Dendritic Morphology Research Articles

Differential intrinsic firing properties in sustained and transient mouse alpha RGCs match their light response characteristics and persist during retinal degeneration

Retinal ganglion cells (RGCs) are the neuronal connections between the eye and the brain conveying multiple features of the outside world through parallel pathways. While there is a large body of literature how these pathways arise in the retinal network, the process of converting presynaptic inputs into RGC spiking output is little understood. In this study, we show substantial differences in the spike generator across three types of alpha RGCs in female and male mice, the αON sustained, αOFF sustained and αOFF transient RGC. The differences in their intrinsic spiking responses match the differences of the light responses across RGC types. While sustained RGC types have spike generators that are able to generate sustained trains of action potentials at high rates, the transient RGC type fired shortest action potentials enabling it to fire high-frequency transient bursts. The observed differences were also present in late-stage photoreceptor-degenerated retina demonstrating long-term functional stability of RGC responses even when presynaptic circuitry is deteriorated for long periods of time. Our results demonstrate that intrinsic cell properties support the presynaptic retinal computation and are, once established, independent of them.Significance StatementSpiking output from retinal ganglion cells (RGCs) has long been thought to be solely determined by synaptic inputs from the retinal network. We show that the cell-intrinsic spike generator varies across RGC populations and therefore that postsynaptic processing shapes retinal spiking output in three types of mouse alpha RGCs (αRGCs). While sustained αRGC types have spike generators that are able to generate sustained trains of action potentials at high rates, the transient αRGC type fired shortest action potentials enabling them to fire high-frequency transient bursts. Computational modeling suggests that intrinsic response differences are not driven by dendritic morphology but by somatodendritc biophysics. After photoreceptor degeneration, the observed variability is preserved indicating stable physiology across the three αRGC types.

Viscoelastic High-Molecular-Weight Hyaluronic Acid Hydrogels Support Rapid Glioblastoma Cell Invasion with Leader-Follower Dynamics.

Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.

Endocytosis restricts dendrite branching via removing ectopically localized branching ligands

Neurons often grow highly branched and cell-type specific dendrite morphologies to receive and integrate information, which is the basis of precise neural circuit formation. Previous studies have identified numerous mechanisms that promote dendrite branching. In contrast, it is much less understood how this process is negatively regulated. Here we show that EAT-17/EVI5 acts together with the dynein adaptor protein BICD-1 and the motor protein dynein in C. elegans epidermal cells to restrict branching of PVD sensory dendrites. Loss-of-function mutants of these genes cause both ectopic branching and accumulation of the dendrite branching ligand SAX-7/L1CAM on epidermal plasma membranes. Mutants of genes regulating endo-lysosomal trafficking, including rab-5/RAB5 and dyn-1/DNM1, show similar defects. Biochemical characterization, genetic analysis, and imaging results support that EAT-17 and BICD-1 directly interact with each other and function in the endocytic degradation pathway to remove ectopically localized dendrite branching ligands to restrict abnormal branching.

Roles of Al/Ni ratio and solidification cooling rate in grain boundary engineering of AlxCrFeMnNi(2-x) high entropy alloy

In this work, the roles of Al/Ni ratio and solidification cooling rate in grain size, dendrite morphology and grain boundary characteristic of the AlxCrFeMnNi(2-x) (x = 0.3, 0.7 and1.0) high-entropy alloys (HEAs) were investigated. The results show that the increasing of Al/Ni ratio results in a transition from single-phase FCC to dual-phase BCC + B2 along with the reverse precipitation behavior of BCC phase. While the phase composition is not affected by solidification cooling rate. With the increasing of Al/Ni ratio and solidification cooling rate, a significant columnar-to-equiaxed transition (CET) behavior can be observed. That is, grain refinement and transition from columnar dendrites to equiaxial and cellular dendrites. This is mainly attributed to the constitutional supercooling (CS) caused by the solute interaction effect of Al and Ni, and which can be evaluated by P and Q parameters. In addition, in-situ formation of serrated grain boundaries (SGBs) can be also observed in solidification microstructures, and with the increasing of Al/Ni ratio, the proportion of SGBs increases gradually. Whether the B2 precipitated phase is present or not, the formation mechanism of SGBs is mainly attributed to the lattice strain energy caused by the segregation of Al and Ni. The strategy simultaneously achieving grain refinement, CET and in-situ forming SGBs during solidification by tailoring Al/Ni ratio opens new perspectives for grain boundary engineering.

Pretreatment with tetramethylpyrazine alleviated the impairment of learning and memory induced by sevoflurane exposure in neonatal rats

Sevoflurane impairs learning and memory of the developing brain. However, strategies to mitigate these detrimental effects have been scarce. Herein, we investigated whether tetramethylpyrazine could alleviate the impairment of learning and memory and its underlying mechanisim in sevoflurane-exposed neonatal rats. Postnatal 7-day Sprague-Dawley (SD) rats or primary hippocampal neurons were pretreated with tetramethylpyrazine and then exposed to sevoflurane. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and lactate dehydrogenase (LDH) assays were used to detect neuronal injury. Learning and memory function were evaluated by novel object recognition and Morris water maze tests. Long-term potentiation (LTP) was recorded to evaluate synaptic plasticity electrophysiologically in the hippocampal slices. Golgi-Cox staining or PSD95 immunochemistry was used to detect the morphology of dendritic spines. Western blotting was employed to assess the expressions of cleaved Caspase-3, PSD95, NMDAR1, NMDAR2A and NMDAR2B in the hippocampus or cultured neurons. It was found that neonatal exposure of sevoflurane impaired learning and memory, increased neuronal apoptosis, altered the morphology of dendritic spine, upregulated the expressions of NMDAR2A and PSD95, and induced LTP deficits. Pretreatment with tetramethylpyrazine not only alleviated impairment of learning and memory, but also improved sevoflurane-induced changes in neuronal damage, dendritic spine morphology, NMDAR2A and PSD95 expressions, as well as LTP. These findings indicated that pretreatment with tetramethylpyrazine alleviated the impairment of learning and memory induced by sevoflurane through improvement of hippocampal synaptic plasticity in neonatal rats.

Neuronal connectivity, behavioral, and transcriptional alterations associated with the loss of MARK2.

Neuronal connectivity is essential for adaptive brain responses and can be modulated by dendritic spine plasticity and the intrinsic excitability of individual neurons. Dysregulation of these processes can lead to aberrant neuronal activity, which has been associated with numerous neurological disorders including autism, epilepsy, and Alzheimer's disease. Nonetheless, the molecular mechanisms underlying abnormal neuronal connectivity remain unclear. We previously found that the serine/threonine kinase Microtubule Affinity Regulating Kinase 2 (MARK2), also known as Partitioning Defective 1b (Par1b), is important for the formation of dendritic spines invitro. However, despite its genetic association with several neurological disorders, the invivo impact of MARK2 on neuronal connectivity and cognitive functions remains unclear. Here, we demonstrate that the loss of MARK2 invivo results in changes to dendritic spine morphology, which in turn leads to a decrease in excitatory synaptic transmission. Additionally, the loss of MARK2 produces substantial impairments in learning and memory, reduced anxiety, and defective social behavior. Notably, MARK2 deficiency results in heightened seizure susceptibility. Consistent with this observation, electrophysiological analysis of hippocampal slices indicates underlying neuronal hyperexcitability in MARK2-deficient neurons. Finally, RNAseq analysis reveals transcriptional changes in genes regulating synaptic transmission and ion homeostasis. These results underscore the invivo role of MARK2 in governing synaptic connectivity, neuronal excitability, and cognitive functions.

Integration across biophysical scales identifies molecular and cellular correlates of person-to-person variability in human brain connectivity

Brain connectivity arises from interactions across biophysical scales, ranging from molecular to cellular to anatomical to network level. To date, there has been little progress toward integrated analysis across these scales. To bridge this gap, from a unique cohort of 98 individuals, we collected antemortem neuroimaging and genetic data, as well as postmortem dendritic spine morphometric, proteomic and gene expression data from the superior frontal and inferior temporal gyri. Through the integration of the molecular and dendritic spine morphology data, we identified hundreds of proteins that explain interindividual differences in functional connectivity and structural covariation. These proteins are enriched for synaptic structures and functions, energy metabolism and RNA processing. By integrating data at the genetic, molecular, subcellular and tissue levels, we link specific biochemical changes at synapses to connectivity between brain regions. These results demonstrate the feasibility of integrating data from vastly different biophysical scales to provide a more comprehensive understanding of brain connectivity.

P-type pilus PapG protein elicits toll-like receptor 2-mediated immune activation during cancer immunotherapy

The immune activation ability of FimH, an adhesion protein in pili of Escherichia coli (E. coli), has been recently reported. However, studies on the immune activity of PapG, another major pili terminal protein, have not been well explored. In this study, the immune stimulatory effect of purified recombinant PapG was evaluated. PapG treatment promoted dramatic changes in dendritic morphology of the bone marrow-derived dendritic cells (BMDCs) and induced upregulation of co-stimulatory molecule levels, major histocompatibility complex (MHC) I and II expression, and pro-inflammatory cytokine production in BMDCs. To identify the stimulatory receptor of PapG, an in silico study was performed. PapG exhibited strong binding affinity with murine toll-like receptor 2 (TLR2). In addition, PapG-induced activation of splenic DC and its subsets was unsuccessful in TLR2-knock out mice. Combination of PapG and ovalbumin (OVA) elicited OVA-specific T cell proliferation and cytokine production and cytotoxicity that consequently promoted anti-cancer immune responses against OVA-expressing B16 melanoma. Furthermore, PapG treatment induced activation of peripheral blood DCs and its subsets in humans in a TLR2 dependent manner. PapG-stimulated human conventional DC2 promoted syngeneic T cell proliferation and activation. The findings of this study demonstrated that PapG could be a useful immune stimulator for immunotherapy against cancer.

Neuroplasticity and Cocaine Exposure During Adolescence

The adolescent brain is particularly vulnerable to the effects of cocaine exposure due to ongoing neurodevelopment especially in areas that are crucial for cognitive and emotional regulation. This review explores the multifaceted impact of cocaine on neuroplasticity during adolescence, thereby highlighting both the immediate and long-term consequences of drug exposure. Key findings from recent studies indicate that cocaine use during adolescence leads to significant alterations in synaptic plasticity, dendritic spine morphology, and neurotransmitter systems, which may persist into adulthood and contribute to addictive behaviors. Additionally, the interaction between genetic predispositions, environmental stressors, and drug exposure is emphasized. The review also analyzed the risks of early-life stress and social isolation on cocaine-induced neuroplasticity, which can render anxiety-related behaviors and lead to neurological changes. Future studies should incorporate longitudinal design to understand the long-term trajectory of neuroplasticity induced by cocaine. This paper can provide some suggestions to the development of prevention and intervention programs for adolescents at risk.

A homozygous variant in ARHGAP39 is associated with lethal cerebellar vermis hypoplasia in a consanguineous Saudi family

Cerebellar vermis hypoplasia refers to a varying degree of incomplete development of the cerebellum and vermis. A Saudi family with four affected individuals with cerebellar vermis hypoplasia, facial dysmorphology, visual impairment, skeletal, and cardiac abnormalities was ascertained in this study. Three out of four patients could not survive longer and had died in early infancy. Genetic analysis of the youngest affected was performed by genome-wide homozygosity mapping coupled with whole exome sequencing (WES), followed by Sanger validation. Genome-wide genotyping analysis mapped the phenotype to chromosome 8q24.3. Using an autosomal recessive model, considering deleterious variants with minor allele frequency of less than 0.001 in WES data, a homozygous missense variant (NM_025251.2; ARHGAP39; c.1301G > T; p.Cys434Phe) was selected as a potential candidate for the phenotype. The variant (c.1301G > T) in the ARHGAP39 is in the region of homozygosity on chromosome 8q24.3. ARHGAP39 is a Rho GTPase-activating protein 39 and has been known to regulate apoptosis, cell migration, neurogenesis, and cerebral and hippocampal dendritic spine morphology. Mice homozygous for arhgap39 knockouts have shown premature embryonic lethality. Our findings present the first ever human phenotype associated with ARHGAP39 alteration.

NEK4 modulates circadian fluctuations of emotional behaviors and synaptogenesis in male mice

GWASs have linked the 3p21.1 locus, which is associated with the expression levels of NEK4, to bipolar disorder. Here, we use integrative analyses of GWAS statistics and eQTL annotations to establish that elevated NEK4 expression in the hippocampus is associated with an increased risk of bipolar disorder. To further study this association, we generate transgenic male mice that conditionally overexpress NEK4 in the pyramidal neurons of the adult forebrain, or use AAV to overexpress NEK4 in the dorsal hippocampus. Compared to the control mice, male mice of both strains exhibit a shift from a diurnal anxiety state to a nocturnal normal or anxiolytic-like state. Overexpression of NEK4 also affects the circadian fluctuations in dendritic spine morphology and synaptic structure. Furthermore, we show that treatment with lithium ameliorates the effects of NEK4 overexpression in male mice. We then perform phosphoproteomic analyses to demonstrate that the diurnal and nocturnal phosphoproteomic profiles of male control and NEK4 overexpressing mice are different. These results suggest that male mice with different NEK4 expression levels may recapitulate some of the core features observed in patients with bipolar disorder, indicating that interruption of the homeostatic dynamics of synapses may underlie the emotional swings in bipolar disorder.

Dendritome Mapping Unveils Spatial Organization of Striatal D1/D2-Neuron Morphology.

Morphology is a cardinal feature of a neuron that mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide study of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstructed and reference-atlas mapped striatal D1- and D2- medium spiny neurons (MSNs). Integrative morphometric analyses reveal distinct impacts of anatomical locations and D1/D2 genetic types on MSN morphologies. To analyze striatal regional features of MSN dendrites without prior anatomical constraints, we assigned MSNs to a lattice of cubic boxes in the reference brain atlas, and summarized morphometric representation ("eigen-morph") for each box and clustered boxes with shared morphometry. This analysis reveals 6 modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found aging confers robust dendritic length and branching defects in MSNs, while Huntington's disease (HD) mice exhibit selective length-related defects. Together, our study demonstrates a systems-biology approach to profile dendritic morphology of genetically-defined single-neurons; and defines novel striatal D1/D2-MSN morphological territories and aging- or HD-associated pathologies.

Preliminary Characterisation of Immune Cell Populations in the Oral Mucosa of a Small Cohort of Healthy Dogs (Canis lupus familiaris).

Pre-determined anatomical locations in the oral cavity were biopsied, and their histomorphology was characterised using haematoxylin and eosin staining (H&E). The most abundant cell type was of dendritic morphology. Lymphocyte foci were not evident in the palatoglossal folds or the gingiva. Immunohistochemical staining (IHC) for validated leukocyte markers followed, including CD3, CD20, CD79α, CD204, andIba1. Consistent with H&E findings, CD204 immunoreactivity predominated amongst all niches. With the exception of the alveolar mucosa and palatoglossal folds, we also demonstrate a significant difference in the population of macrophages by region for only the Iba1 antigen (p < 0.0001). B lymphocytes were found, and a significant difference was noted in the sub-epithelium where CD20-positive cells outnumbered those labelled as CD79a positive (p = 0.001), suggesting the possibility that these cells are in an active state in health. A similar significant difference was found in the subepithelial tissue for myeloid cells, as there were more cells labelled as CD204 positive over Iba1, which, along with their distribution pattern, indicates a possible functional and morphological overlap between these cells. No significant difference was found in epithelial tissues for cells of either myeloid or lymphoid origins. The results from this study suggest different regions of the oral cavity exhibit variations in the distribution of immune cells, particularly macrophages and B lymphocytes. Though more studies would be needed to confirm these findings, these differences may have implications for the immune response and overall health of the oral mucosa.

Harmful Effects on the Hippocampal Morpho-Histology and on Learning and Memory in the Offspring of Rats with Streptozotocin-Induced Diabetes

Learning alterations in the child population may be linked to gestational diabetes as a causal factor, though this remains an open and highly controversial question. In that sense, it has been reported that maternal hyperglycemia generates a threatening condition that affects hippocampal development in offspring. The pyramidal cells of the CA3 subfield, a key structure in learning and memory processes, are particularly important in cognitive deficiencies. We evaluate the effect of the hyperglycemic intrauterine environment on hippocampal histomorphometry in offspring, correlating it with spatial learning and memory, as well as the morphology of dendrites and spines in 30-day-old pups (P30). The maternal hyperglycemia affected the body weight, height, and brain size of fetuses at 21 days of gestation (F21), newborn pups (P0) and P30 pups from diabetic rats, which were smaller compared to the control group. Consequently, this resulted in a decrease in hippocampal size, lower neuronal density and cytoarchitectural disorganization in the CA3 region of the hippocampus in the offspring at the three ages studied. The behavioral tests performed showed a direct relationship between morpho-histological alterations and deficiencies in learning and memory, as well as alterations in the morphology of the dendrites and spines. Therefore, knowing the harmful effects caused by gestational diabetes can be of great help to establish therapeutic and educational strategies that can help to improve learning and memory in children.

Npbwr1 signaling mediates fast antidepressant action.

Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.

Thermodynamic behavior and microstructure evolution of Inconel 718 alloy by laser metal deposition

The temperature evolution, stress evolution, and dendrite growth during the laser metal deposition (LMD) process of Inconel 718 alloy were simulated using a multi-scale model that combines the finite element method and the Cellular Automata (CA) method. This model established the relationship between the thermal behavior of the molten pool and the solidification characteristics, and predicted the morphological size of the solidified structure. Research indicates that under conditions of higher cooling rate and lower shape control factor, equiaxed grains are prone to form, with a lower degree of elemental segregation in this region, which is conducive to the precipitation of granular Laves phase. Conversely, under conditions of lower cooling rate and higher shape control factor, columnar grains are more likely to form, with a higher degree of elemental segregation in this region, leading to the precipitation of chain-like Laves phase. The results of thermo-mechanical coupled simulation suggest that the maximum transient thermal stress is located at the overlap position, and when the component cools down to room temperature, the maximum normal stress along the scanning direction is observed. Dendritic growth results demonstrate that during the equiaxed grain growth process in the top region of the melt pool, the released solute is constrained by time and space, leading to the accumulation of solute and the formation of interdendritic segregation. In areas with a higher grain density, the solute accumulation zones overlap, resulting in an increase in solute concentration, which inhibits dendrite growth. In the middle region of the melt pool, during the columnar grain growth process, the solute concentration in the gaps between adjacent grains continuously increases, resulting in micro-segregation phenomena. Experimental measurements have shown that the temperature field's melt pool morphology, stress values along the scanning path, and dendritic morphology are in good agreement with the experimental outcomes.

Lasting effects of adolescent social instability stress on dendritic morphology in the nucleus accumbens in female and male Long Evans rats

Social instability stress (SS) in adolescence in rats leads to long-lasting changes in social behaviour and reward-related behaviour relative to control rats. Given the role of the nucleus accumbens (NAc) in such behaviours, we investigated the morphology of medium spiny neurons (MSNs), which are most neurons in the NAc, in adult female and male rats exposed to SS in adolescence. Irrespective of sex, SS rats had increased number of dendritic spines in both the core and shell regions of the NAc (2.3 % and 18.1 % increase, respectively). In the core, SS rats had a 16 % reduction in the total dendritic lengths of MSNs, whereas in the shell, SS rats had a greater dendritic length closer to the soma, and particularly in SS female rats, whereas the opposite was found farther from the soma (SS 10.6 % > CTL overall). Although the extent to which such structural changes may underlie the enduring effects of SS in adolescence requires investigation, the results add to evidence that changes to the social environment in adolescence can determine adult neuronal structural.

DTD1 modulates synaptic efficacy by maintaining D-serine and D-aspartate homeostasis.

D-serine and D-aspartate are involved in N-methyl-D-aspartate receptor (NMDAR)-related physiological and pathological processes. D-aminoacyl-tRNA deacylase 1 (DTD1) may biochemically contribute to D-serine or D-aspartate production. However, it is unclear thus far whether DTD1 regulates D-serine or D-aspartate content in neurobiological processes. In the present research, we found that DTD1 was essential to maintain the D-serine or D-aspartate homeostasis, which was consistent with the phenomenon that DTD1-deficiency resulted in changes in the quantity changes of functional NMDAR subunits in postsynaptic compartments. Moreover, DTD1 played a considerable role in regulating dendritic morphology and synaptic structure. As a consequence, DTD1 affected neurobiological events, including the synaptic strength of the CA3-to-CA1 circuit, dendritic spine density of hippocampal pyramidal neurons, and behavioral performance of mice in the Morris water maze. These findings highlight the important role of DTD1 in synaptic transmission, neuronal morphology, and spatial learning and memory and suggest an undisclosed mechanism of DTD1 that participates the regulation of D-serine or D-aspartate homeostasis in hippocampal neurons.

A single dose of glycogen phosphorylase inhibitor improves cognitive functions of aged mice and affects the concentrations of metabolites in the brain

Inhibition of glycogen phosphorylase (Pyg) – a regulatory enzyme of glycogen phosphorolysis – influences memory formation in rodents. We have previously shown that 2-week intraperitoneal administration of a Pyg inhibitor BAY U6751 stimulated the “rejuvenation” of the hippocampal proteome and dendritic spines morphology and improved cognitive skills of old mice. Given the tedious nature of daily intraperitoneal drug administration, in this study we investigated whether a single dose of BAY U6751 could induce enduring behavioral effects. Obtained results support the efficacy of such treatment in significantly improving the cognitive performance of 20-22-month-old mice. Metabolomic analysis of alterations observed in the hippocampus, cerebellum, and cortex reveal that the inhibition of glycogen phosphorolysis impacts not only glucose metabolism but also various other metabolic processes.

Cofilin linked to GluN2B subunits of NMDA receptors is required for behavioral sensitization by changing the dendritic spines of neurons in the caudate and putamen after repeated nicotine exposure

BackgroundNicotine dependence is associated with glutamatergic neurotransmission in the caudate and putamen (CPu) of the forebrain which includes alterations in the structure of dendritic spines at glutamate synapses. These changes after nicotine exposure can lead to the development of habitual behaviors such as smoking. The present study investigated the hypothesis that cofilin, an actin-binding protein that is linked to the GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors regulates the morphology of dendritic spines in the neurons of the CPu after repeated exposure to nicotine.ResultsAdult male rats received subcutaneous injections of nicotine (0.3 mg/kg/day) or vehicle for seven consecutive days. DiI staining was conducted to observe changes in dendritic spine morphology. Repeated subcutaneous injections of nicotine decreased the phosphorylation of cofilin while increasing the formation of thin spines and filopodia in the dendrites of medium spiny neurons (MSN) in the CPu of rats. Bilateral intra-CPu infusion of the cofilin inhibitor, cytochalasin D (12.5 µg/µL/side), restored the thin spines and filopodia from mushroom types after repeated exposure to nicotine. Similar results were obtained from the bilateral intra-CPu infusion of the selective GluN2B subunit antagonist, Ro 25-6981 (4 µM/µL/side). Bilateral intra-CPu infusion of cytochalasin D that interferes with the actin-cofilin interaction attenuated the repeated nicotine-induced increase in locomotor sensitization in rats.ConclusionsThese findings suggest that active cofilin alters the structure of spine heads from mushroom to thin spine/filopodia by potentiating actin turnover, contributing to behavioral sensitization after nicotine exposure.