TRP-KYN) pathway, at 1 week after weaning (7 months) and in middle-age (13 months). Parity increased PSD-95 levels in both age groups and prevented the age-related decrease in neural stem cell density observed in nulliparous rats. Biparity increased cell signalling phosphoproteins (pp706sk, S6RP) and number of microglia in the dentate gyrus, regardless of age. Parity resulted in transient changes to the TRP-KYN system and peripheral inflammation. Thus, parity has lasting effects on synaptic plasticity and alters the trajectory of hippocampal aging. Highlights - Parity increased the postsynaptic protein PSD-95 in the hippocampus, regardless of age. - Biparity increased microglial density and cell signalling in the hippocampus, regardless of age. - Parity prevented the age-related decline in hippocampal neural stem cells. - Parity transiently increased tryptophan-kynurenine pathway metabolites. - Aging reduced plasma cytokine levels, an effect more prominent with nulliparity.
TL;DR: This article found that granule cells and mossy cells are among the least and most active spatially modulated cells in the hippocampus, respectively, and they contribute to orthogonal representations of distinct spatial contexts.
TL;DR: In this article , the authors performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated context (Avoiders), or do not (Nonavoiders).
Abstract: Stress is associated with contextual memory deficits, which may mediate avoidance of trauma‐associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus‐Cornu Ammonis 3 (DG‐CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine‐associated context (Avoiders), or do not (Non‐Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation‐associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signaling were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Nonavoiders. Stress impaired pattern separation performance in Non‐Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower ROS production compared with Non‐Avoiders. Lower ROS production was associated with better OPS performance in Stressed rats, but ROS production was not associated with OPS performance in Controls. These results suggest a strong negative association between HPC ROS production and pattern separation after stress, and that stress effects on these outcome variables may be associated with avoidance of a stress‐paired context.
TL;DR: In this paper , the authors investigated whether changes in cognitive functioning after ECT were associated with hippocampal structural changes and found that volume increase of hippocampal subfields and changes in perfusion and diffusion of the hippocampus correlated with cognitive decline.
TL;DR: In this paper , the authors evaluated the role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus.
Abstract: Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID‐19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular‐, cellular‐, and behavioral‐specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain‐derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R–GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R–GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant‐like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R–GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive‐affecting diseases.
TL;DR: In this paper , the authors showed that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice.
Abstract: Light exposure can profoundly affect neurological functions and behaviors. Here, we show that short-term exposure to moderate (400 lux) white light during Y-maze test promoted spatial memory retrieval and induced only mild anxiety in mice. This beneficial effect involves the activation of a circuit including neurons in the central amygdala (CeA), locus coeruleus (LC), and dentate gyrus (DG). Specifically, moderate light activated corticotropin-releasing hormone (CRH) positive (+) CeA neurons and induced the release of corticotropin-releasing factor (CRF) from their axon terminals ending in the LC. CRF then activated tyrosine hydroxylase-expressing LC neurons, which send projections to DG and release norepinephrine (NE). NE activated β-adrenergic receptors on CaMKIIα-expressing DG neurons, ultimately promoting spatial memory retrieval. Our study thus demonstrated a specific light scheme that can promote spatial memory without excessive stress, and unraveled the underlying CeA-LC-DG circuit and associated neurochemical mechanisms.
TL;DR: The authors showed that phospho-ablated Eif4eS209A Knockin mice are profoundly impaired in dentate gyrus LTP maintenance in vivo, whereas basal perforant path-evoked transmission and LTP induction are intact.