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Left panel: Photomicrograph of a Purkinje cell in the cerebellar cortex corresponding to the paramedian lobule, showing the apical dendritic branchlets (arrows) from where spines were counted. Scale bar = 100 m. Right panel: Photomicrographs of thin (t), mushroom (m), stubby (s) and wide (w) spines (arrows), as counted in this study. Scale bar = 2 m.
Source publication
Purpose: The presynaptic stimulatory activity of parallel fibers on the dendritic spines of cerebellar Purkinje cells (PC) has a strong influence on the organization of motor learning. Motor learning has been shown to modify the synapses established on PC dendritic spines but the plastic changes of the different spine types, possibly underlying mot...
Citations
... Cerebellar circuits exhibit significant neuroplastic properties, allowing the encoding of experiences and, consequently, to learn behaviors [7]. One of the main mechanisms of cerebellar plasticity modifies the density and dimensions of the dendritic spines of Purkinje cells, which receive all afferent information arriving at the cerebellar cortex and are, thus, adaptively controlled by environmental factors [20][21][22]. In this sense, environmental stimuli of different natures that individuals are exposed to throughout their lives could impact the cerebellum in both functional and structural terms, modifying the previously known concept of cerebral cognitive reserve and enriching it with a parallel cerebellar cognitive reserve that may play a modulatory role in the brain's response to cognitive decline. ...
The present study aims to investigate the relationship between cerebellar volumes and cognitive reserve in individuals with Mild Cognitive Impairment (MCI). A description of proxies of cerebellar cognitive reserve in terms of different volumes across lobules is also provided. 36 individuals with MCI underwent neuropsychological (MoCA, MMSE, Clock test, CRIq) assessment and neuroimaging acquisition with magnetic resonance imaging at 3 T. Simple linear correlations were applied between cerebellar volumes and cognitive measures. Multiple linear regression models were then used to estimate standardized regression coefficients and 95% confidence intervals. Simple linear correlations between cerebellar lobules volumes and cognitive features highlighted a significant association between CRIq_Working activity and specific motor cerebellar volumes: Left_V (ρ = 0.40, p = 0.02), Right_V (r = 0.42, p = 0.002), Vermis_VIIIb (ρ = 0.47, p = 0.003), Left_X (ρ = -0.46, p = 0.002) and Vermis_X (r = 0.35, p = 0.03). Furthermore, CRIq_Working activity scores correlated with certain cerebellar lobules implicated in cognition: Left_Crus_II, Vermis VIIb, Left_IX. MMSE was associated only with the Right_VIIB volume (r = 0.35, p = 0.02), while Clock Drawing Test scores correlated with both Left_Crus_I and Right_Crus_I (r = -0.42 and r = 0.42, p = 0.02, respectively). This study suggests that a higher cognitive reserve is associated with specific cerebellar lobule volumes and that Working activity may play a predominant role in this association. These findings contribute to the understanding of the relationship between cerebellar volumes and cognitive reserve, highlighting the potential modulatory role of Working activity on cerebellum response to cognitive decline.
Graphical Abstract
... Another good candidate for contributing to postural learning is the cerebellum, which plays an important role in motor learning phenomena, such as visuomotor adaptation [77][78][79]. It has been shown that Purkinje cells undergo to significant changes in the density of their dendritic spine following an acrobatic training [80]. Indeed, the medial cerebellar vermal area controls stance [81][82][83][84][85][86] and promotes learning processes that modulates postural reflexes [63,[87][88][89][90], enhancing postural stability. ...
The effects of postural training on postural stability and vestibulospinal reflexes (VSRs) were investigated in normal subjects. A period (23 minutes) of repeated episodes (n = 10, 50 seconds) of unipedal stance elicited a progressive reduction of the area covered by centre of pressure (CoP) displacement, of average CoP displacement along the X and Y axes and of CoP velocity observed in this challenging postural task. All these changes were correlated to each other with the only exception of those in X and Y CoP displacement. Moreover, they were larger in the subjects showing higher initial instability in unipedal stance, suggesting that they were triggered by the modulation of sensory afferents signalling body sway. No changes in bipedal stance occurred soon and 1 hour after this period of postural training, while a reduction of CoP displacement was apparent after 24 hours, possibly due to a beneficial effect of overnight sleep on postural learning. The same period of postural training also reduced the CoP displacement elicited by electrical vestibular stimulation (EVS) along the X axis up to 24 hours following the training end. No significant changes in postural parameters of bipedal stance and VSRs could be observed in control experiments where subjects were tested at identical time points without performing the postural training. Therefore, postural training led to a stricter control of CoP displacement, possibly acting through the cerebellum by enhancing feedforward mechanisms of postural stability and by depressing the VSR, the most important reflex mechanism involved in balance maintenance under challenging conditions.
... Furthermore, rats easily discriminate between a familiar and a new object after a short interval, but find it difficult after a 24-hour delay, so the poor memory performance may be related to insufficient strength of the memory trace [66]. Although acrobatic training is sufficient to promote synaptic neuroplasticity in regions such as the prefrontal cortex [27], the cerebellum [68] and motor cortex [34], reports on hippocampus plasticity are inconclusive [67,69]. ...
Chronic cerebral hypoperfusion leads to neuronal loss in the hippocampus and spatial memory impairments. Physical exercise is known to prevent cognitive deficits in animal models; and there is evidence of sex differences in behavioral neuroprotective approaches. The aim of present study was to investigate the effects of acrobatic training in male and female rats submitted to chronic cerebral hypoperfusion. Males and females rats underwent 2VO (two-vessel occlusion) surgery and were randomly allocated into 4 groups of males and 4 groups of females, as follows: 2VO acrobatic, 2VO sedentary, Sham acrobatic and Sham sedentary. The acrobatic training started 45 days after surgery and lasted 4 weeks; animals were then submitted to object recognition and water maze testing. Brain samples were collected for histological and morphological assessment and flow cytometry. 2VO causes cognitive impairments and acrobatic training prevented spatial memory deficits assessed in the water maze, mainly for females. Morphological analysis showed that 2VO animals had less NeuN labeling and acrobatic training prevented it. Increased number of GFAP positive cells was observerd in females; moreover, males had more branched astrocytes and acrobatic training prevented the branching after 2VO. Flow cytometry showed higher mitochondrial potential in trained animals and more reactive oxygen species production in males. Acrobatic training promoted neuronal survival and improved mitochondrial function in both sexes, and influenced the glial scar in a sex-dependent manner, associated to greater cognitive benefit to females after chronic cerebral hypoperfusion.
... Stubby spines are very short spines without a distinguishable neck and stubby appearance and have been proved to be a transitional structure. Stubby spines increase when synaptic intensity increases and decrease when synaptic intensity decreases, showing a very low resistivity to calcium currents that mediate effective synaptic transmission and having the function of consolidating memory [39]. In our study, the results showed that the densities of filopodia spines and thin spines in the AD model rats were significantly increased after treatment with SY and HSYA. ...
Safflower yellow (SY) is the main effective component of Carthamus tinctorius L., and Hydroxysafflor yellow A (HSYA) is the single active component with the highest content in SY. SY and HSYA have been shown to have neuroprotective effects in several AD models. In this study, we aimed to clarify whether the effects of SY and HSYA on the learning and memory abilities of Aβ1-42-induced AD model rats are related to the enhancement of synaptic structural plasticity in brain tissues and the amelioration of disorder of glutamate circulation. We used rats injected with Aβ1-42 into the bilateral hippocampus as a model of AD. After treatment with SY and HSYA, the learning and memory abilities of the Aβ1-42-induced AD model rats were enhanced, Aβ deposition in the AD model rats was decreased, structural damage to dendritic spines and the loss of synaptic-associated proteins were alleviated, and the disorder of glutamate circulation was ameliorated. The results indicated that SY and HSYA improve synaptic structural plasticity by ameliorating the disorder of glutamate circulation in Aβ1-42-induced AD model rats.
... In fact, in some behavior-based experimental models of freely moving rodents, cognitive performance has been seen to be strongly associated with changes in spine density and morphology in several brain regions. Such adaptive changes are directly related to different stages of memory-related information processing (Nabavi et al., 2014), either under normal or pathological conditions (González-Burgos, Alejandre-Gómez, & Cervantes, 2005;González-Tapia, Velázquez-Zamora, Olvera-Cortés, & González-Burgos, 2015;Hofer & Bonhoeffer, 2010;del Valle et al., 2012;González-Burgos, Letechipía-Vallejo, López-Loeza, Moralí, & Cervantes, 2007;Reyes-Corona et al., 2017). ...
... Weaker expression of the genes encoding the α-actinin, Drebrin, Myosin, Profilin and Synaptopodin proteins was observed. Loss of these proteins is consistent with the reduction in dendritic spines observed, with the constant proportion and density of branched spines -a type of spine associated with spine splitting and the formation of two new thin spines (Nieto-Sampedro, Hoff, & Cotman, 1982;Sorra & Harris, 1998)-, and with the persistence in the proportion of stubby and wide spines -related to putative synaptic overstimulation (Harris, Jensen, & Tsao, 1992;González-Burgos, 2012;González-Tapia et al., 2015) and spine maturation (Gipson & Olive, 2017). In addition, the reduction in the number of mushroom spines may reflect the demand for these proteins imposed by their larger head, which would require more of these proteins to polymerize actin filaments. ...
Spatial learning and memory enables individuals to orientate themselves in an external environment. Synaptic stimulation of dendritic spines on hippocampal place cells underlies adaptive cognitive performance, inducing plastic changes such as spinogenesis, pruning and structural interconversion. Such plastic changes are driven by complex molecular machinery that relies on several actin cytoskeleton-associated proteins (ACAP’s), these interacting with actin filaments in the postsynaptic density to guide the conformational changes to spines in accordance with the synaptic information they receive. However, the specific dynamics of the plastic changes in spines driven by ACAP’s are poorly understood. Adult rats exhibit efficient allocentric reference memory 30 days after training in a spatial learning paradigm in the Morris water maze. A Golgi study revealed this behavior to be associated with a reduction in both spine density and in mushroom spines, as well as a concomitant increase in thin spines. These changes were accompanied by the overexpression of mRNA encoding β-actin, Spinophilin and Cortactin, whilst the expression of Profilin, α-actinin, Drebrin, Synaptopodin and Myosin decreased. By contrast, no changes were evident in Cofilin, Gelsolin and Arp2/3 mRNA. From this analysis, it appears that neither spinogenesis nor new mushroom spines are necessary for long-term spatial information retrieval, while thin spines could be potentiated to retrieve pre-learned spatial information. Further studies that focus on the signaling pathways and their related molecules may shed further light on the molecular dynamics of the plastic changes to dendritic spines that underlie cognitive performance, both under normal and pathological conditions.
... However, the cerebellar role in motor functioning has overshadowed the development of insights in the causal relationship between cerebellar pathology and a variety of neurocognitive deficits (Noroozian, 2014). Several studies in humans and animals have shown that the cerebellum plays an important role in cognitive processing, motor learning, and memory (Gonzalez-Tapia et al., 2015;Lawrenson et al., 2018). Since long-term depression (LTD) at the parallel fibers associated with the Purkinje cell synapses within the cerebellar cortex has been considered as a primary cellular mechanism for cerebellar motor learning (Inoshita and Hirano, 2018), we aimed to investigate the effect of diabetes on the cerebellum and the role of LTD pathways in DM-induced cognitive dysfunction. ...
Cognitive dysfunction is a very severe consequence of diabetes, but the underlying causes are still unclear. Recently, the cerebellum was reported to play an important role in learning and memory. Since long-term depression (LTD) is a primary cellular mechanism for cerebellar motor learning, we aimed to explore the role of cerebellar LTD pathways in diabetic rats and the therapeutic effect of gastrodin. Diabetes was induced by a single injection of streptozotocin into adult Sprague–Dawley rats. Motor learning ability was assessed by a beam walk test. Pathological changes of the cerebellum were assessed by Hematoxylin-Eosin (HE) and Nissl staining. Cellular apoptosis was assessed by anti-caspase-3 immunostaining. Protein expression levels of LTD pathway-related factors, including GluR2, protein kinase C (PKC), NR2A, and nNOS, in the cerebellar cortex were evaluated by western blotting and double immunofluorescence. The NO concentration was measured. The cellular degeneration and the apoptosis of Purkinje cells were evident in the cerebellum of diabetic rats. Protein expression levels of GluR2 (NC9W: 1.26 ± 0.12; DM9W + S: 0.81 ± 0.07), PKC (NC9W: 1.66 ± 0.10; DM9W + S: 0.58 ± 0.19), NR2A (NC9W: 1.40 ± 0.05; DM9W + S: 0.63 ± 0.06), nNOS (NC9W: 1.26 ± 0.12; DM9W + S: 0.68 ± 0.04), and NO (NC9W: 135.61 ± 31.91; DM9W + S: 64.06 ± 24.01) in the cerebellum were significantly decreased in diabetic rats. Following gastrodin intervention, the outcome of motor learning ability was significantly improved (NC9W: 6.70 ± 3.31; DM9W + S: 20.47 ± 9.43; DM9W + G: 16.04 ± 7.10). In addition, degeneration and apoptosis were ameliorated, and this was coupled with the elevation of the protein expression of the abovementioned biomarkers. Arising from the above, we concluded that gastrodin may contribute to the improvement of motor learning by protecting the LTD pathways in Purkinje cells.
... As with thin spines, the number of stubby spines also increased after the experimental lesion. Stubby spines lack a neck, which confers them the functional characteristic of providing little resistance to calcium-mediated current 36 ; according to circumstantial evidence, 21,32,37,38 the functional activity of this type of spines would consist in regulating postsynaptic neuronal excitability. Thus, the proportional increase in stubby spines suggests, on the one hand, that the afferent excitatory activity to spinal motor neurons may have increased after the lesion to the corticospinal tract, and on the other hand, that there is a plastic response that tends to regulate the bioelectrical homeostasis of motor neurons. ...
Introduction
Motor function is impaired in multiple neurological diseases associated with corticospinal tract degeneration. Motor impairment has been linked to plastic changes at both the presynaptic and postsynaptic levels. However, there is no evidence of changes in information transmission from the cortex to spinal motor neurons.
Methods
We used kainic acid to induce stereotactic lesions to the primary motor cortex of female adult rats. Fifteen days later, we evaluated motor function with the Basso, Beattie, Bresnahan (BBB) scale and the rotarod and determined the density of thin, stubby, and mushroom spines of motor neurons from a thoracolumbar segment of the spinal cord. Spinophilin, synaptophysin, and β III tubulin expression was also measured.
Results
Pharmacological lesions resulted in poor motor performance. Spine density and the proportion of thin and stubby spines were greater. We also observed increased expression of the 3 proteins analysed.
Conclusion
The clinical symptoms of neurological damage secondary to Wallerian degeneration of the corticospinal tract are associated with spontaneous, compensatory plastic changes at the synaptic level. Based on these findings, spontaneous plasticity is a factor to consider when designing more efficient strategies in the early phase of rehabilitation.
... Another possibility is that rather than being dependent upon de novo protein synthesis, memory consolidation is mediated by non-genomic activity, as proposed by Bello-Medina et al. (2016). They found increased spinogenesis in the DS that correlated positively with the intensity of inhibitory avoidance training; this is congruent with the widely-held notion that memory consolidation involves changes in the density and morphology of dendritic spines in structures implicated in memory processes (Aceti et al., 2015;Eyre et al., 2003;Gónzalez-Tapia et al., 2015;Heinrichs et al., 2013;Leuner et al., 2003;Moser et al., 1994;O'Malley et al., 2000;Restivo et al., 2009). It is known that aversive tasks induce the release of corticosterone in an intensity-dependent manner (Cordero et al., 1998;González-Franco et al., 2017); other authors reported that administration of corticosterone to hippocampal slices also increased spinogenesis, and that blocking NMDA receptors and PI3K, MAPK, PKC, or PKA obstructed this effect (Komatsuzaki et al., 2012). ...
... [4][5][6] Similarly, increased numbers of dendritic spines have been reported in the distal dendrites of PCs after 26 days of acrobatic motor learning, in which the number of foot faults observed decreased during the first 6 days, then asymptotically stabilised. 4,7,8 These findings point to the occurrence of neuroplastic events at the level of distal synapses between PFs and PCs mediated by dendritic spines in the cerebellar paramedian lobule during the critical period of motor learning. According to studies by Doyon and Benali 2 and Dayan and Cohen, 9 motor skills are learnt after several different stages, whose duration depends on the task. ...
... A cage was placed at the end of the course for the animal to enter. 7 Since rats needed motor coordination and balance to overcome the obstacles along the course, we recorded both the time needed to complete the test and the number of foot faults (errors) in each trial, as a measure of motor learning. The animals in all study groups were housed in groups of 6 per cage, in a room different to that used for training. ...
... Although the time taken to complete the task was not significant in comparison with day 1, we did observe a downward trend, which would be partially consistent with previous reports. 7,8 As reported in previous studies, 7,8 the number of errors made by experimental rats decreased with the days of training. This could be interpreted as a gradual and progressive increase in the precision and control of motor activity and demonstrates the appearance of a learning process. ...
Introduction
The paramedian lobule of the cerebellum is involved in learning to correctly perform motor skills through practice. Dendritic spines are dynamic structures that regulate excitatory synaptic stimulation. We studied plastic changes occurring in the dendritic spines of Purkinje cells from the paramedian lobule of rats during motor learning.
Methods
Adult male rats were trained over a 6-day period using an acrobatic motor learning paradigm; the density and type of dendritic spines were determined every day during the study period using a modified version of the Golgi method.
Results
The learning curve reflected a considerable decrease in the number of errors made by rats as the training period progressed. We observed more dendritic spines on days 2 and 6, particularly more thin spines on days 1, 3, and 6, fewer mushroom spines on day 3, fewer stubby spines on day 1, and more thick spines on days 4 and 6.
Conclusion
The initial stage of motor learning may be associated with fast processing of the underlying synaptic information combined with an apparent “silencing” of memory consolidation processes, based on the regulation of the neuronal excitability.
... Several types of behavioral plasticity are associated with changes in dendritic spines, the primary sites of excitatory synapses in the brain. For example, many forms of learning and memory are accompanied by dendritic spinogenesis (Moser et al., 1994;Leuner et al., 2003;Restivo et al., 2009;Vetere et al., 2011a,b;Bock et al., 2014;Kuhlman et al., 2014;Nishiyama, 2014;González-Tapia et al., 2015Mahmmoud et al., 2015;Jasinska et al., 2016;Ma et al., 2016) or spine elimination (Vetere et al., 2011b;Sanders et al., 2012;Jasinska et al., 2016;Ma et al., 2016;Swanson et al., 2017). Spine plasticity is also associated with proficiency of certain motor tasks (Fu et al., 2012;Liston et al., 2013;Hayashi-Takagi et al., 2015;Gonzalez-Tapia et al., 2016) and potentially, action-outcome expectation, given that drugs that enhance action-outcome learning can trigger spine elimination in certain brain regions (Swanson et al., 2017). ...
An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action-outcome expectations. In a separate experiment, we blocked action-outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action-outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action-outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.
