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The Neuroscientist : a Review Journal... Oct 2021Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such... (Review)
Review
Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such as plaques and tangles associated with Alzheimer's disease, stroke, traumatic brain injury, or other lesions. Factors such as physical or mental activity and genetics may contribute to cognitive resilience, but the neurobiological underpinnings remain ill-defined. Emerging evidence suggests that dendritic spine structural plasticity is one plausible mechanism. In this review, we highlight the basic structure and function of dendritic spines and discuss how spine density and morphology change in aging and Alzheimer's disease. We note evidence that spine plasticity mediates resilience to stress, and we tackle dendritic spines in the context of cognitive resilience to Alzheimer's disease. Finally, we examine how lifestyle and genetic factors may influence dendritic spine plasticity to promote cognitive resilience before discussing evidence for actin regulatory kinases as therapeutic targets for Alzheimer's disease.
Topics: Aging; Alzheimer Disease; Brain; Cognition; Dendritic Spines; Humans
PubMed: 32812494
DOI: 10.1177/1073858420945964 -
Cerebral Cortex (New York, N.Y. : 1991) May 2020In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation...
In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how specific cell types in the frontal cortex mature or whether puberty plays a role in the maturation of some cell types but not others. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project through the corpus collosum to the dorsomedial striatum. We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in male mice.
Topics: Animals; Corpus Striatum; Dendritic Spines; Female; Frontal Lobe; Male; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Neuronal Plasticity; Neurons; Orchiectomy; Ovariectomy; Patch-Clamp Techniques; Prefrontal Cortex; Sex Factors; Sexual Maturation
PubMed: 32037445
DOI: 10.1093/cercor/bhz325 -
Brain Stimulation 2018Electroconvulsive therapy (ECT) is a rapid and effective treatment for major depressive disorder. Chronic stress-induced depression causes dendrite atrophy and...
BACKGROUND
Electroconvulsive therapy (ECT) is a rapid and effective treatment for major depressive disorder. Chronic stress-induced depression causes dendrite atrophy and deficiencies in brain-derived neurotrophic factor (BDNF), which are reversed by anti-depressant drugs. Electroconvulsive seizures (ECS), an animal model of ECT, robustly increase BDNF expression and stimulate dendritic outgrowth.
OBJECTIVE
The present study aims to understand cellular and molecular plasticity mechanisms contributing to the efficacy of ECS following chronic stress-induced depression.
METHODS
We quantify Bdnf transcript levels and dendritic spine density and morphology on cortical pyramidal neurons in mice exposed to vehicle or corticosterone and receiving either Sham or ECS treatment.
RESULTS
ECS rescues corticosterone-induced defects in spine morphology and elevates Bdnf exon 1 and exon 4-containing transcripts in cortex.
CONCLUSIONS
Dendritic spine remodeling and induction of activity-induced BDNF in the cortex represent important cellular and molecular plasticity mechanisms underlying the efficacy of ECS for treatment of chronic stress-induced depression.
Topics: Animals; Brain-Derived Neurotrophic Factor; Cerebral Cortex; Dendritic Spines; Depression; Disease Models, Animal; Electroconvulsive Therapy; Gene Expression; Male; Mice; Seizures
PubMed: 29674117
DOI: 10.1016/j.brs.2018.04.003 -
Neurochemistry International Jan 2021Cortical microglia exhibit a ramified shape during sleep, while they have a hyper-ramified shape during wakefulness, which is characterized by their longer processes... (Review)
Review
Cortical microglia exhibit a ramified shape during sleep, while they have a hyper-ramified shape during wakefulness, which is characterized by their longer processes with increased branching points. The microglial molecular circadian clock regulates expressions of both cathepsin S (CatS) and P2Y receptors in the brain with a peak at zeitgeber time 14 (2 h after beginning of the dark phase). We postulated that these two microglia-specific molecules contribute to diurnal alterations of microglial shapes and neuronal activities in the cerebral cortex. During wakefulness, CatS secreted from cortical microglia may be involved in P2Y receptor-dependent process extension. Secreted CatS subsequently degrades the perineuronal nets, initiating the downscaling of both spine density and synaptic strength of cortical neurons toward the beginning of sleep. The downscaling of both spine density and synaptic strength of cortical neurons during sleep could improve signal-to-noise, which would benefit memory consolidation, or allow for new learning to occur during subsequent waking. Furthermore, disruption of CatS induces the sleep disturbance and impaired social interaction in mice. Moreover, the microglial clock system disruption may also play a role in the early pathogenesis of Alzheimer's disease. The reduced expression of BMAL1 in cortical microglia caused by oligomeric amyloid β may induce the increased presence of inflammatory phenotype through a reduction in RORα, which in turn reduced IκBα and enhanced NF-κB activation. These observations suggest that the microglial clock system disruption contribute to pathogeneses of sleep disturbance, impaired social interaction and cognitive impairment. Therefore, the growing understanding of the microglial circadian molecular clock might aid in the development of novel pharmacological interventions against both neuropsychiatric and neurodegenerative disorders.
Topics: Animals; Cerebral Cortex; Circadian Clocks; Dendritic Spines; Humans; Inflammation Mediators; Microglia; Receptors, Purinergic P2Y12; Wakefulness
PubMed: 33217515
DOI: 10.1016/j.neuint.2020.104905 -
Neurobiology of Disease Dec 2019Chronic exposure to high circulating levels of glucocorticoids (GCs) may be a key risk factor for Alzheimer's Disease (AD) development and progression. In addition,...
Chronic exposure to high circulating levels of glucocorticoids (GCs) may be a key risk factor for Alzheimer's Disease (AD) development and progression. In addition, hyper-activation of glucocorticoid receptors (GRs) induces brain alterations comparable to those produced by AD. In transgenic mouse models of AD, GCs increase the production of the most important and typical hallmarks of this dementia such as: Aβ40, Aβ42 and tau protein (both the total tau and its hyperphosphorylated isoforms). Moreover, GCs in brain are pivotal regulators of dendritic spine turnover and microglia activity, two phenomena strongly altered in AD. Although it is well-established that GCs primes the neuroinflammatory response in the brain to some stimuli, it is unknown whether or how GRs modulates dendritic spine plasticity and microglia activity in AD. In this study, we evaluated, using combined Golgi Cox and immunofluorescence techniques, the role of GR agonists and antagonists on dendritic spine plasticity and microglia activation in hippocampus of 3xTg-AD mice. We found that dexamethasone, an agonist of GRs, was able to significantly reduce dendritic spine density and induced proliferation and activation of microglia in CA1 region of hippocampus of 3xTg-AD mice at 6 and 10 months of age. On the contrary, the treatment with mifepristone, an antagonist of GRs, strongly enhanced dendritic spine density, decreased microglia density and improved the behavioural performance of 3xTg-AD mice. Additionally, primary microglial cells in vitro were directly activated by dexamethasone. Together, these data demonstrate that stress exacerbates AD and promotes a rapid progression of the pathology acting on both neurons and glial cells, supporting an important pro-inflammatory role of GC within CNS in AD. Consequently, these results further strengthen the need to test clinical interventions that correct GCs dysregulation as promising therapeutic strategy to delay the onset and slow down the progression of AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; CA1 Region, Hippocampal; Dendritic Spines; Dexamethasone; Disease Models, Animal; Hormone Antagonists; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neuronal Plasticity; Presenilin-1; Receptors, Glucocorticoid; tau Proteins
PubMed: 31394203
DOI: 10.1016/j.nbd.2019.104568 -
Molecular Biology of the Cell Feb 2024Myristoylated, alanine-rich C-kinase substrate (MARCKS) is an F-actin and phospholipid binding protein implicated in numerous cellular activities, including the...
Myristoylated, alanine-rich C-kinase substrate (MARCKS) is an F-actin and phospholipid binding protein implicated in numerous cellular activities, including the regulation of morphology in neuronal dendrites and dendritic spines. MARCKS contains a lysine-rich effector domain that mediates its binding to plasma membrane phosphatidylinositol-4,5-biphosphate (PI(4,5)P) in a manner controlled by PKC and calcium/calmodulin. In neurons, manipulations of MARCKS concentration and membrane targeting strongly affect the numbers, shapes, and F-actin properties of dendritic spines, but the mechanisms remain unclear. Here, we tested the hypothesis that the effects of MARCKS on dendritic spine morphology are due to its capacity to regulate the availability of plasma membrane PI(4,5)P. We observed that the concentration of free PI(4,5)P on the dendritic plasma membrane was inversely proportional to the concentration of MARCKS. Endogenous PI(4,5)P levels were increased or decreased, respectively, by acutely overexpressing either phosphatidylinositol-4-phosphate 5-kinase (PIP5K) or inositol polyphosphate 5-phosphatase (5ptase). PIP5K, like MARCKS depletion, induced severe spine shrinkage; 5ptase, like constitutively membrane-bound MARCKS, induced aberrant spine elongation. These phenotypes involved changes in actin properties driven by the F-actin severing protein cofilin. Collectively, these findings support a model in which neuronal activity regulates actin-dependent spine morphology through antagonistic interactions of MARCKS and PI(4,5)P.
Topics: Actins; Membrane Proteins; Dendritic Spines; Intracellular Signaling Peptides and Proteins; Protein Kinase C; Phosphorylation
PubMed: 38088877
DOI: 10.1091/mbc.E23-09-0370 -
Molecular Brain Jun 2020Propionic acid (PPA) is a short-chain fatty acid that is an important mediator of cellular metabolism. It is also a by-product of human gut enterobacteria and a common...
Propionic acid (PPA) is a short-chain fatty acid that is an important mediator of cellular metabolism. It is also a by-product of human gut enterobacteria and a common food preservative. A recent study found that rats administered with PPA showed autistic-like behaviors like restricted interest, impaired social behavior, and impaired reversal in a T-maze task. This study aimed to identify a link between PPA and autism phenotypes facilitated by signaling mechanisms in hippocampal neurons. Findings indicated autism-like pathogenesis associated with reduced dendritic spines in PPA-treated hippocampal neurons. To uncover the mechanisms underlying this loss, we evaluated autophagic flux, a functional readout of autophagy, using relevant biomedical markers. Results indicated that autophagic flux is impaired in PPA-treated hippocampal neurons. At a molecular level, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway was activated and autophagic activity was impaired. We also observed that a MAPK inhibitor rescued dendritic spine loss in PPA-treated hippocampal neurons. Taken together, these results suggest a previously unknown link between PPA and autophagy in spine formation regulation in hippocampal neurons via MAPK/ERK signaling. Our results indicate that MAPK/ERK signaling participates in autism pathogenesis by autophagy disruption affecting dendritic spine density. This study may help to elucidate other mechanisms underlying autism and provide a potential strategy for treating ASD-associated pathology.
Topics: Animals; Autophagosomes; Autophagy; Biomarkers; Dendritic Spines; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Hippocampus; Lysosomes; MAP Kinase Signaling System; Phenotype; Propionates; Rats
PubMed: 32487196
DOI: 10.1186/s13041-020-00626-0 -
Cerebral Cortex (New York, N.Y. : 1991) Mar 2020It is well established that motor impairment often occurs alongside healthy aging, leading to problems with fine motor skills and coordination. Although previously...
It is well established that motor impairment often occurs alongside healthy aging, leading to problems with fine motor skills and coordination. Although previously thought to be caused by neuronal death accumulating across the lifespan, it is now believed that the source of this impairment instead stems from more subtle changes in neural connectivity. The dendritic spine is a prime target for exploration of this problem because it is the postsynaptic partner of most excitatory synapses received by the pyramidal neuron, a cortical cell that carries much of the information processing load in the cerebral cortex. We repeatedly imaged the same dendrites in young adult and aged mouse motor cortex over the course of 1 month to look for differences in the baseline state of the dendritic spine population. These experiments reveal increased dendritic spine density, without obvious changes in spine clustering, occurring at the aged dendrite. Additionally, aged dendrites exhibit elevated spine turnover and stabilization alongside decreased long-term spine survival. These results suggest that at baseline the aged motor cortex may exist in a perpetual state of relative instability and attempts at compensation. This phenotype of aging may provide clues for future targets of aging-related motor impairment remediation.
Topics: Aging; Animals; Dendritic Spines; Female; Male; Mice, Transgenic; Motor Cortex; Pyramidal Cells
PubMed: 31298696
DOI: 10.1093/cercor/bhz124 -
Neuroscience Research Sep 2022BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2)....
BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.
Topics: Adenosine Triphosphate; Animals; Dendritic Spines; GTP Phosphohydrolases; Mice; Mitochondrial Dynamics; Mitochondrial Proteins; bcl-2-Associated X Protein
PubMed: 35688289
DOI: 10.1016/j.neures.2022.06.002 -
PloS One 2023Proteins from the NANOS family are conserved translational repressors with a well-known role in gonad development in both vertebrates and invertebrates. In addition,...
Proteins from the NANOS family are conserved translational repressors with a well-known role in gonad development in both vertebrates and invertebrates. In addition, Drosophila Nanos controls neuron maturation and function, and rodent Nanos1 affects cortical neuron differentiation. Here we show that rat Nanos1 is expressed in hippocampal neurons and that the siRNA-mediated knockdown of Nanos1 impairs synaptogenesis. We found that both dendritic spine size and number were affected by Nanos1 KD. Dendritic spines were smaller and more numerous. Moreover, whereas in control neurons most dendritic PSD95 clusters contact pre-synaptic structures, a larger proportion of PSD95 clusters lacked a synapsin counterpart upon Nanos1 loss-of-function. Finally, Nanos1 KD impaired the induction of ARC typically triggered by neuron depolarization. These results expand our knowledge on the role of NANOS1 in CNS development and suggest that RNA regulation by NANOS1 governs hippocampal synaptogenesis.
Topics: Animals; Rats; RNA; Hippocampus; RNA-Binding Proteins; Dendritic Spines
PubMed: 37058523
DOI: 10.1371/journal.pone.0284589