Changes In Neuronal Structure Research Articles

Neuronal Functions of ESCRTs

The endosomal sorting complexes required for transport (ESCRTs) regulate protein trafficking from endosomes to lysosomes. Recent studies have shown that ESCRTs are involved in various cellular processes, including membrane scission, microRNA function, viral budding, and the autophagy pathway in many tissues, including the nervous system. Indeed, dysfunctional ESCRTs are associated with neurodegeneration. However, it remains largely elusive how ESCRTs act in post-mitotic neurons, a highly specialized cell type that requires dynamic changes in neuronal structures and signaling for proper function. This review focuses on our current understandings of the functions of ESCRTs in neuronal morphology, synaptic plasticity, and neurodegenerative diseases.

A VBM study demonstrating ‘apparent’ effects of a single dose of medication on T1-weighted MRIs

Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM 'gray matter' signal in the dorsal rostral anterior cingulate (family wise error corrected at p<0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.

Increased expression of Kalirin-9 in the auditory cortex of schizophrenia subjects: Its role in dendritic pathology

Reductions in dendritic arbor length and complexity are among the most consistently replicated changes in neuronal structure in post mortem studies of cerebral cortical samples from subjects with schizophrenia, however, the underlying molecular mechanisms have not been identified. This study is the first to identify an alteration in a regulatory protein which is known to promote both dendritic length and arborization in developing neurons, Kalirin-9. We found Kalirin-9 expression to be paradoxically increased in schizophrenia. We followed up this observation by overexpressing Kalirin-9 in mature primary neuronal cultures, causing reduced dendritic length and complexity. Kalirin-9 overexpression represents a potential mechanism for dendritic changes seen in schizophrenia.

Loss of PSD-95 Enrichment Is Not a Prerequisite for Spine Retraction

Changes in neuronal structure are thought to underlie long-term behavioral modifications associated with learning and memory. In particular, considerable evidence implicates the destabilization and retraction of dendritic spines along with the loss of spine synapses as an important cellular mechanism for refining brain circuits, yet the molecular mechanisms regulating spine elimination remain ill-defined. The postsynaptic density protein, PSD-95, is highly enriched in dendritic spines and has been associated with spine stability. Because spines with low levels of PSD-95 are more dynamic, and the recruitment of PSD-95 to nascent spines has been associated with spine stabilization, we hypothesized that loss of PSD-95 enrichment would be a prerequisite for spine retraction. To test this hypothesis, we used dual-color time-lapse two-photon microscopy to monitor rat hippocampal pyramidal neurons cotransfected with PSD-95-GFP and DsRed-Express, and we analyzed the relationship between PSD-95-GFP enrichment and spine morphological changes. Consistent with our hypothesis, we found that the majority of spines that retracted were relatively unenriched for PSD-95-GFP. However, in the subset of PSD-95-GFP-enriched spines that retracted, spine shrinkage and loss of PSD-95-GFP were tightly coupled, suggesting that loss of PSD-95-GFP enrichment did not precede spine retraction. Moreover, we found that, in some instances, spine retraction resulted in a significant enrichment of PSD-95-GFP on the dendritic shaft. Our data support a model of spine retraction in which loss of PSD-95 enrichment is not required prior to the destabilization of spines.

Evidence that angiogenesis lags behind neuron and astrocyte growth in experience‐dependent plasticity

Bill Greenough's work on the cell biology of information storage suggests that we cannot understand the mechanism of long-term memory without understanding the series of cellular transactions that drive coordinated structural changes in neurons, glia, and blood vessels. Here, we show that after 4 days of differential housing, neuropil of EC cortex has expanded significantly, but the vasculature has not, resulting in a dilution of the blood supply. Significant growth of neurons and astrocytes has been reported within this time period, suggesting expression of synaptic plasticity might involve temporally coordinated genomic responses by both neurons and glia. Given that astrocytes appear to couple neuronal and vascular growth during development, we hypothesize that they may also mediate the onset of angiogenesis in response to neural demand in the EC brain. Further, these results may imply that a neuron's capacity for plasticity could be constrained by the rate of vascular expansion.

Developmental changes in propagation patterns and transmitter dependence of waves of spontaneous activity in the mouse cerebral cortex.

Waves of spontaneous electrical activity propagate across many regions of the central nervous system during specific stages of early development. The patterns of wave propagation are critical in the activation of many activity-dependent developmental programs. It is not known how the mechanisms that initiate and propagate spontaneous waves operate during periods in which major changes in neuronal structure and function are taking place. We have recently reported that spontaneous waves of activity propagate across the neonatal mouse cerebral cortex and that these waves are initiated at pacemaker sites in the septal nucleus and ventral cortex. Here we show that spontaneous waves occur between embryonic day 18 (E18) and postnatal day 12 (P12), and that during that period they undergo major changes in transmitter dependence and propagation patterns. At early stages, spontaneous waves are largely GABA dependent and are mostly confined to the septum and ventral cortex. As development proceeds, wave initiation depends increasingly on AMPA-type glutamate receptors, and an ever increasing fraction of waves propagate into the dorsal cortex. The initiation sites and restricted propagation of waves at early stages are highly correlated with the position of GABAergic neurons in the cortex. The later switch to a glutamate-based mechanism allows propagation of waves into the dorsal cortex, and appears to be a compensatory mechanism that ensures continued wave generation even as GABA transmission becomes inhibitory.

Observation of the changes of protein gene product 9.5, mucosal C-kit, gastrin and somatostatin in rat with experimental induced gastritis

Objective To find the possible pathogenesis of enteric nervous system, gut hormone and gastric Cajal interstitial cell ( ICC ) in gastritis related gastrointestinal ( GI ) motor disorders on the changes of protein gene product 9. 5 in neurons , mucosal expression of C-kit, gastrin and somatostatin from the gastric wall of gastritis rat. Methods 45 rats were divided into 3 groups which included gastritis group A, gastritis group B and control group. Rats in gastritis group A were fed with Hp Sydney Strain 1, the mixture of 2% aspirin and 0. 6N hydrochloric acid was fed in gastritis group B. The control group only received saline. All of the rats were killed and mucosal tissue was obtained from antrum and greater curvature of the gastric body. Pathological and Hp examination were performed in the tissue slides, and then it was stained to check PGP 9. 5, gastric body's mucosal expression of C-kit, antrium's mucosal expression of gastrin and somatostatin. The cell body, the maximum diameter (Dmax, μm), mean area( μm2) and optical density (nm), integral optical density of the gastrin and somatostatin in the C-kit expression positive neurons from the gastric wall were compared among the groups. Result The mean area and optical density of PGP 9. 5 expression in neurons from the gastric wall of rat in group A or B were obviously lower than that of the control group ( P ＜0. 01 ), while there was no difference between gastric group A and B ( P ＞0. 05). Gastric group A had higher GAS expression than control group, while SS expression was lower than control group( P＜0. 05). There was no difference between group B and the control group in the two variances( P ＞0. 05).By linear correlation analysis, it showed that SS was negatively correlated with GAS ( r = - 0. 333, P ＜0. 01 ). The distributive area and diameter of cells with C-kit expression in both group A and B were significantly smaller than that in the control group ( P ＜ 0. 05 ), while there was no obvious difference between group A and B ( P ＞ 0. 05 ). There was no difference of integral optical density of the C-kit expression positive neurons among the three groups. Conclusions Hp infection and NSAIDs might cause gastritis and had influence on the structural changes of neurons from gastric wall and ICC. Hp infection could obviously inhibit SS excretion from antrum mucosa while increase Gastrin excretion. NSAIDs induced gastritis had little influence on GAS and SS. Key words: Gastritis/ME; Proteins/ME; Proto-oncogene proteins c-kit/ME; Gastrins/ME; Somatostatin/ME

Tau Protein Role in Sleep-Wake Cycle

Evidence has shown that the lack of tau produces subtle changes in neuronal structure and modest impairment in complex behaviors, suggesting compensatory mechanisms carried out by other neuronal microtubule-associated proteins. Here we show major abnormalities in sleep-wake cycle of tau-deficient animals including increased wakefulness duration and decreased non-rapid eye movement (NREM) sleep time, a higher number of state transitions between NREM and wake, and shortened sleep bouts. Altered sleep structure in tau-/- mice was accompanied by a significant decline in delta power together with an enhanced spectral density of sleep spindles during NREM sleep. No significant differences were observed in rapid eye movement (REM) sleep between the two mouse strains. Taken together, these results suggest that tau indirectly participates in the regulation of the sleep-wake cycle modulating not only the control and maintenance of global brain states but also the cerebral oscillatory patterns underlying sleep-wake states.

Brain plasticity in Diptera and Hymenoptera

To mediate different types of behaviour, nervous systems need to coordinate the proper operation of their neural circuits as well as short- and long-term alterations that occur within those circuits. The latter ultimately devolve upon specific changes in neuronal structures, membrane properties and synaptic connections that are all examples of plasticity. This reorganization of the adult nervous system is shaped by internal and external influences both during development and adult maturation. In adults, behavioural experience is a major driving force of neuronal plasticity studied particularly in sensory systems. The range of adaptation depends on features that are important to a particular species, and is therefore specific, so that learning is essential for foraging in honeybees, while regenerative capacities are important in hemimetabolous insects with long appendages. Experience is usually effective during a critical period in early adult life, when neural function becomes tuned to future conditions in an insect's life. Tuning occur at all levels, in synaptic circuits, neuropile volumes, and behaviour. There are many examples, and this review incorporates only a select few, mainly those from Diptera and Hymenoptera.

Plastic effects of L-DOPA treatment in the basal ganglia and their relevance to the development of dyskinesia

The development of L-DOPA-induced dyskinesia (LID) is attributed to plastic responses triggered by dopamine (DA) receptor stimulation in the parkinsonian brain. This article reviews studies that have uncovered different levels of maladaptive plasticity in animal models of LID. Rats developing dyskinesia on chronic L-DOPA treatment show abnormal patterns of signaling pathway activation and synaptic plasticity in striatal neurons. In addition, these animals show a gene expression profile indicative of structural cellular plasticity, including pronounced upregulation of genes involved in extracellular matrix remodeling, neurite extension, synaptic vesicle trafficking, and endothelial and cellular proliferation. Structural changes of neurons and microvessels within the basal ganglia are currently being unraveled by detailed morphological analyses. The structural and functional adaptations induced by L-DOPA in the brain can be viewed as an attempt to meet increased metabolic demands and to boost cellular defense mechanisms. These homeostatic responses, however, also predispose to the appearance of dyskinesia and other complications during the course of the treatment.

Cortical excitability and post-stroke recovery

Stroke is the leading cause of adult disability. Recent studies show that the brain can engage in a limited process of neural repair after stroke: re-mapping of sensory and motor function and sprouting of new connections in peri-infarct cortex surrounding the stroke. Changes in cortical sensory and motor maps and alterations in axonal structure are dependent on patterned neuronal activity. The central cellular process in these events is alteration in neuronal response to incoming inputs--manipulations that increase neuronal firing to a given input are likely to induce changes in neuronal structure and alterations in cortical maps. Because post-stroke neural repair and recovery also involves neuronal sprouting and re-mapping of cortical sensory and motor representations, it has been assumed that changes in neuronal excitability underlie neural repair.

D1 receptors involved in the acquisition of sexual experience in male rats

As we found previously, changes in ultrasonic vocalizations in the 50-kHz band emitted before a female is introduced into a copulatory chamber (precontact vocalizations—PVs) and shortening of ejaculation latency (EL) in subsequent copulatory sessions are correlated and reflected acquisition of sexual experience in male rats. In the present experiments, we investigate the role of the D1 receptor in this phenomenon. First, the effects of a D1 antagonist and D1 agonists injected subcutaneously during the first sexual contacts were analyzed. The antagonist (SCH-23390) inhibited changes in PVs and EL as well as rearing (R) and mount latency (ML). Both agonists (SKF-38393 and selective SKF-82957) inhibited PVs also at doses where no effects on EL and ML were observed. Repeated injections of five agonists, with or without socio-sexual contacts, had an effect on later PVs and R (long-term effect) but not on copulatory performance during the subsequent four sessions. In the last experiment, a D1 agonist (SKF-82957, 0.5μg) was injected bilaterally into nucleus accumbens (N.Acc) before each of the first five sessions. The D1 agonist in N.Acc facilitated initiation of copulation in treatment-naïve rats. Repeated administration of the D1 agonist into the brain had long-lasting effects on PVs, R and ML, probably as a result of long-term changes in neuronal structures involved in acquisition of sexual experience, in this part of the nucleus accumbens. Repeated D1 agonist administration probably inhibits/reverses sensitization processes in dopamine structures. The results indicate a role of D1 receptors in acquisition of socio-sexual experience and suggest independent neuronal pathways for changes in PVs and EL.

Maternal separation decreases the stability of mushroom spines in adult mice somatosensory cortex

Maternal-separation (MS) is an important model to study the effects of maternal care on infant neuronal development. It has been previously shown that MS contributes to not only structural changes of neurons in the infralimbic cortex but also to significant behavioral changes in adulthood. However, the underlying mechanism of the MS effect on neuronal circuits is not clearly understood. In this study, we studied the effects of MS on the function related to somatosensory cortex (SSC) and spine remodeling in the SSC. We found that MS mice showed hypersensitivity to somatosensory stimulation at post-natal 4, 8 and 12 weeks. MS enhanced the turnover of mushroom-type spines, leading to a decrease of the number of spines in the SSC in young and adult mice observed by using in vivo two-photon laser microscopy imaging. We conclude that MS during development affects the stability of dendritic mushroom spines in the SSC, which possibly produces impairment of the sensory behavior in adult mice.

The Formation of Recent and Remote Memory Is Associated with Time-Dependent Formation of Dendritic Spines in the Hippocampus and Anterior Cingulate Cortex

Although hippocampal-cortical interactions are crucial for the formation of enduring declarative memories, synaptic events that govern long-term memory storage remain mostly unclear. We present evidence that neuronal structural changes, i.e., dendritic spine growth, develop sequentially in the hippocampus and anterior cingulate cortex (aCC) during the formation of recent and remote contextual fear memory. We found that mice placed in a conditioning chamber for one 7 min conditioning session and exposed to five footshocks (duration, 2 s; intensity, 0.7 mA; interstimulus interval, 60 s) delivered through the grid floor exhibited robust fear response when returned to the experimental context 24 h or 36 d after the conditioning. We then observed that their fear response at the recent, but not the remote, time point was associated with an increase in spine density on hippocampal neurons, whereas an inverse temporal pattern of spine density changes occurred on aCC neurons. At each time point, hippocampal or aCC structural alterations were achieved even in the absence of recent or remote memory tests, thus suggesting that they were not driven by retrieval processes. Furthermore, ibotenic lesions of the hippocampus impaired remote memory and prevented dendritic spine growth on aCC neurons when they were performed immediately after the conditioning, whereas they were ineffective when performed 24 d later. These findings reveal that gradual structural changes modifying connectivity in hippocampal-cortical networks underlie the formation and expression of remote memory, and that the hippocampus plays a crucial but time-limited role in driving structural plasticity in the cortex.

EXERCISE‐INDUCED PLASTICITY IN THE RAT HIPPOCAMPUS, MOTOR CORTEX AND BRAIN STEM

Increasing evidence shows that physical exercise is neuroprotective and enhances brain function by improving memory, cognitive functions, neuroplasticity, and learning. The aim of this study was to observe the plastic effects physical exercise has on regions of the CNS related to cognitive and motor functions by evaluating the expression of structural proteins. A group of 40 adult male Wistar rats were subjected to an exercise protocol on an adapted treadmill. Following a 2 day adaptation period, the exercised group ran for 40 min/day, at 0.6km/h for 3 (3D), 7 (7D) or 15 (15D) days. At the end of the exercise protocol, brains were subjected to immunoblotting analysis to evaluate the expression of neurofilaments (NF) in the hippocampus, motor cortex and brain stem. In the hippocampus, immunoblot analysis showed increased expression of NF68 (p&lt;0.005) following 3D exercise. In the motor cortex, however, the levels of both NF68 and NF160 decreased (p&lt;0.05) after 3D exercised and increased at 15D for NF68 (p&lt;0.05). The brain stem showed increased expression of all NFs at 15D (p&lt;0.05). These results suggest that physical exercise alters the expression of structural neuronal proteins in brain regions associated with motor control, cognition, memory and learning. Our current ongoing studies focuses on the functional role astrocytes have on exercise‐induced structural neuronal changes.Support: FAPESP, CNPq, CAPES

Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory

We previously reported that chronic hyperglycemia, but not hypoglycemia, was associated with the reduction of neuronal size in the rat brain. We hypothesized that hyperglycemia-induced changes in neuronal structure would have negative consequences, such as impaired learning and memory. We therefore assessed the effects of hyperglycemia and hypoglycemia on neuronal dendritic structure and cognitive functioning in young rats. Experimental manipulations were conducted on male Wistar rats for 8 wk, beginning at 4 wk of age. At the completion of the treatments, all rats were trained in the radial-arm water maze, a spatial (hippocampus-dependent) learning and memory task. Three groups of rats were tested: an untreated control group, a streptozotocin-induced diabetic (STZ-D) group, and an intermittent hypoglycemic group. Following behavioral training, the brains of all animals were examined with histologic and biochemical measurements. Peripheral hyperglycemia was associated with significant increases in brain sorbitol (7.5 +/- 1.6 vs. 5.84 +/- 1.0 microM/mg) and inositol (9.6 +/- 1.4 vs. 7.1 +/- 1.1 microM/mg) and reduced taurine (0.65 +/- 0.1 vs. 1.3 +/- 0.1 mg/mg). Histologic evaluation revealed neurons with reduced dendritic branching and spine density in STZ-D rats but not in control or hypoglycemic animals. In addition, the STZ-D group exhibited impaired performance on the water maze memory test. Hyperglycemia, but not hypoglycemia, was associated with adverse effects on the brain polyol pathway activity, neuronal structural changes, and impaired long-term spatial memory. This finding suggests that the hyperglycemic component of diabetes mellitus has a greater adverse effect on brain functioning than does intermittent hypoglycemia.

AP-1 activity rises by stimulation-dependent c-Fos expression in auditory neurons

Acoustical or intracochlear stimulation may induce expression of the immediate early gene product c-Fos in neurons throughout the auditory brainstem. Attempting to estimate its consequences, we sought to determine if c-Fos expression occurs in neurons that also contain c-Jun p39 with which it could form the heterodimeric transcription factor AP-1 to activate a large number of genes, among them several involved in neuroplastic remodeling. Following intracochlear stimulation, c-Fos and c-Jun were found to be colocalized in nuclei of many neurons at all levels of the subcortical auditory system. We conclude that stimulation triggers Fos-Jun dimerization, causing cascades of gene expression that potentially culminate in structural changes of neurons affected by the specific pattern of activity imposed on the neuronal system.

Synaptic Function for the Nogo-66 Receptor NgR1: Regulation of Dendritic Spine Morphology and Activity-Dependent Synaptic Strength

In the mature nervous system, changes in synaptic strength correlate with changes in neuronal structure. Members of the Nogo-66 receptor family have been implicated in regulating neuronal morphology. Nogo-66 receptor 1 (NgR1) supports binding of the myelin inhibitors Nogo-A, MAG (myelin-associated glycoprotein), and OMgp (oligodendrocyte myelin glycoprotein), and is important for growth cone collapse in response to acutely presented inhibitors in vitro. After injury to the corticospinal tract, NgR1 limits axon collateral sprouting but is not important for blocking long-distance regenerative growth in vivo. Here, we report on a novel interaction between NgR1 and select members of the fibroblast growth factor (FGF) family. FGF1 and FGF2 bind directly and with high affinity to NgR1 but not to NgR2 or NgR3. In primary cortical neurons, ectopic NgR1 inhibits FGF2-elicited axonal branching. Loss of NgR1 results in altered spine morphologies along apical dendrites of hippocampal CA1 neurons in vivo. Analysis of synaptosomal fractions revealed that NgR1 is enriched synaptically in the hippocampus. Physiological studies at Schaffer collateral-CA1 synapses uncovered a synaptic function for NgR1. Loss of NgR1 leads to FGF2-dependent enhancement of long-term potentiation (LTP) without altering basal synaptic transmission or short-term plasticity. NgR1 and FGF receptor 1 (FGFR1) are colocalized to synapses, and mechanistic studies revealed that FGFR kinase activity is necessary for FGF2-elicited enhancement of hippocampal LTP in NgR1 mutants. In addition, loss of NgR1 attenuates long-term depression of synaptic transmission at Schaffer collateral-CA1 synapses. Together, our findings establish that physiological NgR1 signaling regulates activity-dependent synaptic strength and uncover neuronal NgR1 as a regulator of synaptic plasticity.

290 – Changes in neuron structure within the nucleus basalis in schizophrenia

290 – Changes in neuron structure within the nucleus basalis in schizophrenia

Behavioral reactions of gerbils and structural alterations in their hippocampus after cerebral ischemia-reperfusion

We studied changes in behavior of Mongolian gerbils (Meriones unguiculatus) after ischemia-reperfusion of the brain (7-min-long occlusion of both arteriae carotis) and structural alterations in the hippocampus of such animals. Behavioral manifestations were observed under conditions of the open field test within 7 days of the postischemic period; immunofluorescent staining of brain sections with antibodies against specific proteins of neurons and glial cells was used. Motor hyperactivity reaching its maximum a day after ischemization and gradually decreasing within the postocclusion period was found in ischemized animals. On the 7th day, the level of locomotor activity in experimental gerbils was practically equal to that in the control group. In contrast, a postischemic decrease in the duration of episodes of resting was preserved for a longer time. A week after ischemia-reperfusion, intense delayed neuronal death and activation of glial cells were observed in the CA1 hippocampal area. Thus, cerebral ischemia-reperfusion results in significant transient disorders of behavioral phenomena in gerbils; at the same time, a clear correlation is observed between structural changes of neurons and the level of reactivity of glial cells in the hippocampus. These events can be significant aspects of the dynamics of postischemic damage to the above structure.