New role for astroglia in learning: Formation of muscle memory

Muscle memory can be described as gradual adaptation of muscles over a period of time to perform a new movement or action. Its precise mechanism is unknown; however, it is now known that when a motor skill is learned it leads to significant brain activity. Astrocytes are the most abundant glial cell types in the CNS that play an associative active role with neurons in learning and memory. They are interconnected to neurons via gap junctions forming astroglial network for fast communication and synchronization. We hypothesize that astroglial cells play main role in the formation of muscle memory and evaluate it by the experimental evidence published so far that indicates role of astroglia on various cellular and molecular aspects of muscle memory. The basis of our hypothesis is the fact that during training or motor learning period, neuronal output data related to learning lead to certain specific pattern for stimulating target muscles over a period of time and partly these data are stored in astroglial network. This stored data fine tune glial parameters that affect synaptic space and neuronal output used to perform rapid motor actions. For the validation of our hypothesis, we have generated a computational model for a section of neural pathway with astroglial network and have shown that the astroglial network by using inhibitory and stimulatory neurotransmitters can generate certain patterns, modulate and balance synaptic space across the neural pathway during acquisition of muscle memory.     

“The seven sins” of the Hebbian synapse: Can the hypothesis of synaptic plasticity explain long-term memory consolidation?

Memorizing new facts and events means that entering information produces specific physical changes within the brain. According to the commonly accepted view, traces of memory are stored through the structural modifications of synaptic connections, which result in changes of synaptic efficiency and, therefore, in formations of new patterns of neural activity (the hypothesis of synaptic plasticity). Most of the current knowledge on learning and initial stages of memory consolidation ("synaptic consolidation") is based on this hypothesis. However, the hypothesis of synaptic plasticity faces a number of conceptual and experimental difficulties when it deals with potentially permanent consolidation of declarative memory ("system consolidation"). These difficulties are rooted in the major intrinsic self-contradiction of the hypothesis: stable declarative memory is unlikely to be based on such a non-stable foundation as synaptic plasticity. Memory that can last throughout an entire lifespan should be "etched in stone." The only "stone-like" molecules within living cells are DNA molecules. Therefore, I advocate an alternative, genomic hypothesis of memory, which suggests that acquired information is persistently stored within individual neurons through modifications of DNA, and that these modifications serve as the carriers of elementary memory traces.     

Lock-and-key mechanisms of cerebellar memory recall based on rebound currents

A basic question for theories of learning and memory is whether neuronal plasticity suffices to guide proper memory recall. Alternatively, information processing that is additional to readout of stored memories might occur during recall. We formulate a "lock-and-key" hypothesis regarding cerebellum-dependent motor memory in which successful learning shapes neural activity to match a temporal filter that prevents expression of stored but inappropriate motor responses. Thus, neuronal plasticity by itself is necessary but not sufficient to modify motor behavior. We explored this idea through computational studies of two cerebellar behaviors and examined whether deep cerebellar and vestibular nuclei neurons can filter signals from Purkinje cells that would otherwise drive inappropriate motor responses. In eyeblink conditioning, reflex acquisition requires the conditioned stimulus (CS) to precede the unconditioned stimulus (US) by >100 ms. In our biophysical models of cerebellar nuclei neurons this requirement arises through the phenomenon of postinhibitory rebound depolarization and matches longstanding behavioral data on conditioned reflex timing and reliability. Although CS–US intervals <100 ms may induce Purkinje cell plasticity, cerebellar nuclei neurons drive conditioned responses only if the CS–US training interval was >100 ms. This bound reflects the minimum time for deinactivation of rebound currents such as T-type Ca²⁺. In vestibulo-ocular reflex adaptation, hyperpolarization-activated currents in vestibular nuclei neurons may underlie analogous dependence of adaptation magnitude on the timing of visual and vestibular stimuli. Thus, the proposed lock-and-key mechanisms link channel kinetics to recall performance and yield specific predictions of how perturbations to rebound depolarization affect motor expression.     

Synaptic connections between motor neurons and interneurons in the fourth thoracic ganglion of the crayfish, Procambarus clarkii

1. A new preparation of the thoracic nervous system of the crayfish, Procambarus clarkii, has been developed, in which it is possible to work with identified members of motor neuronal pools. 2. In such a preparation, it is possible to dissect all specific proximal motor nerves (protractor, retractor, anterior elevator, posterior elevator, and depressor). Motor neurons innervating the four proximal muscles of the fourth walking leg have been identified both physiologically and anatomically by staining the recorded motor neuron with Lucifer yellow through the microelectrode. 3. By the use of cobalt chloride, we have mapped the distribution of somata of all motor neurons within the fourth thoracic ganglion that innervate the different groups of muscles controlling the movement of the fourth walking leg. 4. Most motor neurons innervating the same muscle seem to be electrically coupled, except some depressor motor neurons. 5. Motor neurons innervating antagonist muscles are linked by inhibitory connections. These connections are reciprocal for protractor and retractor motor neurons but usually not reciprocal between elevator and depressor motor neurons. 6. Walking interneurons were identified as neurons without axons in any motor nerve, which modified the motor neuronal activity. Some of them have been injected with Lucifer yellow. 7. Some interneurons make synaptic connections only with antagonist motor neurons that control the movement of one joint. Probably their functional role is to reinforce or to limit the antagonism between each pair of antagonist motor neurons. 8. Other interneurons make synaptic connections with motor neurons innervating muscles controlling different leg joints. These interneurons may play a role in generating the motor patterns that underlie forward and backward walking.     

Muscles express motor patterns of non-innervating neural networks by filtering broad-band input

We describe three slow muscles that responded to low-frequency modulation of a high-frequency neuronal input and, consequently, could express the motor patterns of neural networks whose neurons did not directly innervate the muscles. Two of these muscles responded to different frequency components present in the same input, and as a result each muscle expressed the motor pattern of a different, non-innervating, neural network. In an analogous manner, the distinct dynamics of the multiple intracellular processes that most cells possess may allow each process to respond to, and hence differentiate among, specific frequency ranges present in broad-band input.     

Temporal sparseness of the premotor drive is important for rapid learning in a neural network model of birdsong

Sparse neural codes have been widely observed in cortical sensory and motor areas. A striking example of sparse temporal coding is in the song-related premotor area high vocal center (HVC) of songbirds: The motor neurons innervating avian vocal muscles are driven by premotor nucleus robustus archistriatalis (RA), which is in turn driven by nucleus HVC. Recent experiments reveal that RA-projecting HVC neurons fire just one burst per song motif. However, the function of this remarkable temporal sparseness has remained unclear. Because birdsong is a clear example of a learned complex motor behavior, we explore in a neural network model with the help of numerical and analytical techniques the possible role of sparse premotor neural codes in song-related motor learning. In numerical simulations with nonlinear neurons, as HVC activity is made progressively less sparse, the minimum learning time increases significantly. Heuristically, this slowdown arises from increasing interference in the weight updates for different synapses. If activity in HVC is sparse, synaptic interference is reduced, and is minimized if each synapse from HVC to RA is used only once in the motif, which is the situation observed experimentally. Our numerical results are corroborated by a theoretical analysis of learning in linear networks, for which we derive a relationship between sparse activity, synaptic interference, and learning time. If songbirds acquire their songs under significant pressure to learn quickly, this study predicts that HVC activity, currently measured only in adults, should also be sparse during the sensorimotor phase in the juvenile bird. We discuss the relevance of these results, linking sparse codes and learning speed, to other multilayered sensory and motor systems.     

Electric Field Assisted Patterning of Neuronal Networks for the Study of Brain Functions

It is estimated that about 18 million people worldwide suffer from dementia and it is projected to increase to about 35 million by the year 2025. All types of dementia occur due to an aberration in memory retention and development, caused by malfunctioning neurons. Experimental investigation of the dynamics of neuronal networks is a fundamental step towards understanding how the nervous system works. Activity-dependant modification of synaptic strength is widely recognized as the cellular basis of learning, memory and developmental plasticity. Understanding memory formation and development thus translates to changes in the electrical activity of the neurons. To map the changes in the electrical activity, it is essential to conduct in vitro studies on individual neurons. Hence, there is an enormous need to develop novel ways for the assembly of highly controled neuronal networks. To this end, we used a 5×5 multiple microelectrode array system to spatially arrange neurons by applying a combination of DC and AC fields. We characterized the electric field distribution inside our test platform by using 2-dimensional finite element modeling (FEM) and determined the location of neurons over the electrode array as well as the expected direction of neurite growth. As the first stage in forming a neuronal network, dielectrophoretic AC fields were utilized to separate the neurons from the glial cells and to position the neurons over the electrodes. DC fields were then applied to induce directed neurite growth and achieve network formation. The neurons were obtained from 18 days old rat embryos from wild type Rattus Norvegicus. The technique of using a combination of DC and AC electric fields to achieve network formation has implications in neural engineering, elucidating a new and simpler method to develop and study neuronal networks as compared to conventional microelectrode array techniques.     

Glial-toxin-mediated disruption of spinal cord locomotor network function and its modulation by 5-HT

While it is established that glial cells actively influence neuronal and synaptic properties, the functional effects of glial-neuronal interactions are still not well understood. To address the role of glia at the network level we have examined the effects of the specific gliotoxin L-aminoadipic acid on the locomotor network output and cellular and synaptic properties in the lamprey spinal cord. The gliotoxic effect of aminoadipic acid was associated with a specific depolarization of glial cells. Aminoadipic acid depolarized the membrane potential of spinal cord neurons, suggesting a functional link between glia and neurons. The depolarization was significantly reduced by glutamate receptor antagonists in adults, but by gap junction blockers in larvae, suggesting a developmental difference in glial-neuronal interactions. Aminoadipic acid also reduced the amplitude of monosynaptic excitatory postsynaptic potentials (EPSPs), an effect that was not associated with changes in the presynaptic release probability or postsynaptic response to glutamate. These cellular and synaptic effects of aminoadipic acid were associated with disruption of the locomotor network output. This could not be accounted for by changes in glutamate uptake or potassium buffering by glia, suggesting a direct role for glia in the network. Interestingly, we found that the aminoadipic acid-evoked disruption of network activity and reduction of monosynaptic EPSP amplitudes did not occur in the presence of the endogenous spinal modulator 5-HT. These results thus provide evidence for an active functional role for glial cells in spinal cord locomotor networks, and suggest a potential glial modulatory effect of 5-HT.     

High frequency oscillations in respiratory networks: functionally significant or phenomenological?

Inspiratory activities, whether recorded from medullary neurons, motoneurons or motor nerves, feature prominent oscillations in high (50-120 Hz) and medium (15-50 Hz) frequency ranges. These oscillations have been extensively characterized and are considered signatures of respiratory network activity. Their functional significance, however, if any, remains unknown. Here we review the literature describing the nature and origin of these oscillations as well as their modulation during development and by mechanoreceptive and chemoreceptive feedback, respiratory- and non-respiratory-related behaviors, temperature and anesthesia. We then consider the potential significance of these oscillations for respiratory network function by drawing on analyses of distributed motor and sensory networks of the cortex where current interest in oscillatory activity, and the synchronization of neural discharge that can result, is based on the increased efficacy with which synchronous inputs influence neuronal output, and the role that synchronous activity may play in information coding. We speculate that synchronized oscillations at the network level help coordinate activity in distributed rhythm and pattern generating systems and at the muscle level enhance force development. Data most strongly support that oscillatory synaptic inputs play an important role in controlling timing and pattern of action potential output.     

Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin

With recent progress in neuroscience and stem-cell research, neural transplantation has emerged as a promising therapy for treating CNS diseases. The success of transplantation has been limited, however, by the restricted ability of neural implants to survive and establish neuronal connections with the host. Little is known about the mechanisms responsible for this failure. Neural implantation triggers reactive gliosis, a process accompanied by upregulation of intermediate filaments in astrocytes and formation of astroglial scar tissue. Here we show that the retinas of adult mice deficient in glial fibrillary acidic protein and vimentin, and consequently lacking intermediate filaments in reactive astrocytes and Müller cells, provide a permissive environment for grafted neurons to migrate and extend neurites. The transplanted cells integrated robustly into the host retina with distinct neuronal identity and appropriate neuronal projections. Our results indicate an essential role for reactive astroglial cells in preventing neural graft integration after transplantation.     

Neuronal structure and synaptic distribution of a uropod doser motor neuron in the crayfish terminal ganglion

Summary One of the uropod closer muscles in the crayfish, the adductor exopodite, is innervated by two large identified motor neurons. They were injected intracellularly with horseradish peroxidase or nickel chloride to reveal the structure and distribution of the input and output synapses using electron microscopy. The development of nickel with rubeanic acid greatly improved the tissue preservation at the ultrastructural level compared with ammonium sulphide. Cell bodies of the motor neurons lying in the ventro-lateral cortex of the ganglion are extensively invaginated by glial cells. Input synapses occur directly upon the primary neurite within the neuropil or upon the major anterior neurite. They are most abundant, however, upon the numerous smaller neurites of the motor neuron. The primary neurite in the dorsal region of the neuropil, upon which no synapses were made, is wrapped with glial cells. Occasionally, these two adductor exopodite motor neurons were found as adjacent postsynaptic profiles at the same synapse when both cells were stained simultaneously in the same preparation. In the present study we could not locate any sites of synaptic output which strictly fulfil the structural criteria of a synapse on the processes of the motor neuron. This result is inconsistent with physiological evidence which suggests that spikeless interactions occur between the two adductor exopodite motor neurons and their synergists. This might be the result of two possible features of the interaction: the sites of synaptic output may be limited to a few restricted branches, and the interaction between these motor neurons may depend largely upon electrical synapses.     

Cellular and molecular connections between sleep and synaptic plasticity

The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca(2+) channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal-neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity.     

The neuro-glial-vascular interrelations in genomic instability symptoms

A hallmark of neurodegenerative diseases is impairment of certain aspects of "brain functionality", which is defined as the total input and output of the brain's neural circuits and networks. A given neurodegenerative disorder is characterized by affected network organization and topology, cell numbers, cellular functionality, and the interactions between neural circuits. Neuroscientists generally view neurodegenerative disorders as diseases of neuronal cells; however, recent advances suggest a role for glial cells and an impaired vascular system in the etiology of certain neurodegenerative diseases. It is now clear that brain pathology is, to a very great extent, pathology of neurons, glia and the vascular system as these determine the degree of neuronal death as well as the outcome and scale of the neurological deficit. This review article is focused on the intricate interrelations among neurons, glia, the vascular system, neuronal cells, and the DNA damage response. Here I describe various aspects of neural and glial cell fate and the vascular system in genomic instability disorders including ataxia telangiectasia (A-T) and Nijmegen breakage syndrome.     

Ageing, hippocampal synaptic activity and magnesium.

Ageing is associated with a general decline in physiological functions. Amongst the different aspects of body deterioration, cognitive impairments, and particularly defects in learning and memory, represent one of the most frequent features in the elderly. However, a great variability exists among aged subjects. Clinical reports and experimental data in animal models of ageing have shown that age-associated memory deficits are broadly identical to those induced by damage to the hippocampus. It is therefore not surprising that many functional properties of hippocampal neuronal networks are particularly altered with ageing. Whereas passive membrane properties of neurons are conserved with age, neuronal excitability is altered, in keeping with weaker performances of aged subjects in memory tasks. Synaptic transmission within hippocampal networks also decreases in brain ageing. Deficits concern both glutamatergic and cholinergic pathways, which represent the main excitatory neurotransmitter systems responsible for neuronal communication in the hippocampus. In addition, long-term changes in synaptic transmission, possible cellular substrates for learning and memory, are also impaired in ageing in correlation with cognitive impairments. Neuronal properties and synaptic plasticity closely depend on ion exchanges between intra- and extracellular compartments. Changes in ion regulation during ageing may therefore participate in altering functional properties of neuronal networks. Calcium dysregulation has been extensively investigated in brain ageing but the role of magnesium has received less attention though ageing constitutes a risk factor for magnesium deficit. One of general properties of magnesium at presynaptic fibre terminals is to reduce transmitter release. At the postsynaptic level, it closely controls the activation of the N-methyl-D-aspartate receptor, a subtype of glutamate receptor, which is critical for the expression of long-term changes in synaptic transmission. In addition, magnesium is a cofactor of many enzymes localized either in neurons or in glial cells that control neuronal properties and synaptic plasticity such as protein-kinase C, calcium/calmodulin-dependent protein kinase II and serine racemase. It is therefore likely that a change in magnesium concentration would significantly impair synaptic functions in the aged hippocampus. Experiments addressing this question remain too scarce but recent data indicate that magnesium is involved in age-related deficits in transmitter release, neuronal excitability and in some forms of synaptic plasticity such as long-term depression of synaptic transmission. Further studies are still necessary to better delineate to what extent magnesium contributes to the impaired cellular mechanisms of cognitive functions in the elderly which will help to develop new strategies to minimize age-related memory declines.     

Adaptive Plasticity in Primate Motor Cortex as a Consequence of Behavioral Experience and Neuronal Injury

It is now clear that the motor cortex of adult mammals is capable of widespread functional reorganization. After specific types of motor skill training, the cortical representations of the movements used to perform the task expand, invading adjacent motor representations. After peripheral nerve injury, representations of unaffected muscles expand, invading those of the denervated muscles. After focal cortical injury, representations in the uninjured, adjacent cortical tissue undergo widespread alterations. Specific changes are dependent upon the use of the affected limb during the postinjury period. It now appears likely that motor map alterability results from changes in synaptic efficacy of intrinsic horizontal connections within motor cortex. Taken together, these studies suggest that the neurophysiological circuitry underlying muscle and movement maps within primary motor cortex is continually remodeled throughout an individual's life. The functional organization of motor cortex is constantly reshaped by behavioral demands for the learning of new motor skills.     

Striatum-hippocampus balance: from physiological behavior to interneuronal pathology

In neurological disorders in which the cross-talk between striatal and hippocampal memory systems is affected, such as epilepsy, Down syndrome and Huntington's disease, cell-type specific alterations in synaptic plasticity lead to distinctive patterns causing functional imbalance between the two memory systems. Despite the complex network in which their neuronal activity is likely to be engaged, a common property of striatal and hippocampal neurons is to undergo bidirectional synaptic plasticity that relies on activity of interneurons and correlates with specific learning skills. As interneuronal dysfunction plays a primary role in the pathogenesis of these disorders, interneurons can be viewed as critical elements in neurophysiological substrates of such flexible relationships between these two memory systems.     

Axo-somatic inhibition of projection neurons in the lateral nucleus of amygdala in human temporal lobe epilepsy: an ultrastructural study

Here, we report ultrastructural alterations in the synaptic circuitry of the human amygdala related to neuronal cell densities in surgical specimens of patients suffering from temporal lobe epilepsy (TLE). The neuronal cell densities quantified in the basolateral complex of amygdala were significantly reduced only in the lateral nucleus (LA) of TLE patients as compared to autopsy or non-Ammon’s horn sclerosis (AHS) controls (Nissl staining, immunostaining against the neuronal marker NeuN). For this reason, we focussed on the LA to perform a more detailed quantitative ultrastructural analysis, which revealed an inverse correlation between the number of axo-somatic inhibitory synaptic profiles at the somata of glutamic acid decarboxylase (GAD)-negative projection neurons and the extent of perisomatic fibrillary gliosis. In contrast, the density of GAD-immunoreactive interneurons positively correlated with the number of axo-somatic inhibitory synaptic profiles. The fibrillary material in perisomatic glial cell processes was preferentially labeled by the astroglial marker S100B. In addition, a qualitative study of the dendrites of GAD- and parvalbumin (PARV)-containing interneurons showed that they were often contacted by asymmetrical excitatory synapses. Our results are in line with anatomical data from rodents and cats, which show that amygdalar interneurons form axo-somatic inhibitory synapses on GAD-negative projection neurons, whereas the interneurons themselves receive excitatory input from recurrent collaterals of projection neurons and from cortico- and thalamo-amygdalar afferents. The structural reorganization patterns observed in the GABAergic circuitry are compatible with a reduced feedback or feed forward inhibition of amygdalar projection neurons in human TLE.     

Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis via induction of BMPs

In the mammalian central nervous system, neurogenesis precedes gliogenesis; neurons are primarily generated at the neural stage, whereas most glial cells are generated perinatally and postnatally. However, the signals that regulate this sequence of events remain unclear. Here we show that Wnt signaling induces neuronal and astroglial differentiation but suppresses oligodendroglial differentiation. We observed that precursor cells infected with a retrovirus encoding beta-catenin differentiated into neurons, while astrocytes developed from uninfected precursor cells surrounding infected cells. As neurogenesis proceeded, expression of the bone morphogenetic proteins (BMPs), BMP2, 4 and 7, progressively increased in the cells infected with the retrovirus encoding beta-catenin. Furthermore, treatment of cells with Noggin, a BMP antagonist, completely inhibited astroglial differentiation but partially restored oligodendroglial differentiation. These results suggest that Wnt signaling indirectly regulates gliogenesis by inducing BMPs in neuronal cells. Thus, cooperation between Wnt and BMP signaling may play a key role in determining the sequence of neurogenesis and gliogenesis.     

Growth factors stimulate expression of neuronal and glial miR-132

Brain-specific microRNAs (miRs) and brain-derived neurotrophic factor (BDNF) are both involved in synaptic function. We previously reported that upregulation of miR-132 is involved in BDNF-increased synaptic proteins, including glutamate receptors (NR2A, NR2B, and GluR1) in mature cortical neurons [7]. However, the potential role of other growth factors in miR-132 induction has not been clarified. Here, we examined the effect of growth factors including basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), glial cell line-derived neurotrophic factor (GDNF), and epidermal growth factor (EGF), on expression of miR-132 and glutamate receptors in immature cortical neurons. We found that BDNF and bFGF upregulated levels of miR-132 in cortical cultures, though bFGF failed to increase glutamate receptors such as NR2A, NR2B, and GluR1. IGF-1, GDNF, and EGF did not have a positive influence on miR-132 and glutamate receptors in neuronal cultures. Furthermore, bFGF significantly upregulated miR-132 in cultured astroglial cells, while other growth factors failed to elicit such a response. It is possible that the growth factor-stimulated neuronal and glial action of miR-132 plays a critical role in brain function.