Dendritic Spine Density Research Articles

Morphological heterogeneity of neurons in the human central amygdaloid nucleus.

The central amygdaloid nucleus (CeA) has an ancient phylogenetic development and functions relevant for animal survival. Local cells receive intrinsic amygdaloidal information that codes emotional stimuli of fear, integrate them, and send cortical and subcortical output projections that prompt rapid visceral and social behavior responses. We aimed to describe the morphology of the neurons that compose the human CeA (N = 8 adult men). Cells within CeA coronal borders were identified using the thionine staining and were further analyzed using the "single-section" Golgi method followed by open-source software procedures for two-dimensional and three-dimensional image reconstructions. Our results evidenced varied neuronal cell body features, number and thickness of primary shafts, dendritic branching patterns, and density and shape of dendritic spines. Based on these criteria, we propose the existence of 12 morphologically different spiny neurons in the human CeA and discuss the variability in the dendritic architecture within cellular types, including likely interneurons. Some dendritic shafts were long and straight, displayed few collaterals, and had planar radiation within the coronal neuropil volume. Most of the sampled neurons showed a few to moderate density of small stubby/wide spines. Long spines(thin and mushroom) were observed occasionally. These novel data address the synaptic processing and plasticity in the human CeA. Our morphological description can be combined with further transcriptomic, immunohistochemical, and electrophysiological/connectional approaches.It serves also to investigate how neurons are altered in neurological and psychiatric disorders with hindered emotional perception, in anxiety, following atrophy in schizophrenia, and along different stages of Alzheimer's disease.

Bergamot essential oil improves CUMS-induced depression-like behaviour in rats by protecting the plasticity of hippocampal neurons.

Bergamot essential oil (BEO) is an extract of the bergamot fruit with significant neuroprotective effect. This study was to investigate the effects and the underlying mechanism of BEO in mitigating depression. GC-MS were used to identify its constituents. Antidepressive properties of BEO were evaluated by sucrose preference test (SPT), force swimming test (FST) and open field test (OFT). Nissl staining was used to determine the number of Nissl bodies in hippocampus (HIPP) of rats. Changes in HIPP dendritic length and dendritic spine density were detected by Golgi-Cox staining. Immunohistochemistry and Western blot were used to detect the postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the HIPP of rats. The enzyme-linked immunosorbent assay was used to determine the 5-hydroxytryptamine (5-HT), insulin-like growth factor 1 (IGF-1) and interleukin-1β (IL-1β) in the HIPP, serum and cerebrospinal fluid (CSF) of rats. Inhaled BEO significantly improved depressive behaviour in chronic unpredictable mild stress (CUMS) rats. BEO increased Nissl bodies, dendritic length and spine density, PSD-95 and SYP protein in the HIPP. Additionally, BEO upregulated serum 5-HT, serum and CSF IGF-1, while downregulating serum IL-1β. Collectively, inhaled BEO mitigates depression by protecting the plasticity of hippocampal neurons, hence, providing novel insights into treatment of depression.

Synaptically-targeted long non-coding RNA SLAMR promotes structural plasticity by increasing translation and CaMKII activity

Long noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity impacts the transcriptional regulation of lncRNAs, or if this leads to synapse-related changes and contributes to the formation of long-term memories. Here, we report the identification of a lncRNA, SLAMR, which becomes enriched in CA1-hippocampal neurons upon contextual fear conditioning but not in CA3 neurons. SLAMR is transported along dendrites via the molecular motor KIF5C and is recruited to the synapse upon stimulation. Loss of function of SLAMR reduces dendritic complexity and impairs activity-dependent changes in spine structural plasticity and translation. Gain of function of SLAMR, in contrast, enhances dendritic complexity, spine density, and translation. Analyses of the SLAMR interactome reveal its association with CaMKIIα protein through a 220-nucleotide element also involved in SLAMR transport. A CaMKII reporter reveals a basal reduction in CaMKII activity with SLAMR loss-of-function. Furthermore, the selective loss of SLAMR function in CA1 disrupts the consolidation of fear memory in male mice, without affecting their acquisition, recall, or extinction, or spatial memory. Together, these results provide new molecular and functional insight into activity-dependent changes at the synapse and consolidation of contextual fear.

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study.

Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites. The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/μm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy). The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema. dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

Tanshinone IIA Regulates Synaptic Plasticity in Mg2+-Free-Induced Epileptic Hippocampal Neurons via the PI3K/Akt Signaling Pathway.

Tanshinone IIA (TSIIA) is an element of the effective ingredients of Salvia miltiorrhiza Bunge (Labiatae), exhibits a significant therapeutic effect in brain neuroprotection. The focus of this study was the examination of synaptic plasticity of in Mg2+-free-induced epileptic hippocampus neurons and how TSIIA protects against it. The purity of the primary hippocampal neurons extracted from Sprague Dawley rats was assessed within 24 hours by microtubule-associated protein (MAP2) immunofluorescence staining. A hippocampal neuron model for Mg2+-free-induced spontaneous recurrent epileptiform discharge was developed, five experimental groups were then randomized: blank (Blank), model (Model), TSIIA (TSIIA, 20 µM), LY294002 (LY294002, 25 µM), and TSIIA+LY294002 (TSIIA+LY294002, 20 µM+25 µM). FIJI software was used to examine variations of neurite complexity, total length of hippocampal neurons, number of primary dendrites and density of dendritic spines. Developmental regulation brain protein (Drebrin) and brain-derived neurotrophic factor (BDNF) expression was evaluated using immunofluorescence staining and the relative expression of phospho-protein kinase B (p-Akt)/Akt, BDNF, synaptophysin (SYN) and postsynaptic density 95 (PSD-95) determined by Western blot. In contrast to the model group, TSIIA drastically reduced damage to synaptic plasticity of hippocampal neurons caused by epilepsy (p < 0.05). The TSIIA group showed a significant increase in the relative expression of PSD-95, SYN, BDNF, and p-Akt/Akt (p < 0.01). TSIIA was effective in reducing harm to the synaptic plasticity of hippocampal neurons induced by persistent status epilepticus, with the possible mechanism being regulation of the phosphatidylinositol 3-kinase 56 (PI3K)/Akt signaling pathway.

Increased gene dosage of RFWD2 causes autistic-like behaviors and aberrant synaptic formation and function in mice

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions, communication deficits and repetitive behaviors. A study of autistic human subjects has identified RFWD2 as a susceptibility gene for autism, and autistic patients have 3 copies of the RFWD2 gene. The role of RFWD2 as an E3 ligase in neuronal functions, and its contribution to the pathophysiology of ASD, remain unknown. We generated RFWD2 knockin mice to model the human autistic condition of high gene dosage of RFWD2. We found that heterozygous knockin (Rfwd2+/−) male mice exhibited the core symptoms of autism. Rfwd2+/− male mice showed deficits in social interaction and communication, increased repetitive and anxiety-like behavior, and spatial memory deficits, whereas Rfwd2+/− female mice showed subtle deficits in social communication and spatial memory but were normal in anxiety-like, repetitive, and social behaviors. These autistic-like behaviors in males were accompanied by a reduction in dendritic spine density and abnormal synaptic function on layer II/III pyramidal neurons in the prelimbic area of the medial prefrontal cortex (mPFC), as well as decreased expression of synaptic proteins. Impaired social behaviors in Rfwd2+/− male mice were rescued by the expression of ETV5, one of the major substrates of RFWD2, in the mPFC. These findings indicate an important role of RFWD2 in the pathogenesis of autism.

Neuronal Ensembles in the Amygdala Allow Social Information to Motivate Later Decisions.

Social experiences carry tremendous weight in our decision-making, even when social partners are not present. To determine mechanisms, we trained female mice to respond for two food reinforcers. Then, one food was paired with a novel conspecific. Mice later favored the conspecific-associated food, even in the absence of the conspecific. Chemogenetically silencing projections from the prelimbic subregion (PL) of the medial prefrontal cortex to the basolateral amygdala (BLA) obstructed this preference while leaving social discrimination intact, indicating that these projections are necessary for socially driven choice. Further, mice that performed the task had greater densities of dendritic spines on excitatory BLA neurons relative to mice that did not. We next induced chemogenetic receptors in cells active during social interactions-when mice were encoding information that impacted later behavior. BLA neurons stimulated by social experience were necessary for mice to later favor rewards associated with social conspecifics but not make other choices. This profile contrasted with that of PL neurons stimulated by social experience, which were necessary for choice behavior in social and nonsocial contexts alike. The PL may convey a generalized signal allowing mice to favor particular rewards, while units in the BLA process more specialized information, together supporting choice motivated by social information.

The role of glia in the dysregulation of neuronal spinogenesis in Ube3a-dependent ASD

Overexpression of the Ube3a gene and the resulting increase in Ube3a protein are linked to autism spectrum disorder (ASD). However, the cellular and molecular processes underlying Ube3a-dependent ASD remain unclear. Using both male and female mice, we find that neurons in the somatosensory cortex of the Ube3a 2× Tg ASD mouse model display reduced dendritic spine density and increased immature filopodia density. Importantly, the increased gene dosage of Ube3a in astrocytes alone is sufficient to confer alterations in neurons as immature dendritic protrusions, as observed in primary hippocampal neuron cultures. We show that Ube3a overexpression in astrocytes leads to a loss of astrocyte-derived spinogenic protein, thrombospondin-2 (TSP2), due to a suppression of TSP2 gene transcription. By neonatal intraventricular injection of astrocyte-specific virus, we demonstrate that Ube3a overexpression in astrocytes in vivo results in a reduction in dendritic spine maturation in prelimbic cortical neurons, accompanied with autistic-like behaviors in mice. These findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels. Significance statementIncreased gene dosage of Ube3a is tied to autism spectrum disorders (ASDs), yet cellular and molecular alterations underlying autistic phenotypes remain unclear. We show that Ube3a overexpression leads to impaired dendritic spine maturation, resulting in reduced spine density and increased filopodia density. We find that dysregulation of spine development is not neuron autonomous, rather, it is mediated by an astrocytic mechanism. Increased gene dosage of Ube3a in astrocytes leads to reduced production of the spinogenic glycoprotein thrombospondin-2 (TSP2), leading to abnormalities in spines. Astrocyte-specific Ube3a overexpression in the brain in vivo confers dysregulated spine maturation concomitant with autistic-like behaviors in mice. These findings indicate the importance of astrocytes in aberrant neurodevelopment and brain function in Ube3a-depdendent ASD.

Neuron type-specific proteomics reveals distinct Shank3 proteoforms in iSPNs and dSPNs lead to striatal synaptopathy in Shank3B–/– mice

Combinatorial expression of postsynaptic proteins underlies synapse diversity within and between neuron types. Thus, characterization of neuron-type-specific postsynaptic proteomes is key to obtaining a deeper understanding of discrete synaptic properties and how selective dysfunction manifests in synaptopathies. To overcome the limitations associated with bulk measures of synaptic protein abundance, we developed a biotin proximity protein tagging probe to characterize neuron-type-specific postsynaptic proteomes in vivo. We found Shank3 protein isoforms are differentially expressed by direct and indirect pathway spiny projection neurons (dSPNs and iSPNs). Investigation of Shank3B–/– mice lacking exons 13–16 within the Shank3 gene, reveal distinct Shank3 protein isoform expression in iSPNs and dSPNs. In Shank3B-/- striatum, Shank3E and Shank3NT are expressed by dSPNs but are undetectable in iSPNs. Proteomic analysis indicates significant and selective alterations in the postsynaptic proteome of Shank3B–/– iSPNs. Correspondingly, the deletion of exons 13–16 diminishes dendritic spine density, reduces spine head diameter, and hampers corticostriatal synaptic transmission in iSPNs. Remarkably, reintroducing Shank3E in adult Shank3B–/– iSPNs significantly rectifies the observed dendritic spine morphological and corticostriatal synaptic transmission deficits. We report unexpected cell-type specific synaptic protein isoform expression which could play a key causal role in specifying synapse diversity and selective synapse dysfunction in synaptopathies.

Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

Maternal exposure to deltamethrin during pregnancy and lactation impairs neurodevelopment of male offspring

Deltamethrin (DM) is a highly effective and widely used pyrethroid pesticide. It is an environmental factor affecting public and occupational health and exerts direct toxic effects on the central nervous system. As the major target organs for neurotoxicity of DM, the hippocampus and the cerebellum are critical to the learning and motor function. Pregnant Wistar rats were randomly divided into four groups and gavaged at doses of 0, 1, 4or 10 mg/kg/d DM from gestational day (GD) 0 to postnatal day (PN) 21. The PC12 cells were selected to further verify the regulatory mechanisms of DM on the neurodevelopmental injury. We found that maternal exposure to DM caused learning, memory and motor dysfunction in male offspring. Maternal exposure to DM induced the decrease in the density of hippocampal dendritic spines in male offspring through the reduced expression of M1 mAchRs, which in turn reduced the mediated AKT/mTOR signaling pathway, contributing to the inhibition of dynamic changes of GluA1. Meanwhile, DM exposure inhibited the BDNF/TrkB signaling pathway, thereby reducing phosphorylation of stathmin and impairing cerebellar purkinje cell dendrite growth and development. Taken together, maternal exposure to DM during pregnancy and lactation could impair neurodevelopment of male offspring.

Chemogenetic activation of astrocytic Gi signaling promotes spinogenesis and motor functional recovery after stroke.

Ischemic stroke is the leading cause of adult disability. The rewiring of surviving neurons is the fundamental process for functional recovery. Accumulating evidence implicates astrocytes in synapses and neural circuits formation, but few studies have further studied how to enhance the effects of astrocytes on synapse and circuits after stroke and its impacts on post-stroke functional recovery. In this study, we made use of chemogenetics to specifically activate astrocytic Gi signaling in the peri-infarcted sensorimotor cortex at different time epochs in a mouse model of photothrombotic stroke. We found that early activation of astrocytic hM4Di after stroke by CNO modulates astrocyte activity and upregulates synaptogenic molecules including thrombospondin-1 (TSP1) as revealed by bulk RNA-sequencing, but no significant improvement was observed in dendritic spine density and behavioral performance in grid walking test. Interestingly, when the manipulation was initiated at the subacute phase of stroke, the recovery of spine density and motor function could be effectively promoted, accompanied by increased TSP1 expression. Our data highlight the important role of astrocytes in synapse remodeling during the repair phase of stroke and suggest astrocytic Gi signaling activation as a potential strategy for synapse regeneration, circuit rewiring, and functional recovery.

Dendrobine Ameliorates Alzheimer's Disease-like Pathology and Cognitive Decline in 3 × Tg-AD Mice.

Previous studies have shown that Dendrobium nobile Lindl. alkaloids (DNLAs) have neuroprotective effects in several Alzheimer's disease (AD) models. Dendrobine (DDB) is one of the monomer components with the highest content in DNLAs. However, the effects of DDB on cognitive impairments in AD remain unknown. In this study, we investigated the efficacy of DDB in 3 × Tg-AD mice to determine whether DDB was a key component of the anti-AD effect of DNLAs. Five-month mice were intragastrically administrated with DDB (10 and 20 mg/kg/d) or DNLAs (20 mg/kg/d) for seven consecutive months, and the effects of DDB and DNLAs were evaluated at twelve months. The results revealed that 3 × Tg-AD mice treated with DDB showed enhanced nesting ability. DDB also effectively rescued spatial learning and memory deficits in 3 × Tg-AD mice. Meanwhile, DDB treatment prevented the loss of dendritic spine density, with increased expression levels of synaptophysin, PSD95, and NCAM in the hippocampus. Finally, DDB ameliorated the increase in APP, sAPPβ, CTF-β, and β-amyloid peptides, accompanied by the promotion of GSK phosphorylation at the Ser9 site, thereby reducing hyperphosphorylated tau levels. As the active component of DNLA, DDB can preserve cognitive function, alleviate neuronal and synaptic defects, and improve APP/tau pathology in 3 × Tg-AD mice.

Modeling sporadic Alzheimer's disease in mice by combining Apolipoprotein E4 risk gene with environmental risk factors.

Developing effective treatment for Alzheimer's disease (AD) remains a challenge. This can be partially attributed to the fact that the mouse models used in preclinical research largely replicate familial form of AD, while majority of human cases are sporadic; both forms differ widely in the onset and origin of pathology, therefore requiring specific/targeted treatments. In this study, we aimed to model sporadic AD in mice by combining two of the many risk factors that are strongly implicated in AD: ApoE4, a major genetic risk factor, together with an inflammatory stimuli. Accordingly, we subjected ApoE4 knock in (KI) mice, expressing humanized ApoE4, to low doses of Lipopolysaccharide (LPS) injections (i.p, weekly, for 4 months). We assessed these animals for behavioral impairments at 6 months of age using Open Field, Y-maze, and Barnes Maze Test. LPS induced hypoactivity was observed in the Open Field and Y-maze test, whereas spatial learning and memory was intact. We then quantified differences in dendritic spine density, which is a strong correlate of AD. ApoE4KI mice showed a significant reduction in the number of spines after treatment with LPS, whereas there were no obvious differences in the total number of microglia and astrocytes. To conclude, in the current study the APoEe4 risk gene increases the vulnerability of hippocampal neurons to inflammation induced spine loss, laying a foundation for an early sporadic AD mouse model.

Monomeric pilose antler peptide improves depression-like behavior in mice by inhibiting FGFR3 protein expression

Ethnopharmacological relevanceIt has been found that pilose antler peptide has an antidepressant effect on depression. However, the exact molecular mechanism of its antidepressant effect is still unclear. Aim of the studyThe study sought to determine the impact of monomeric pilose antler peptide (PAP; sequence LVLVEAELRE) on depression as well as investigate potential molecular mechanisms. Materials and methodsChronic unexpected mild stress (CUMS) was used to establish the model, and the effect of PAP on CUMS mice was detected by the behavioral test. The influence of PAP on neuronal cells and dendritic spine density was observed by immunofluorescence and Golgi staining. FGFR3 and the CaMKII-associated pathway were identified using quantitative real-time polymerase chain reaction, and Western blot analysis was utilized to measure their proteins and gene expression levels. Molecular docking and microscale thermophoresis were applied to detect the binding of PAP and FGFR3. Finally, the effect of FGFR3's overexpression on PAP treatment of depression was detected. ResultsPAP alleviated the changes in depressive behavior induced by CUMS, promoted the growth of nerve cells, and the density of dendritic spines was increased to its original state. PAP therapy successfully downregulated the expression of FGFR3 and ERK1/2 while upregulating the expression of CREB, BDNF, and CaMKII. ConclusionBased on the current research, PAP has a therapeutic effect on depression brought on by CUMS by inhibiting FGFR3 expression and enhancing synaptic plasticity.

Accumulation of NMDA receptors in accumbal neuronal ensembles mediates increased conditioned place preference for cocaine after prolonged withdrawal

Cue-induced cocaine craving gradually intensifies following abstinence, a phenomenon known as the incubation of drug craving. Neuronal ensembles activated by initial cocaine use, are critically involved in this process. However, the mechanisms by which neuronal changes occurring in the ensembles after withdrawal contribute to incubation remain largely unknown. Here we labeled neuronal ensembles in the shell of nucleus accumbens (NAcSh) activated by cocaine conditioned place preference (CPP) training. NAcSh ensembles showed an increasing activity induced by CPP test after 21-day withdrawal. Inhibiting synaptic transmission of NAcSh ensembles suppressed the preference for cocaine paired-side after 21-day withdrawal, demonstrating a critical role of NAcSh ensembles in increased preference for cocaine. The density of dendritic spines in dopamine D1 receptor expressing ensembles was increased after 21-day withdrawal. Moreover, the expression of Grin1, a subunit of the N-methyl-D-aspartate (NMDA) receptor, specifically increased in the NAcSh ensembles after cocaine withdrawal in both CPP and self-administration (SA) mouse models. Targeted knockdown or dysfunction of Grin1 in NAcSh ensembles significantly suppressed craving for cocaine. Our results suggest that the accumulation of NMDA receptors in NAcSh ensembles mediates increased craving for cocaine after prolonged withdrawal, thereby providing potential molecular targets for treatment of drug addiction.

Histological analysis of neuronal changes in the olfactory cortex during pregnancy

Fluctuations in olfactory sensitivity are widely known to occur during pregnancy and may be responsible for hyperemesis gravidarum. These changes are thought to be caused by structural and functional alterations in neurons in response to marked changes of the hormonal milieu. In this study, we examined changes in neurons in the olfactory cortex during pregnancy and after delivery in rats. Dendritic spine densities were measured in the piriform cortex (PIR) and posterolateral cortical amygdala (COApl), which are involved in olfaction. The results showed increased numbers of dendritic spines in the PIR in mid-pregnancy and in the COApl during early and late pregnancy, but not in the motor area of the cerebral cortex, indicating a correlation with changes in olfactory sensitivity during pregnancy. Immunohistochemical analysis of expression of ovarian hormone receptors in these brain regions revealed a decrease in the number of estrogen receptor α-positive cells during pregnancy in the PIR and during pregnancy and the postpartum period in the COApl. Regarding pregnancy-related peptide hormones, oxytocin receptors were expressed in the PIR and COApl, while prolactin receptors were not found in these regions. Accordingly, oxytocin-containing neurites were distributed in both regions. These results suggest that the balance of these hormonal signals has an effect on olfactory sensitivity in pregnant females.

Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract.

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera, commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length (p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.

C1ql3 knockout affects microglia activation, neuronal integrity, and spontaneous behavior in Wistar rats.

C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons. However, its function is still not clear. We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain. C1ql3 knockout (KO) rats were generated using CRISPR/Cas9. C1ql3 KO was determined by polymerase chain reaction (PCR), DNA sequencing, and western blotting. Microglia morphology and cytokine expression with or without lipopolysaccharide (LPS) stimulus were analyzed using immunohistochemistry and real-time PCR. The brain structure changes in KO rats were examined using magnetic resonance imaging. Neuronal architecture alteration was analyzed by performing Golgi staining. Behavior was evaluated using the open field test, Morris water maze test, and Y maze test. C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia, whereas C1ql3 KO did not influence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10. C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation. The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats. C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density. C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory. C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation, resulting in hyperactive behavior and impaired short memory in rats, which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) via regulating the synaptic plasticity in hippocampus

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.