Region-specific changes in the microanatomy of single dendritic spines over time might account for selective memory alterations in ageing hAPPsweTg2576 mice, a mouse model for Alzheimer disease

Tg2576 mice over-expressing human mutant APP (hAPPswe) show progressive impairments in hippocampal plasticity and episodic memory while fronto-striatal plasticity and procedural memory remain intact. Here we examine the status of synaptic connectivity in the hippocampus and the dorsolateral striatum (DLS) of 3- and 15-month-old Tg2576 and wild-type mice through the analysis of single dendritic spines microanatomy. We found that, in each region, all mice showed a global reduction in the size of spines as a function of age. Ageing mutants, however, exhibited smaller spines with shorter necks on CA1 pyramidal neurons but larger spines with longer necks on DLS spiny neurons compared to their age-matched wild-type controls. Our findings indicate that hippocampal and DLS dendritic spines in hAPPswe mutants undergo a different pattern of morphological changes over time and point to minor alterations in the microanatomy of DLS spines as a compensatory mechanism maintaining procedural abilities in the ageing mutants.     

Altered daylength affects dendritic structure in a song-related brain region in red-winged blackbirds.

Substantial neural and behavioral plasticity occurs in the avian song system in adulthood. Changes in the volume of one of the song control nuclei, robustus archistriatalis (RA), have been associated with seasonal changes in singing behavior in adult canaries (Serinus canarius) and red-winged blackbirds (Agelaius phoeniceus). The present work assessed the effects of changed daylength on dendritic morphology in RA in adult male red-winged blackbirds. Brains from hand-reared red-winged blackbirds maintained on long days or long days followed by short days were stained with a Golgi-Cox procedure. Dendritic morphology and spine density of type IV neurons from nucleus RA were compared between long and short day birds. Neurons from short day birds have smaller dendritic fields than neurons from long day birds, with the difference greatest for distal dendrites. In addition, the density of dendritic spines is significantly smaller for neurons from short day birds. Together, these changes result in the loss of approximately 40% of the spines on this neuron class. In previous work in adult female canaries, external testosterone administration has been shown to be associated with increases in dendritic field size and synapse number. The similarity of the neuronal changes in RA that are associated with the two sorts of manipulations suggest that some consequences of altered daylength are mediated by changes in the levels of gonadal steroids.     

Plasticity of nonneuronal brain tissue: roles in developmental disorders

Neuronal and nonneuronal plasticity are both affected by environmental and experiential factors. Remodeling of existing neurons induced by such factors has been observed throughout the brain, and includes alterations in dendritic field dimensions, synaptogenesis, and synaptic morphology. The brain loci affected by these plastic neuronal changes are dependent on the type of experience and learning. Increased neurogenesis in the hippocampal dentate gyrus is a well-documented response to environmental complexity ("enrichment") and learning. Exposure to challenging experiences and learning opportunities also alters existing glial cells (i.e., astrocytes and oligodendrocytes), and up-regulates gliogenesis, in the cerebral cortex and cerebellum. Such glial plasticity often parallels neuronal remodeling in both time and place, and this enhanced morphological synergism may be important for optimizing the functional interaction between glial cells and neurons. Aberrant structural plasticity of nonneuronal elements is a contributing factor, as is aberrant neuron plasticity, to neurological and developmental disorders such as epilepsy, autism, and mental retardation (i.e., fragile X syndrome). Some of these nonneuronal pathologies include abnormal cerebral and cerebellar white matter and myelin-related proteins in autism; abnormal myelin basic protein in fragile X syndrome (FXS); and abnormal astrocytes in autism, FXS, and epilepsy. A number of recent studies demonstrate the possibility of using environmental and experiential intervention to reduce or ameliorate some of the neuronal and nonneuronal abnormalities, as well as behavioral deficits, present in these neurological and developmental disorders.     

Age-dependent glutamate induction of synaptic plasticity in cultured hippocampal neurons

A common denominator for the induction of morphological and functional plasticity in cultured hippocampal neurons involves the activation of excitatory synapses. We now demonstrate massive morphological plasticity in mature cultured hippocampal neurons caused by a brief exposure to glutamate. This plasticity involves a slow, 70%-80% increase in spine cross-section area associated with a significant reduction in the width of dendrites. These changes are age dependent and expressed only in cells >18 d in vitro (DIV). Activation of both NMDARs and AMPARs as well as a sustained rise of internal calcium levels are necessary for induction of this plasticity. On the other hand, blockade of network activity or mGluRs does not abolish the observed morphological plasticity. Electrophysiologically, a brief exposure to glutamate induces an increase in the magnitude of EPSCs evoked between pairs of neurons, as well as in mEPSC frequency and amplitude, in mature but not young cultures. These results demonstrate an age-dependent, rapid and robust morphological and functional change in cultured central neurons that may contribute to their ability to express long term synaptic plasticity.     

Electroconvulsive stimulations prevent stress-induced morphological changes in the hippocampus

Stress can precipitate major depression and other disorders linked to hippocampal shrinkage. It is hypothesized but not established that treatment of these disorders reverses and prevents the hippocampal changes. Dendritic retraction of individual neurons might in concert with other pathophysiological events contribute to the shrinkage phenomenon. Animal studies have shown that various stress paradigms can induce dendritic retraction in the CA3 pyramidal neurons of the hippocampus. Since electroconvulsive treatment is the most effective treatment in humans with major depression, we investigated whether repeated electroconvulsive stimulations (ECSs) could influence such changes in stressed rats. Furthermore, we investigated whether ECSs per se could influence neuronal branching and total length of the CA3 hippocampal neuronal dendritic tree in normal rats. Rats were stressed using the 21-day 6 h daily restraint stress paradigm. The study shows that stress caused remodelling of the pyramidal neurons by significantly reducing the number of dendritic branch points and total length of the apical dendritic tree. Concomitant administration of ECSs prevented these effects. ECSs had no effect on pyramidal neuron dendrites in normal rats.     

Layer and regional effects of environmental enrichment on the pyramidal neuron morphology of the rat

The environmental enrichment (EE) paradigm is widely used to study experience-dependent brain plasticity. Several studies have investigated functional and anatomical EE effects. However, as EE effects are different according to cerebral region, cortical layer, dendritic field and morphological index considered, a univocal characterization of neuronal morphological changes following rearing in enriched environments is lacking.Aim of the present study was to characterize in the rat the effects of EE on the neuronal morphology of frontal and parietal cortical regions, the main target areas of the stimulation provided by the paradigm. Male Wistar rats were housed in an enriched environment for 3.5 months from the 21st postnatal day. For the morphological analysis, biotinylated dextran amine (BDA)-labeled pyramidal neurons were selected from frontal (M1–M2) and parietal (S1–S2) cortical layers III and V. Apical and basal dendritic branching and spines were analyzed using the Sholl method.Results showed that EE increased branching and spines in both layers of frontal cortex, but had a greater effect on apical arborization. In parietal cortex, EE significantly affected branching and spines in layer III but not layer V neurons, in which only a tendency to be influenced by the rearing conditions was observed in basal arborization.It is hypothesized that these multifaceted morphological EE effects are connected to the heavy involvement of a sensory-motor circuit engaged in the guidance of voluntary action and in motor learning activated by EE stimulation.     

Basketball training increases striatum volume

The striatum is associated with the learning and retention of motor skills. Several studies have shown that motor learning induces neuronal changes in the striatum. We investigated whether macroscopic change in striatum volume occurs in a segment of the human population who learned basketball-related motor skills and practiced them throughout their entire athletic life. Three-dimensional magnetic resonance imaging volumetry was performed in basketball players and healthy controls, and striatum volumes were compared based on basketball proficiency, region and side. We identified morphological enlargement in the striatum of basketball players in comparison with controls. Our results suggest that continued practice and repetitive performance of basketball-related motor skills may induce plastic structural changes in the human striatum.     

ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons

Brain-derived neurotrophic factor (BDNF) is a potent modulator of synaptic transmission and plasticity in the CNS, acting both pre- and postsynaptically. We demonstrated recently that BDNF/TrkB signaling increases dendritic spine density in hippocampal CA1 pyramidal neurons. Here, we tested whether activation of the prominent ERK (MAPK) signaling pathway was responsible for BDNF's effects on spine growth. Slice cultures were transfected with enhanced yellow fluorescent protein (eYFP) by particle-mediated gene transfer, and CA1 pyramidal neurons were imaged by laser-scanning confocal microscopy. We confirmed that BDNF (24 h) increases spine density in apical dendrites of CA1 neurons. The MEK (ERK kinase) inhibitors PD98059 and U0126 completely prevented the increase in spine density induced by BDNF, without having an effect on spine density by themselves. In contrast to its actions on cortical pyramidal neurons, BDNF had minor and rather localized effects on dendritic complexity in hippocampal pyramidal neurons, increasing the total length, but not the branching of apical dendrites within CA1 stratum radiatum, without affecting basal dendrites in stratum oriens. Our results support the hypothesis that the ERK-signaling pathway not only mediates long-term synaptic plasticity and hippocampal-dependent learning, but it is also involved in the structural remodeling of excitatory spine synapses triggered by neurotrophins.     

Effects of Paired and Unpaired Eye-Blink Conditioning on Purkinje Cell Morphology

This experiment addressed (1) the importance of conjunctive stimulus presentation for morphological plasticity of cerebellar Purkinje cells and inhibitory interneurons and (2) whether plasticity is restricted to the spiny branches of Purkinje cells, which receive parallel fiber input. These issues were investigated in naive rabbits and in rabbits that received paired or unpaired presentations of the conditioned stimulus (CS) and unconditioned stimulus (US). To direct CS input to the cerebellar cortex, pontine stimulation served as the CS. Air puffs to the cornea served as the US. Paired condition rabbits received pontine stimulation for 350 msec paired with a coterminating 100-msec air puff. Unpaired condition rabbits received the same stimuli in a pseudorandom order at 1- to 32-sec intervals. Rabbits were trained for a mean of 12 days. Naive rabbits received no treatment. In Golgi-stained Purkinje neurons in lobule HVI, total dendritic length, main branch length, total spiny branch length, and number of spiny branch arbors were all greater in the naive group than in the paired and unpaired groups, which did not differ. No differences were found between the hemispheres ipsilateral and contralateral to the trained eye. The dendritic length and number of branches for inhibitory interneurons did not differ across groups. The Purkinje cell morphological changes detected with these methods do not appear to be uniquely related to the conjunctive activation of the CS and US in the paired condition.     

Methodological issues in pediatric neuroimaging

The emergence of new technologies to study brain function in vivo has resulted in an explosion of interest in cognitive neuroscience within the last ten years. While most research in functional neuroimaging has been geared toward adult normal volunteers, the development of functional magnetic resonance imaging (fMRI) has made it possible to study neural development in normal children, as well as those with developmental disorders. This technology provides an unprecedented opportunity to expand our knowledge of brain function throughout childhood. A variety of technological, experimental, and practical difficulties are amplified when imaging children. This paper reviews some of the more challenging theoretical and practical concerns and provides suggestions for their management.     

The Critical Role of Cholinergic Basal Forebrain Neurons in Morphological Change and Memory Encoding: A Hypothesis

It has been known for a long time that cholinergic basal forebrain neurons which project to the cerebral cortex play a role in learning and memory. Behavioral studies following lesions, for example, repeatedly have suggested multiple learning-related roles for these neurons. Apart from behavioral studies, cholinergic neurons have been shown to possess extraordinarily plastic axons. This plasticity has not been related comprehensively to mnemonic devises, even though morphological changes in the CNS are prime candidates for the neural engram. In this paper, I propose a hypothesis that relates these two characteristics of cholinergic neurons. This hypothesis is that plastic cholinergic axon terminals induce structural reorganization in their targets during memory storage. Possible intracellular mechanisms are examined, whereby acetylcholine release in the cerebral cortex could cause postsynaptic structural changes. Finally, the characteristics of the overall cholinergic–cholinoceptive cell “engram” are elaborated with particular attention paid to the encoding of the stimulus properties along with the context and meaning of the stimulus.     

下丘脑异常与抑郁症

近年来的研究发现了抑郁模型动物或抑郁症病人下丘脑异常的大量证据, 诸如下丘脑体积及神经元数目的改变, 下丘脑-垂体-内分泌轴的改变, 下丘脑相关激素、受体及其基因、神经肽的改变, 下丘脑与其他脑区功能联系的改变等等。然而, 下丘脑与抑郁症关系的研究所获证据多来自动物实验、或临床间接指标(如病人外周血激素水平等), 或病人脑组织尸检, 缺乏来自病人活体下丘脑异常的直接证据。今后的研究可考虑运用影像学的手段更直接地探索抑郁症患者活体下丘脑的结构特征和功能特征, 以期发现抑郁症的生物学标记及其可靠性指标, 为抑郁症的客观诊断提供依据, 为揭示抑郁症病理机制提供线索。     

Characterization of state transitions in spatially distributed,chaotic, nonlinear,dynamical systems in cerebral cortex

The neurons of cerebral cortex are largely autonomous and generate activity that is manifested in trains of microscopic axonal action potentials. The neurons interact by sparse but numerous synaptic connections to generate macroscopic dendritic activity patterns that are observed in electroencephalographic (EEG) waves. The macroscopic patterns are constructed by the populations and they shape the output of cortical neurons in parallel arrays. Sensory cortexes receive sensory information in the form of microscopic action potentials, which induce state transitions in population dynamics. Each state transition transforms sensory information to perceptual meaning. The EEG reflects both kinds of activity. The sensory input is accessed by time ensemble averaging, whereas the perceptual output is found by spatial ensemble averaging. Spatial phase gradients in the EEG are useful for identifying EEG segments in a sequence of state transitions in response to sensory input. The rapidity and flexibility with which they take place give strong reason to postulate that the mechanism for the construction of these sequences of patterns is a dynamical system operating in a chaotic domain.     

Inertia and memory in ambiguous visual perception

Perceptual multistability during ambiguous visual perception is an important clue to neural dynamics. We examined perceptual switching during ambiguous depth perception using a Necker cube stimulus, and also during binocular rivalry. Analysis of perceptual switching time series using variance–sample size analysis, spectral analysis and time series shuffling shows that switching times behave as a 1/f noise and possess very long range correlations. The long memory feature contrasts sharply with the traditional satiation models of multistability, where the memory is not incorporated, as well as with recently published models of multistability and neural processing, where memory is excluded. On the other hand, the long memory feature favors the concept of “dynamic core” or coalition of neurons, where neurons form transient coalitions. Perceptual switching then corresponds to replacement of one coalition of neurons by another. The inertia and memory measures the stability of a coalition: a strong and stable coalition has to be won over by another similarly strong and stable coalition, resulting in long switching times. The complicated transient dynamics of competing coalitions of neurons may be addressable using a combination of functional imaging, measurement of frequency-tagged magnetoencephalography and frequency-tagged encephalography, simultaneous recordings of groups of neurons in many areas of the brain, and concepts from statistical mechanics and nonlinear dynamics theory.     

Using proton magnetic resonance imaging and spectroscopy to understand brain "activation"

Upon stimulation, areas of the brain associated with specific cognitive processing tasks may undergo observable physiological changes, and measures of such changes have been used to create brain maps for visualization of stimulated areas in task-related brain "activation" studies. These perturbations usually continue throughout the period of the stimulating event, and then subside when the event is terminated. In this communication, we consider the nature and meaning of these task-related brain activations. Since stimulation usually results in an increase in the frequency of neuron depolarizations or "spikes", an energy expensive activity that requires ATP for restoration of ionic gradients, additional energy supplies must be rapidly deployed to the stimulated areas or rates of re-polarization could be decreased, and refractory periods between spikes increased. As a result, maximum spiking rates may be decreased and some frequency-encoded information lost. The energy available to brain cells to re-synthesize ATP from ADP is a function of levels of glucose and oxygen in blood, and their availability to stimulated neurons is a function of the rate at which focal blood supplies can be increased (hyperemia). In this review we explore how neurons transmit meaningful encoded information; how the integrity of that information is dependent on a continuous supply of energy, and how proton magnetic imaging and spectroscopy may aid in understanding the process. Finally, evidence is presented that the neuropeptide, N-acetylaspartylglutamate, is a neuronal astrocyte-vascular feedback signal that regulates activation induced focal hyperemic responses.     

Words in the brain's language

If the cortex is an associative memory, strongly connected cell assemblies will form when neurons in different cortical areas are frequently active at the same time. The cortical distributions of these assemblies must be a consequence of where in the cortex correlated neuronal activity occurred during learning. An assembly can be considered a functional unit exhibiting activity states such as full activation ("ignition") after appropriate sensory stimulation (possibly related to perception) and continuous reverberation of excitation within the assembly (a putative memory process). This has implications for cortical topographies and activity dynamics of cell assemblies forming during language acquisition, in particular for those representing words. Cortical topographies of assemblies should be related to aspects of the meaning of the words they represent, and physiological signs of cell assembly ignition should be followed by possible indicators of reverberation. The following postulates are discussed in detail: (1) assemblies representing phonological word forms are strongly lateralized and distributed over perisylvian cortices; (2) assemblies representing highly abstract words such as grammatical function words are also strongly lateralized and restricted to these perisylvian regions; (3) assemblies representing concrete content words include additional neurons in both hemispheres; (4) assemblies representing words referring to visual stimuli include neurons in visual cortices; and (5) assemblies representing words referring to actions include neurons in motor cortices. Two main sources of evidence are used to evaluate these proposals: (a) imaging studies focusing on localizing word processing in the brain, based on stimulus-triggered event-related potentials (ERPs), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI), and (b) studies of the temporal dynamics of fast activity changes in the brain, as revealed by high-frequency responses recorded in the electroencephalogram (EEG) and magnetoencephalogram (MEG). These data provide evidence for processing differences between words and matched meaningless pseudowords, and between word classes, such as concrete content and abstract function words, and words evoking visual or motor associations. There is evidence for early word class-specific spreading of neuronal activity and for equally specific high-frequency responses occurring later. These results support a neurobiological model of language in the Hebbian tradition. Competing large-scale neuronal theories of language are discussed in light of the data summarized. Neurobiological perspectives on the problem of serial order of words in syntactic strings are considered in closing.     

Ultrastructural plasticity associated with hippocampal-dependent learning: a meta-analysis

In order to develop a profile of how individual synapses in the hippocampal formation alter their structure following learning experience, a meta-analysis synthesized the available literature on morphological change following hippocampal-dependent learning. Analysis of the 132 calculated effect sizes suggest a consistent profile of morphological change in the hippocampus following learning experience. Across the hippocampal formation, dendritic complexity, spine density, and the size of perforated postsynaptic densities showed consistent increases following training. Both the density of synapses in general and perforated synapses in particular showed unique responses to training, depending on the duration of training and/or different cell layers of the hippocampal formation. Most importantly, it seems that this profile, while consistent, is small and specific--only a select few of the morphological parameters typically measured in anatomical studies of plasticity showed significant change following training. Collectively, these data suggest that the distinct electrophysiological properties of neocortical versus hippocampal synapses may be at least partially mediated by distinct morphological cascades. That is, on the basis of theory, and with the support of the current data, it seems that synaptogenesis correlates with enduring neocortical plasticity, while structural changes correlate with more transient hippocampal plasticity. To be able to state these conclusions with conviction, however, more data are needed in several key areas for continued pursuit of the morphological correlates of hippocampal-dependent learning.     

Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density

Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice.     

Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use

Previously, the authors found that partial denervation of the motor cortex in adult animals can enhance this region's neuronal growth response to relevant behavioral change. Rats with partial corpus callosum transections that were forced to rely on one forelimb for 18 days had increased dendritic arborization of layer V pyramidal neurons in the opposite motor cortex compared to controls. This was not found as a result of denervation alone or of forced forelimb use alone. However, it seemed possible that each independent manipulation (i.e., forced forelimb use alone and callosal transections alone) resulted in neural structural alterations that were simply not revealed in measurements of dendritic branch number and/or not inclusive of layer V dendrites. This possibility was assessed in the current study with a reexamination of the Golgi-Cox impregnated tissue generated in the previous study. Tissue was quantified from rats that received either partial transections of the rostral two-thirds of the corpus callosum (CCX) or sham operations (Sham) followed either by 18 days of forced use of one forelimb (Use) or unrestricted use of both forelimbs (Cont). Measurements of apical and basilar dendrites from pyramidal neurons of layer II/III and layer V were performed to detect spine addition resulting from either increased spine density or the addition of dendritic material. As hypothesized, significant spine addition was found following forced forelimb use alone (Sham+Use) and callosal transections alone (CCX+Cont). However, forced use primarily increased spines on layer II/III pyramidal neurons, whereas callosal transections primarily increased dendritic spines on layer V pyramidal neurons in comparison to Sham+Cont. A much more robust increase in layer V dendritic spines was found in animals with the combination of forced forelimb use and denervation (CCX+Use). In contrast to the effects of forced use alone, however, CCX+Use rats failed to show major net increases in spines on layer II/III neurons. These results indicate that while callosal denervation may greatly enhance the neuronal growth and synaptogenic response to behavioral change in layer V, it may also limit spine addition associated with forced forelimb use in layer II/III of the motor cortex.