Spine Morphology Research Articles

Leveraging interindividual variability of regulatory activity for refining genetic regulation of gene expression in schizophrenia

Schizophrenia is a polygenic psychiatric disorder with limited understanding about the mechanistic changes in gene expression regulation. To elucidate on this, we integrate interindividual variability of regulatory activity (ChIP-sequencing for H3K27ac histone mark) with gene expression and genotype data captured from the prefrontal cortex of 272 cases and controls. By measuring interindividual correlation among proximal chromatin peaks, we show that regulatory element activity is structured into 10,936 and 10,376 cis-regulatory domains in cases and controls, respectively. The schizophrenia-specific cis-regulatory domains are enriched for fetal-specific (p = 0.0014, OR = 1.52) and depleted of adult-specific regulatory activity (p = 3.04 × 10−50, OR = 0.57) and are enriched for SCZ heritability (p = 0.001). By studying the interplay among genetic variants, gene expression, and cis-regulatory domains, we ascertain that changes in coordinated regulatory activity tag alterations in gene expression levels (p = 3.43 × 10−5, OR = 1.65), unveil case-specific QTL effects, and identify regulatory machinery changes for genes affecting synaptic function and dendritic spine morphology in schizophrenia. Altogether, we show that accounting for coordinated regulatory activity provides a novel mechanistic approach to reduce the search space for unveiling genetically perturbed regulation of gene expression in schizophrenia.

Rehabilitation on a treadmill induces plastic changes in the dendritic spines of spinal motoneurons associated with improved execution after a pharmacological injury to the motor cortex in rats

Lesions to the corticospinal tract result in several neurological symptoms and several rehabilitation protocols have proven useful in attempts to direct underlying plastic phenomena. However, the effects that such protocols may exert on the dendritic spines of motoneurons to enhance accuracy during rehabilitation are unknown. Thirty three female Sprague-Dawley adult rats were injected stereotaxically at the primary motor cerebral cortex (Fr1) with saline (CTL), or kainic acid (INJ), or kainic acid and further rehabilitation on a treadmill 16 days after lesion (INJ+RB). Motor performance was evaluated with the the Basso, Beatie and Bresnahan (BBB) locomotion scale and in the Rotarod. Spine density was quantified in a primary dendrite of motoneurons in Lamina IX in the ventral horn of the thoracolumbar spinal cord as well as spine morphology. AMPA, BDNF, PSD-95 and synaptophysin expression was evaluated by Western blot. INJ+RB group showed higher scores in motor performance. Animals from the INJ+RB group showed more thin, mushroom, stubby and wide spines than the CTL group, while the content of AMPA, BDNF, PSD-95 and Synaptophysin was not different between the groups INJ+RB and CTL. AMPA and synaptophysin content was greater in INJ group than in CTL and INJ+RB groups. The increase in the proportion of each type of spine observed in INJ+RB group suggest spinogenesis and a greater capability to integrate the afferent information to motoneurons under relatively stable molecular conditions at the synaptic level.

Sagittal alignment of the cervical spine: radiographic analysis of 111 asymptomatic adolescents, a retrospective observational study

PurposeTo describe the cervical spine morphology and explore its relationship to global sagittal alignment parameters in the asymptomatic adolescent population. MethodsA total of 111 adolescent subjects were included. Sagittal alignment parameters, including C7 Slope, C2-C7 Cobb, C2-7 plumb line (PL), C2-S1 Sagittal Vertical Axis (SVA), C7-S1 SVA, T5-12 Cobb, T10-L2 Cobb, L1-S1 Cobb, pelvic incidence (PI), pelvic tilt (PT) and sacral slope (SS), were obtained from lateral radiographs. ResultsForty-four males and sixty-seven females with a mean age of 16.12 ± 2.40 years were included in this study. The mean values of C7 Slope, C2-7 Cobb and C2-7PL were 20.45 ± 8.88°, -7.72 ± 12.10°, and 13.53 ± 11.63 mm, respectively. C2-7 Cobb, C7 Slope showed significant differences between the male and female groups. Correlation analysis showed that C7 slope was significantly correlated with C2-7 Cobb (r = -0.544, P < 0.001), C2-S1 SVA (r = 0.335, P < 0.001), and C7-S1 SVA (r = 0.310, P = 0.001), but not lumbosacral parameters(L5-S1 Cobb, PI, PT, SS). Using a modified method of Toyama to describe the cervical spine morphology, there were 37 cases (33.3%) in the Lordotic group, and C7 slope, C2-7 Cobb and C2-7PL showed significant differences between groups. According to C2-C7 Cobb, there were 80 Lordotic cases (72.1%). C7 slope and C2-7PL were significantly different between the two groups.ConclusionThe cervical spine morphology of asymptomatic adolescents varies widely, from lordotic to kyphotic. Combining different classification methods provides a better understanding of the morphology of the cervical spine. C7 slope is an important predictor of global sagittal balance and C2-7PL is a key parameter for restoring cervical lordosis, which should be considered pre-operatively and for conservative treatment. Cervical regional sagittal alignment parameters are not correlated with lumbosacral parameters, and C2-7 Cobb, C7 Slope showed significant differences between males and females.

A morphometric and genetic investigation of Opuntia engelmannii population variation in Africa

AbstractOpuntia engelmannii Salm‐Dyck (Cactaceae:Opuntioideae) is a morphologically variable cactus that has invaded pasture lands in South Africa and Kenya. Biological control of invasive Opuntia species can be very successful when the correct agent is matched with the appropriate host. This research investigated the similarity (morphological and genetic) between several populations of O. engelmannii and a morphologically uniform, O. stricta, that occur in South Africa and Kenya to help understand the identity of the target weed. Spine and cladode morphology showed that the Limpopo (South African) and Kenyan populations were most similar, while the spiny Eastern Cape (South African) population was more similar to Opuntia stricta. Multivariate analysis showed that spine morphometry was a useful diagnostic character in identifying different putative O. engelmannii populations in the field. In addition, we used amplified fragments length polymorphisms to estimate genetic similarity and genetic structure among populations that represent the morphologically variable populations. There was relatively little differentiation in the population structure between the Limpopo and Kenyan populations. The spiny Eastern Cape population showed moderate genetic differentiation (FST = 0.05 − 0.15) relative to other O. engelmannii populations and was genetically more similar to the O. stricta population. These results will facilitate the search for suitable biocontrol agents by directing future collections of the appropriate biotype of Dactylopius opuntiae Cockerell (Hemiptera: Dactylopiidae) to relevant populations of O. engelmannii in its home range. In addition, given the genetic similarity of the spiny Eastern Cape population to O. stricta, we recommend the efficacy of D. opuntiae ‘stricta’ biotype be tested on the spiny Eastern Cape population as a potential biocontrol agent.

Effects of short-segment pedicle screw internal fixation surgery combined with hyperbaric oxygen treatment for acute spinal injury on the morphology and function of the spine

To explore effect of short-segment pedicle screw internal fixation combined with hyperbaric oxygen in treating acute spinal fractures and its influence on recovery of spinal nerve function. A total of 96 patients with acute spinal fracture admitted from February 2017 to March 2020 were divided into combined group and control group, with 48 cases in each group. Both groups were treated with short-segment pedicle screw internal fixation. The combined group was given hyperbaric oxygen after surgery. The operation time, surgical blood loss, incision length and other general operation conditions between two groups were recorded. The differences in spinal morphology and function, Ameraican Spinal Injury Assiciation(ASIA) neurological function grade, serum inflammatory factors and ability of daily living activities were observed before and after surgery. There was no significant difference in operation time, surgical blood loss, and incision length between combined group and control group(P>0.05). There were no significant differences in anterior height ratio and Cobb angle between two groups before surgery, 1 week and 6 months after surgery(P>0.05). The height ratio of anterior margin of the injured spine was significantly improved in both groups at 1 week and 6 months after surgery compared with preoperative period (P<0.05), and Cobb angle was significantly reduced in both groups compared with preoperative period (P<0.05). There was no statistically significant difference in serum interleukin-6(IL-6), interleukin-8(IL-8), and tumor necrosis factor-α(TNF-α) levels between two groups at 1 d after surgery(P>0.05);the serum IL-6, IL-8, and TNF-α levels of combined group were lower than those of control group at 1 week after surgery (P<0.05). At 6 months after surgery, ASIA neurological function grade of combined group was C grade in 2 cases, D grade in 23 cases, E grade in 22 cases. In control group, 7 cases was grade C, 26 cases was grade D, 13 cases was grade E, and the difference between two groups was statistically significant(P<0.05). The Barthel score of combined group was higher than that of control group at 1 month and 3 months after surgery, and the difference was statistically significant (P<0.05);at 6 months after surgery, there was no significant difference in Barthel score between two groups(P>0.05). Short-segment pedicle screw internal fixation combined with hyperbaric oxygen for the treatment of acute spinal fractures is beneficial to the recovery of spinal nerve function after surgery, and has a certain effect on the early improvement of the patients' activities of daily living.

A Review of Research on the Effects of Backpacks on Body Posture and Spinal Morphology in Children and Adolescents

Introduction: The purpose of the study was to investigate the effects of backpacks on body posture and spinal morphology in children and adolescents, and the relationship between them and back pain in adolescents, in order to provide a theoretical basis for further research in this area. Methods: The literature on backpacks, body posture, spinal morphology and back pain was searched and the results were analyzed. Results: The studies mainly focused on the effects of backpack type, weight and position on their muscle activity; and the main muscles studied were upper trapezius, erector spinae, and rectus abdominis, while the studies on other muscles were still insufficient. Conclusion: Backpack type and method, backpack weight, backpack strap design, backpack position, and backpack time all have different effects on muscle activity in various parts of the adolescent body, and these effects may lead to back pain, which is one of the factors affecting spinal health that cannot be ignored.

Combined hyperforin and lanicemine treatment instead of ketamine or imipramine restores behavioral deficits induced by chronic restraint stress and dietary zinc restriction in mice.

Clinical and preclinical studies show evidence that chronic stress or nutritional deficits in dietary zinc (Zn) intake may be risk factors for developing major depressive disorder (MDD). Furthermore, there may be possible links between low serum Zn levels and development of treatment-resistant depression. In the present work, we combined chronic restraint stress (CRS) and a low-zinc diet (ZnD) in mice and carried out a set of behavioral and biochemical studies. The mice were treated with four different antidepressant compounds, namely, ketamine, Ro 25–6981 (Ro), hyperforin and lanicemine (Hyp + Lan), and imipramine (IMI). We show that CRS or ZnD alone or a combination of CRS and ZnD (CRS + ZnD) induces anhedonia observed in the sucrose preference test (SPT). The behavioral effects of CRS were restored by ketamine or IMI. However, only Hyp + Lan restored the deficits in behavioral phenotype in mice subjected to CRS + ZnD. We also showed that the antidepressant-like effects observed in Hyp + Lan-treated CRS + ZnD mice were associated with changes in the morphology of the dendritic spines (restored physiological level) in the hippocampus (Hp). Finally, we studied the metabolism of ketamine and its brain absorption in CRS and CRS + ZnD mice. Our results suggest that CRS + ZnD does not alter the metabolism of ketamine to (2R,6R;2S,6S)-HNK; however, CRS + ZnD can induce altered bioavailability and distribution of ketamine in the Hp and frontal cortex (FC) in CRS + ZnD animals compared to the control and CRS groups.

Changes in Dendritic Spine Morphology and Density of Granule Cells in the Olfactory Bulb of Anguilla anguilla (L., 1758): A Possible Way to Understand Orientation and Migratory Behavior.

Simple SummaryThe olfactory bulb can process odour cues through granular cells (GCs) and dendritic spines, changing their synaptic plasticity properties and their morphology. The GCs’ dendritic spines density and morphology were analysed in Anguilla anguilla, considering the olfaction as a driver involved in fish orientation and migration. For the head and neck morphology, spines were classified as mushroom, long thin, stubby, and filopodia. Spines’ density decreased from juvenile migrants to no-migrant stages and increased in the adult migrants. Spines’ density was comparable between glass and silver eels as an adaptation to migration, while at non-migrating phases, spines’ density decreased. For its phylogenetic Elopomorph attribution and its complex life cycle, A. anguilla could be recommended as a model species to study the development of dendritic spines in GCs of the olfactory bulb. Considering the role of olfaction in the orientation and migration of A. anguilla, the modification of environmental stimuli (ocean alterations and climate change) could represent contributing factors that threaten this critically endangered species.Olfaction could represent a pivotal process involved in fish orientation and migration. The olfactory bulb can manage olfactive signals at the granular cell (GC) and dendritic spine levels for their synaptic plasticity properties and changing their morphology and structural stability after environmental odour cues. The GCs’ dendritic spine density and morphology were analysed across the life stages of the catadromous Anguilla anguilla. According to the head and neck morphology, spines were classified as mushroom (M), long thin (LT), stubby (S), and filopodia (F). Total spines’ density decreased from juvenile migrants to no-migrant stages, to increase again in the adult migrant stage. Mean spines’ density was comparable between glass and silver eels as an adaptation to migration. At non-migrating phases, spines’ density decreased for M and LT, while M, LT, and S density increased in silver eels. A great dendritic spine development was found in the two migratory phases, regressing in trophic phases, but that could be recreated in adults, tracing the migratory memory of the routes travelled in juvenile phases. For its phylogenetic Elopomorph attribution and its complex life cycle, A. anguilla could be recommended as a model species to study the development of dendritic spines in GCs of the olfactory bulb as an index of synaptic plasticity involved in the modulation of olfactory stimuli. If olfaction is involved in the orientation and migration of A. anguilla and if eels possess a memory, these processes could be influenced by the modification of environmental stimuli (ocean alterations and rapid climate change) contributing to threatening this critically endangered species.

Pedicle Morphology of Lower Thoracic and Lumbar Spine in Ankylosing Spondylitis Patients with Thoracolumbar Kyphosis: A Comparison with Fracture Patients.

ObjectiveThe pedicle morphology of ankylosing spondylitis (AS)‐related thoracolumbar kyphosis patients may be different from that of individuals with normal spine due to the ectopic ossification and kyphotic deformity. However, there was no literature analyzing the pedicle morphology of AS patients with thoracolumbar kyphosis. Therefore, the present study aimed to investigate the pedicle morphology of lower thoracic and lumbar spine (T9‐L5) in ankylosing spondylitis (AS)‐related thoracolumbar kyphosis patients.MethodsA retrospective review of AS patients with thoracolumbar kyphosis (AS group) and the patients with spinal or rib fracture (fracture group) who underwent CT scans of the lower thoracic and lumbar spine between February 2017 and September 2018 was performed. Patients with spinal tumor, spinal tuberculosis, severe degenerative spinal diseases including degenerative scoliosis, degenerative spondylolisthesis, degenerative spinal stenosis or history of previous spine surgery, or AS patients with pseudarthrosis which influenced the measurement of pedicle parameters were excluded. The measured parameters on CT images included transverse pedicle angle (TPA), transverse pedicle width (TPW), chord length (CL), pedicle length (PL), and sagittal pedicle angle (SPA). The intraclass correlation coefficient (ICC) was used to evaluate the agreement of radiographic parameters between observers. The independent sample t test was applied for the comparison of pedicle parameters between the two groups. The gender distribution between the two groups were compared using the Fisher's exact test.ResultsA total of 1444 pedicles of 53 AS‐related thoracolumbar kyphosis patients and 30 patients with fracture were analyzed. TPA was significantly smaller in AS group (p < 0.05). Significantly larger TPW was found in AS group in the lumbar spine (p < 0.05). TPW ≥ 7.5 mm was observed in 95.3%–98.1% of the pedicles at the levels of L3‐L5 in AS group. The CL and PL were significantly larger in AS group at the levels of T9‐L5 (p < 0.05). The CL ≥ 50 mm was found in 84.0%–96.2% of the pedicles in mid‐to‐lower lumbar spine in AS group. Significantly smaller SPA was found in AS group at the levels from L3 to L5 (p < 0.05).ConclusionsPedicle screws with relatively large diameter of 7.5 mm and length of 50 mm could be used in mid‐to‐lower lumbar spine in the majority of AS‐related thoracolumbar kyphosis patients. Also, the insertion angle of pedicle screws in both the transverse and sagittal plane should be appropriately reduced in these patients. This study may help surgeons select the pedicle screws of appropriate size in AS patients.

Cranial irradiation induces cognitive decline associated with altered dendritic spine morphology in the young rat hippocampus.

Therapeutic irradiation is commonly used to treat brain cancers but can induce cognitive dysfunction, especially in children. The mechanism is unknown but likely involves alterations in dendritic spine number and structure. To explore the impact of radiation exposure on the alteration of dendritic spine morphology in the hippocampus of young brains, 21-day-old Sprague-Dawley rats received cranial irradiation (10Gy), and changes in spine density and morphology in dentate gyrus (DG) granules and CA1 pyramidal neurons were detected 1 and 3months later by using Golgi staining. Moreover, we analyzed synapse-associated proteins within dendritic spines after irradiation. Our data showed that cognitive deficits were detected in young rats at both time points postirradiation, accompanied by morphological changes in dendritic spines. Our results revealed significant reductions in spine density in the DG at both 1month (40.58%) and 3months (28.92%) postirradiation. However, there was a decrease in spine density only at 1month (33.29%) postirradiation in the basal dendrites of CA1 neurons and no significant changes in the apical dendrites of CA1 neurons at either time point. Notably, among our findings were the significant dynamic changes in spine morphology that persisted 3months following cranial irradiation. Meanwhile, we found that depletion of the synapse-associated proteins PSD95 and Drebrin coincided with alterations in dendritic spines. These data suggest that the decreased levels of PSD95 and Drebrin after ionizing radiation may cause changes in synaptic plasticity by affecting the morphological structure of dendritic spines, blocking the functional connectivity pathways of the brain and leading to cognitive impairment. Although the mechanism involved is unclear, understanding how ionizing radiation affects young brain hippocampal tissue may be useful to gain new mechanistic insights into radiation-induced cognitive dysfunction.

Early Changes in Transcriptomic Profiles in Synaptodendrosomes Reveal Aberrant Synaptic Functions in Alzheimer's Disease.

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by the progressive decline of cognitive functions, and is closely associated with the dysfunction of synapses, which comprise the basic structure that mediates the communication between neurons. Although the protein architecture and machinery for protein translation at synapses are extensively studied, the impact that local changes in the mRNA reservoir have on AD progression is largely unknown. Here, we investigated the changes in transcriptomic profiles in the synaptodendrosomes purified from the cortices of AD mice at ages 3 and 6 months, a stage when early signatures of synaptic dysfunction are revealed. The transcriptomic profiles of synaptodendrosomes showed a greater number of localized differentially expressed genes (DEGs) in 6-month-old AD mice compared with mice 3 months of age. Gene Ontology (GO) analysis showed that these DEGs are majorly enriched in mitochondrial biogenesis and metabolic activity. More specifically, we further identified three representative DEGs in mitochondrial and metabolic pathways—Prnp, Cst3, and Cox6c—that regulate the dendritic spine density and morphology in neurons. Taken together, this study provides insights into the transcriptomic changes in synaptodendrosomes during AD progression, which may facilitate the development of intervention strategies targeting local translation to ameliorate the pathological progression of AD.

Redundant nerve roots indicate higher degree of stenosis in lumbar spine stenotic patients.

Redundant Nerve Root (RNR) is a tortuous and elongated radiological appearance of cauda equina on Magnetic Resonance Imaging (MRI) in Lumbar Spinal Canal Stenosis (LSCS) patients. This study evaluated preoperative spinal morphometry associated with the development of RNR. The retrospective cohort was conducted at The Aga Khan University Hospital, and included patients undergoing decompressive spinal surgery secondary to degenerative LSCS in 2015. The patients were divided into two groups with respect to the presence of preoperative RNR. Spinal morphometry was defined by several radiological parameters, including areas of dural sac (DSA), spinal canal, spinal foramen, facets, and spinal joints, and bilateral angles based on vertebral anatomy. A total of 55 patients were enrolled with a mean age of 57.1years, in which 22 (40%) expressed RNR in their MRI. The RNR group had significantly lower mean DSA (59.64 vs 84.01 mm2; p = 0.028), bilateral posterior facet angle (Right: 33.84 vs 46.21, p = 0.004; Left: 36.43 vs 43.80, p = 0.039) and higher bilateral anterior facet angles (Right: 54.85 vs 44.57, p = 0.026; Left: 55.27 vs 46.36, p = 0.050) compared to the non-RNR group. The other bidimensional and angular parameters did not observe any statistical difference between the two groups. RNR was associated with a higher degree of stenosis in patients with LSCS. Bilateral anterior and posterior facets angles contribute to its development, indicating particular spinal morphology to be vulnerable to the stenotic disease.

A genetic labeling system to study dendritic spine development in zebrafish models of neurodevelopmental disorders.

ABSTRACTDendritic spines are the principal site of excitatory synapse formation in the human brain. Several neurodevelopmental disorders cause spines to develop abnormally, resulting in altered spine number and morphology. Although spine development has been thoroughly characterized in the mammalian brain, spines are not unique to mammals. We have developed a genetic system in zebrafish to enable high-resolution in vivo imaging of spine dynamics during larval development. Although spiny neurons are rare in the larval zebrafish, pyramidal neurons (PyrNs) of the zebrafish tectum form an apical dendrite containing a dense array of dendritic spines. To characterize dendritic spine development, we performed mosaic genetic labeling of individual PyrNs labeled by an id2b:gal4 transgene. Our findings identify a developmental period during which PyrN dendrite growth is concurrent with spine formation. Throughout this period, motile, transient filopodia gradually transform into stable spines containing postsynaptic specializations. The utility of this system to study neurodevelopmental disorders was validated by examining spine development in fmr1 mutant zebrafish, a model of fragile X syndrome. PyrNs in fmr1 mutants exhibited pronounced defects in dendrite growth and spine stabilization. Taken together, these findings establish a genetic labeling system to study dendritic spine development in larval zebrafish. In the future, this system could be combined with high-throughput screening approaches to identify genes and drug targets that regulate spine formation.

Contralateral synaptic changes following severe unilateral brain injury

The brain is highly integrated and thus unilateral injury can impact the contralateral hemisphere. However, further research is needed to clarify the changes in the response of the contralateral homotopic area to ipsilateral injury. We hypothesized that severe unilateral brain injury would be accompanied by contralateral synaptic changes that are related to functional recovery. To test this, we divided rats into sham and experimental groups. In the experimental group, we performed right motor cortex resection. These rats were further divided into three subgroups according to post-injury time: 7 days, 14 days, and 30 days post-injury. Rats in each group were evaluated using a beam walking test to quantify the recovery of motor function, and all rats received an injection of adeno-associated virus-containing green fluorescent protein (GFP). Finally, we conducted morphological and histological analyses to identify synaptic changes. Over time, the behavior of the rats that underwent right motor cortex resection recovered. Furthermore, in contrast to the sham group, the experimental groups exhibited an increase in the spine density and expression of synaptic proteins in layer V of the contralateral motor cortex, which was consistent with the GFP-labeled neurons. Moreover, more immature spines were observed 7 days post-injury. Notably, spine morphology matured from 7 to 30 days, and the increase in Synapsin-1 intensity in layer V peaked 14 days after the resection, whereas PSD-95 intensity continued to increase until day 30. Our findings suggested that following motor function recovery from unilateral brain injury, spine morphology and synaptic proteins change dynamically in the contralateral hemisphere.

Effect of incremental intensities on the spinal morphology and core muscle activation in competitive cyclists

ABSTRACT Cycling is a sport where cyclists predominantly adopt a sitting posture, with the trunk tilted forward. This posture requires a high volume of training and duration in several intensities of effort. This study aims to: 1) evaluate the behaviour of the thoracic and lumbar spine flexion and sacral inclination in the sagittal plane, the thoracic and lumbar spine flexion in the frontal plane, and the trunk torsion in the transverse plane; 2) compare the activation of the core muscles as the intensity of effort increases during an incremental test in cycling, and 3) identify which core muscle has a greater activation in each intensity zone. The spinal posture and the activation of the eight core muscles were evaluated in twelve competitive cyclists during incremental cycling intensities. Thoracic and lumbar spine flexion and sacral inclination statistically increased as the intensity of effort increased (Start < VT1 < VT2 < VO2max). A significant increase in muscle activation was observed in all core muscles evaluated as the intensity increased. The rectus abdominis showed statistically significant greater muscle activation than the other core muscles evaluated. In conclusion, as the intensity of effort in cycling increases, cyclists significantly increase the thoracic and lumbar spine flexion, the sacral inclination in the sagittal plane, the thoracic and lumbar spine flexion in the frontal plane, trunk rotation in the transverse plane, as well as the activation of the core muscles.

Dendritic spine morphology regulates calcium-dependent synaptic weight change.

Dendritic spines act as biochemical computational units and must adapt their responses according to their activation history. Calcium influx acts as the first signaling step during postsynaptic activation and is a determinant of synaptic weight change. Dendritic spines also come in a variety of sizes and shapes. To probe the relationship between calcium dynamics and spine morphology, we used a stochastic reaction-diffusion model of calcium dynamics in idealized and realistic geometries. We show that despite the stochastic nature of the various calcium channels, receptors, and pumps, spine size and shape can modulate calcium dynamics and subsequently synaptic weight updates in a deterministic manner. Through a series of exhaustive simulations and analyses, we found that the calcium dynamics and synaptic weight change depend on the volume-to-surface area of the spine. The relationships between calcium dynamics and spine morphology identified in idealized geometries also hold in realistic geometries, suggesting that there are geometrically determined deterministic relationships that may modulate synaptic weight change.

Effects of membrane androgen receptor binding on synaptic plasticity in primary hippocampal neurons

Androgens play an important role in the regulation of hippocampal synaptic plasticity. While the classical molecular mechanism of androgen's genomic activity is their binding to intracellular androgen receptors (iARs), they can also induce rapid non-genomic effects through specific membrane androgen receptors (mARs). In this study, we aimed to localize and characterize these mARs in primary rat hippocampal neurons. Specific punctate fluorescent signals on the cell surface, observed by testosterone-fetal bovine serum albumin conjugated fluorescein isothiocyanate (T-BSA-FITC), indicated the presence of mARs in hippocampal neurons. T-BSA-FITC binding to the cell membrane was incompletely blocked by the iAR-antagonist flutamide, and mAR binding site was competitively bound by free testosterone (T). Most neurons expressing androgen membrane binding sites are glutamatergic (excitatory), although several are γ-aminobutyric acid (GABA)ergic (inhibitory). Confocal microscopy and live-cell imaging techniques were used to observe the real-time rapid effects of androgens on hippocampal dendritic spine morphology. Immunofluorescence cell staining was used to observe their effects on the postsynaptic density protein 95 (PSD95) and synapsin (SYN) synaptic markers. While androgens did not cause a short-term increase in dendritic spine density of rat primary hippocampal neurons, they promoted the transformation of dendritic spines from thin to mushroom, promoted dendritic spine maturation, increased dendritic spine surface area, and rapidly increased PSD95 and SYN expression in the primary hippocampal neurons. Hippocampal synaptosomes were prepared using the Optiprep and Percoll density gradient two-step centrifuge methods, and the gene expression profiles of the synaptosomes and hippocampus were compared using a gene chip; PSD95 mRNA expression was detected by reverse transcription-polymerase chain reaction. Several mRNAs were detected at the synaptic site, including PSD95. Finally, the Venus-PSD95 plasmid was constructed and transfected into HT22 cells, which is a mouse hippocampal neuronal cell line. The real-time effect of androgen on synaptic protein PSD95 was observed by fluorescence recovery after photobleaching experiments, which involved the translation process of PSD95 mRNA. In conclusion, our findings increased our understanding of how androgens exert the neuroprotective mechanisms on synaptic plasticity.

Swimming exercise prevents hippocampal dendritic spine changes and memory loss caused by aging: An application of a new semi-automated spine analysis software

Dendritic spines are small, ratchet-like protrusions on neuronal dendrites that form synapses for receiving neuronal messages. Dendritic spine morphology is associated with synapse function. If neurons degrade or are damaged, the spine morphology of neurons changes. Given that most commercially available spine analysis software is expensive and complex, this study investigated a semi-automated spine analysis software, CTSpine, and used previously published data to verify the accuracy of the analysis results of this software. We also applied CTSpine to understand whether aging causes alterations in the hippocampal spine morphology and whether physical exercise can impede dendritic spine changes in 20 male Sprague Dawley rats. The spines of pyramidal cells in the hippocampal Cornu Ammonis 1 (CA1) region in the aging group were more enriched in filopodium type pattern than those in the control group, whereas the spines of the exercised aging group showed a similar pattern to that of the control. No significant changes were observed in neuronal dendritic spines in other hippocampal regions. However, long-term hippocampal memory was considerably decreased in the aging group, which was reversed to some extent in the exercised aging group. CTSpine, a self-developed semi-automatic spine analysis software, showed results similar to those noted in published data and can be effectively applied to the study of dendritic patterns, including neurodevelopment and disease.

Rapid Eocene diversification of spiny plants in subtropical woodlands of central Tibet

Spinescence is an important functional trait possessed by many plant species for physical defence against mammalian herbivores. The development of spinescence must have been closely associated with both biotic and abiotic factors in the geological past, but knowledge of spinescence evolution suffers from a dearth of fossil records, with most studies focusing on spatial patterns and spinescence-herbivore interactions in modern ecosystems. Numerous well-preserved Eocene (~39 Ma) plant fossils exhibiting seven different spine morphologies discovered recently in the central Tibetan Plateau, combined with molecular phylogenetic character reconstruction, point not only to the presence of a diversity of spiny plants in Eocene central Tibet but a rapid diversification of spiny plants in Eurasia around that time. These spiny plants occupied an open woodland landscape, indicated by numerous megafossils and grass phytoliths found in the same deposits, as well as numerical climate and vegetation modelling. Our study shows that regional aridification and expansion of herbivorous mammals may have driven the diversification of functional spinescence in central Tibetan woodlands, ~24 million years earlier than similar transformations in Africa.

Ras Inhibitor Lonafarnib Rescues Structural and Functional Impairments of Synapses of Aβ1-42 Mice via α7nAChR-Dependent BDNF Upregulation.

Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ1-42 mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Aβ1-42 mice. Furthermore, lonafarnib enhanced α7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Aβ1-42 mice, which were inhibited by α7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Aβ1-42 mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of α7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Aβ1-42 mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Aβ1-42 mice, which may be related to the improvement of BDNF content through the H-Ras-α7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition.SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. However, no effective drugs have not been developed for the treatment of AD synaptic. This study for the first time reported the beneficial effects of Ras inhibitor lonafarnib on the synaptic structure and function in AD mice, providing an alternative way for the treatment of "synaptic disease" in AD patients.