The scalable mammalian brain: emergent distributions of glia and neurons

In this paper, we demonstrate that two characteristic properties of mammalian brains emerge when scaling-up modular, cortical structures. Firstly, the glia-to-neuron ratio is not constant across brains of different sizes: large mammalian brains have more glia per neuron than smaller brains. Our analyses suggest that if one assumes that glia number is proportional to wiring, a particular quantitative relationship emerges between brain size and glia-to-neuron ratio that fits the empirical data. Secondly, many authors have reported that the number of neurons underlying one mm² of mammalian cortex is remarkably constant, across both areas and species. Here, we will show that such a constancy emerges when enlarging modular, cortical brain structures. Our analyses thus corroborate recent studies on the mammalian brain as a scalable architecture, providing a possible mechanism to explain some of the principles, constancies and rules that hold across brains of different size.     

The Possible Role of Spike Patterns in Cortical Information Processing

When the same visual stimulus is presented across many trials, neurons in the visual cortex receive stimulus-related synaptic inputs that are reproducible across trials (S) and inputs that are not (N). The variability of spike trains recorded in the visual cortex and their apparent lack of spike-to-spike correlations beyond that implied by firing rate fluctuations, has been taken as evidence for a low S/N ratio. A recent re-analysis of in vivo cortical data revealed evidence for spike-to-spike correlations in the form of spike patterns. We examine neural dynamics at a higher S/N in order to determine what possible role spike patterns could play in cortical information processing. In vivo-like spike patterns were obtained in model simulations. Superpositions of multiple sinusoidal driving currents were especially effective in producing stable long-lasting patterns. By applying current pulses that were either short and strong or long and weak, neurons could be made to switch from one pattern to another. Cortical neurons with similar stimulus preferences are located near each other, have similar biophysical properties and receive a large number of common synaptic inputs. Hence, recordings of a single neuron across multiple trials are usually interpreted as the response of an ensemble of these neurons during one trial. In the presence of distinct spike patterns across trials there is ambiguity in what would be the corresponding ensemble, it could consist of the same spike pattern for each neuron or a set of patterns across neurons. We found that the spiking response of a neuron receiving these ensemble inputs was determined by the spike-pattern composition, which, in turn, could be modulated dynamically as a means for cortical information processing.     

The time window for generation of dendritic spikes by coincidence of action potentials and EPSPs is layer specific in somatosensory cortex

The precise timing of events in the brain has consequences for intracellular processes, synaptic plasticity, integration and network behaviour. Pyramidal neurons, the most widespread excitatory neuron of the neocortex have multiple spike initiation zones, which interact via dendritic and somatic spikes actively propagating in all directions within the dendritic tree. For these neurons, therefore, both the location and timing of synaptic inputs are critical. The time window for which the backpropagating action potential can influence dendritic spike generation has been extensively studied in layer 5 neocortical pyramidal neurons of rat somatosensory cortex. Here, we re-examine this coincidence detection window for pyramidal cell types across the rat somatosensory cortex in layers 2/3, 5 and 6. We find that the time-window for optimal interaction is widest and shifted in layer 5 pyramidal neurons relative to cells in layers 6 and 2/3. Inputs arriving at the same time and locations will therefore differentially affect spike-timing dependent processes in the different classes of pyramidal neurons.     

Structural plasticity at identified synapses during long-term memory in Aplysia

We have used the gill- and siphon-withdrawal reflex of Aplysia californica to determine the morphological basis of the prolonged changes in synaptic effectiveness that underlie long-term habituation and sensitization. We have found that clear structural changes accompany behavioral modification and have demonstrated that these can be detected at the level of identified sensory neuron synapses, a critical site of plasticity for the short-term forms of both types of learning. These alterations occur at two different levels of synaptic organization and include (1) changes in focal regions of synaptic membrane specialization--the number, size and vesicle complement of sensory neuron active zones are larger in sensitized animals and smaller in habituated animals compared with controls--and (2) a parallel but more dramatic and global trend involving modulation of the total number of presynaptic varicosities per sensory neuron. Quantitative analysis of the time course over which these structural alterations occur during sensitization has further demonstrated that changes in the number of varicosities and active zones persist in parallel with the behavioral retention of the memory. This increase in the number of sensory neuron synapses during long-term sensitization in Aplysia is similar to changes in the number of synapses in the mammalian brain following various forms of environmental manipulations and learning (Greenough, 1984). Therefore learning may involve a form of neuronal growth across a broad segment of the animal kingdom, thereby suggesting a role for structural synaptic plasticity during long-term behavioral modifications.     

Neuron-astrocyte interactions in the regulation of brain energy metabolism: a focus on NMR spectroscopy

An adequate and timely production of ATP by brain cells is of cardinal importance to support the major energetic cost of the rapid processing of information via synaptic and action potentials. Recently, evidence has been accumulated to support the view that the regulation of brain energy metabolism is under the control of an intimate dialogue between astrocytes and neurons. In vitro studies on cultured astrocytes and in vivo studies on rodents have provided evidence that glutamate and Na(+) uptake in astrocytes is a key triggering signal regulating glucose use in the brain. With the advent of NMR spectroscopy, it has been possible to provide experimental evidence to show that energy consumption is mainly devoted to glutamatergic neurotransmission and that glutamate-glutamine cycling is coupled in a approximately 1 : 1 molar stoichiometry to glucose oxidation, at least in the cerebral cortex. This improved understanding of neuron-astrocyte metabolic interactions offers the potential for developing novel therapeutic strategies for many neurological disorders that include a metabolic deficit.     

Stereological and allometric studies on neurons and axo-dendritic synapses in the superior cervical ganglia of rats, capybaras and horses

The superior cervical ganglion (SCG) in mammals varies in structure according to developmental age, body size, gender, lateral asymmetry, the size and nuclear content of neurons and the complexity and synaptic coverage of their dendritic trees. In small and medium-sized mammals, neuron number and size increase from birth to adulthood and, in phylogenetic studies, vary with body size. However, recent studies on larger animals suggest that body weight does not, in general, accurately predict neuron number. We have applied design-based stereological tools at the light-microscopic level to assess the volumetric composition of ganglia and to estimate the numbers and sizes of neurons in SCGs from rats, capybaras and horses. Using transmission electron microscopy, we have obtained design-based estimates of the surface coverage of dendrites by postsynaptic apposition zones and model-based estimates of the numbers and sizes of synaptophysin-labelled axo-dendritic synaptic disks. Linear regression analysis of log-transformed data has been undertaken in order to establish the nature of the relationships between numbers and SCG volume (V_scg). For SCGs (five per species), the allometric relationship for neuron number (N) is N=35,067×V_scg^0.781 and that for synapses is N=20,095,000×V_scg^1.328, the former being a good predictor and the latter a poor predictor of synapse number. Our findings thus reveal the nature of SCG growth in terms of its main ingredients (neurons, neuropil, blood vessels) and show that larger mammals have SCG neurons exhibiting more complex arborizations and greater numbers of axo-dendritic synapses.     

Effect of different glucose supply conditions on neuronal energy metabolism

The glucose-excited neurons in brain can sense blood glucose levels and reflect different firing states, which are mainly associated with regulation of blood glucose and energy demand in the brain. In this paper, a new model of glucose-excited neuron in hypothalamus is proposed. The firing properties and energy consumption of this type of neuron under conditions of different glucose levels are simulated and analyzed. The results show that the firing rate and firing duration of the neuron both increase with increasing extracellular glucose levels, but the maximum energy power for an AP is reduced. Further study suggests that the neuron firstly absorbs energy substrates (e.g. glucose) from the blood to prepare for the high energy demand of high-frequency spikes.     

Changes in brain glycogen after sleep deprivation vary with genotype

Sleep has been functionally implicated in brain energy homeostasis in that it could serve to replenish brain energy stores that become depleted while awake. Sleep deprivation (SD) should therefore lower brain glycogen content. We tested this hypothesis by sleep depriving mice of three inbred strains, i.e., AKR/J (AK), DBA/2J (D2), and C57BL/6J (B6), that differ greatly in their sleep regulation. After a 6-h SD, these mice and their controls were killed by microwave irradiation, and glycogen and glucose were quantified in the cerebral cortex, brain stem, and cerebellum. After SD, both measures significantly increased by approximately 40% in the cortex of B6 mice, while glycogen significantly decreased by 20-38% in brain stem and cerebellum of AK and D2 mice. In contrast, after SD, glucose content increased in all three structures in AK mice and did not change in D2 mice. The increase in glycogen after SD in B6 mice persisted under conditions of food deprivation that, by itself, lowered cortical glycogen. Furthermore, the strains that differ most in their compensatory response to sleep loss, i.e., AK and D2, did not differ in their glycogen response. Thus glycogen content per se is an unlikely end point of sleep's functional role in brain energy homeostasis.     

Expression of alpha-synuclein in different brain parts of adult and aged rats.

The synucleins are a family of presynaptic proteins that are abundant in neurons and include alpha-, beta, and gamma-synuclein. Alpha-synuclein (ASN) is involved in several neurodegenerative age-related disorders but its relevance in physiological aging is unknown. In the present study we investigated the expression of ASN mRNA and protein in the different brain parts of the adult (4-month-old) and aged (24-month-old) rats by using RT-PCR technique and Western blot, respectively. Our results indicated that mRNA expression and immunoreactivity of ASN is similar in brain cortex, hippocampus and striatum but markedly lower in cerebellum comparing to the other brain parts. Aging lowers ASN mRNA expression in striatum and cerebellum by about 40%. The immunoreactivity of ASN in synaptic plasma membranes (SPM) from aged brain cortex, hippocampus and cerebellum is significantly lower comparing to adult by 39%, 24% and 65%, respectively. Beta-synuclein (BSN) was not changed in aged brain comparing to adult. Age-related alteration of ASN may affect the nerve terminals structure and function.     

Decabrominated diphenyl ether and methylmercury impair fetal nervous system development in mice at documented human exposure levels

The central nervous system (CNS) is extremely vulnerable to the toxic effects of environmental pollutants during development. Polybrominated diphenyl ethers (PBDEs) are persistent contaminants, increasingly present in the environment and in human tissues. Recent investigations identified a correlation between maternal exposure to PBDEs and impairment in fetal neurobehavioral development, suggesting that these contaminants pose a potential risk for children. We investigated on the potential effects of environmental decabrominated diphenyl ether (decaBDE, the fully brominated congener) on key neurodevelopmental molecules (e.g., synaptic proteins and immature neuron markers) in fetal mouse neurons. Methylmercury was used as reference neurotoxic contaminant and to evaluate its possible synergism with decaBDE. The neurotoxic effects of decaBDE and methylmercury were determined in developing cultured neurons from mouse fetal hippocampus and cerebellum. Neuron death, dendritic branching, synaptic protein expression, markers of immature neurons, and microglia activation were evaluated by immunocytochemistry. Brain samples from prenatally treated embryos were also examined for neurotoxicity signs by immunoblotting and histochemistry. DecaBDE significantly affected (down to 0.4 nM) the number of dendritic branches, and the levels of synaptic proteins and doublecortin in cultured neurons. Prenatal exposure to decaBDE decreased the synaptic proteins and increased the expression of the immature neuron and microglial markers in mouse fetuses. In conclusion, prenatal exposure to realistic (relevant for human exposure) concentrations of decaBDE induces impairment of fetal CNS development in mice, suggesting a potential risk of fetotoxicity in humans. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 23–38, 2015     

The clock input to the first optic neuropil of Drosophila melanogaster expressing neuronal circadian plasticity

In the first optic neuropil (lamina) of the fly's visual system, two interneurons, L1 and L2 monopolar cells, and epithelial glial cells show circadian rhythms in morphological plasticity. These rhythms depend on clock gene period (per) and cryptochrome (cry) expression. In the present study, we found that rhythms in the lamina of Drosophila melanogaster may be regulated by circadian clock neurons in the brain since the lamina is invaded by one neurite extending from ventral lateral neurons; the so-called pacemaker neurons. These neurons and the projection to the lamina were visualized by green fluorescent protein (GFP). GFP reporter gene expression was driven by the cry promotor in cry-GAL4/UAS-GFP transgenic lines. We observed that the neuron projecting to the lamina forms arborizations of varicose fibers in the distal lamina. These varicose fibers do not form synaptic contacts with the lamina cells and are immunoreactive to the antisera raised against a specific region of Schistocerca gregaria ion transport peptide (ITP). ITP released in a paracrine way in the lamina cortex, may regulate the swelling and shrinking rhythms of the lamina monopolar cells and the glia by controlling the transport of ions and fluids across cell membranes at particular times of the day.     

Structure of peripheral synapses: autonomic ganglia

Final motor neurons in sympathetic and parasympathetic ganglia receive synaptic inputs from preganglionic neurons. Quantitative ultrastructural analyses have shown that the spatial distribution of these synapses is mostly sparse and random. Typically, only about 1%-2% of the neuronal surface is covered with synapses, with the rest of the neuronal surface being closely enclosed by Schwann cell processes. The number of synaptic inputs is correlated with the dendritic complexity of the target neuron, and the total number of synaptic contacts is related to the surface area of the post-synaptic neuron. Overall, most neurons receive fewer than 150 synaptic contacts, with individual preganglionic inputs providing between 10 and 50 synaptic contacts. This variation is probably one determinant of synaptic strength in autonomic ganglia. Many neurons in prevertebral sympathetic ganglia receive additional convergent synaptic inputs from intestinofugal neurons located in the enteric plexuses. The neurons support these additional inputs via larger dendritic arborisations together with a higher overall synaptic density. There is considerable neurochemical heterogeneity in presynaptic boutons. Some synapses apparently lack most of the proteins normally required for fast transmitter release and probably do not take part in conventional ganglionic transmission. Furthermore, most preganglionic boutons in the ganglionic neuropil do not form direct synaptic contacts with any neurons. Nevertheless, these boutons may well contribute to slow transmission processes that need not require conventional synaptic structures.     

A quantitative histological study of Golgi II neurons and pale cells in different cerebellar regions of the adult and ageing mouse brain

Two types of medium to large sized neurons are present in the granular layer of the mouse cerebellum. One type has a large nucleus with a prominent nucleolus and a moderate amount of cytoplasm containing Nissl substance. This type corresponds to the classical Golgi II neuron. The second type has a much smaller nucleus (mean diameter 8.4 microns) with a darkly staining nuclear envelope which is almost invariably deeply indented by cytoplasmic intrusions. The nucleolus is smaller and less conspicuous than in Golgi II neurons. These neurons are identical to the pale cells described by Altman and Bayer (1977). The numbers of both types of neuron were estimated in the spinocerebellum, lobus simplex and nodulus in mice aged 6, 15, 22, 25, 28 and 31 months. There was no significant variation in the number of either Golgi II neurons or pale cells with age in any part of the cerebellum. The number of Golgi II neurons per mm3 was similar in all parts of the cerebellum (mean 3560 mm3). This was identical to the mean number of pale cells per mm3 in the spinocerebellum and pontocerebellum but in the nodulus pale cells were much more numerous (mean 41,170 per mm3). It is postulated that pale cells are small Golgi II neurons.     

A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons

Pyramidal neurons in the cerebral cortex span multiple cortical layers. How the excitable properties of pyramidal neuron dendrites allow these neurons to both integrate activity and store associations between different layers is not well understood, but is thought to rely in part on dendritic backpropagation of action potentials. Here we demonstrate that the sign of synaptic plasticity in neocortical pyramidal neurons is regulated by the spread of the backpropagating action potential to the synapse. This creates a progressive gradient between LTP and LTD as the distance of the synaptic contacts from the soma increases. At distal synapses, cooperative synaptic input or dendritic depolarization can switch plasticity between LTD and LTP by boosting backpropagation of action potentials. This activity-dependent switch provides a mechanism for associative learning across different neocortical layers that process distinct types of information.     

星形胶质细胞糖代谢对神经元的支持及保护作用

脑组织有着极其复杂的功能,这些功能的完成有赖于神经元细胞与胶质细胞之间的广泛合作。星形胶质细胞作为人脑内数量最多的细胞,其与神经元细胞之间的相互作用就显得十分重要。葡萄糖代谢途径包括糖酵解,有氧氧化及磷酸戊糖三条途径。其为脑组织维持其正常功能的前提。研究表明星形胶质细胞和神经元在糖代谢方面有着各自的特点,神经元在能量底物及抗氧化应激中对星形胶质细胞糖代谢途径存在一定的依赖性,干扰星形胶质细胞与神经元之间的代谢过程会导致疾病的发生。本综述主要从糖酵解及磷酸戊糖两条糖代谢途径阐述了星形胶质细胞与神经元的关系。这或许会对研究脑的代谢,脑疾病中神经元的损伤机制及如何保护神经元提供全新的视角,并可能为一些疾病的治疗开辟了新的途径。     

Establishment of high reciprocal connectivity between clonal cortical neurons is regulated by the Dnmt3b DNA methyltransferase and clustered protocadherins

Background

The specificity of synaptic connections is fundamental for proper neural circuit function. Specific neuronal connections that underlie information processing in the sensory cortex are initially established without sensory experiences to a considerable extent, and then the connections are individually refined through sensory experiences. Excitatory neurons arising from the same single progenitor cell are preferentially connected in the postnatal cortex, suggesting that cell lineage contributes to the initial wiring of neurons. However, the postnatal developmental process of lineage-dependent connection specificity is not known, nor how clonal neurons, which are derived from the same neural stem cell, are stamped with the identity of their common neural stem cell and guided to form synaptic connections.

Results

We show that cortical excitatory neurons that arise from the same neural stem cell and reside within the same layer preferentially establish reciprocal synaptic connections in the mouse barrel cortex. We observed a transient increase in synaptic connections between clonal but not nonclonal neuron pairs during postnatal development, followed by selective stabilization of the reciprocal connections between clonal neuron pairs. Furthermore, we demonstrate that selective stabilization of the reciprocal connections between clonal neuron pairs is impaired by the deficiency of DNA methyltransferase 3b (Dnmt3b), which determines DNA-methylation patterns of genes in stem cells during early corticogenesis. Dnmt3b regulates the postnatal expression of clustered protocadherin (cPcdh) isoforms, a family of adhesion molecules. We found that cPcdh deficiency in clonal neuron pairs impairs the whole process of the formation and stabilization of connections to establish lineage-specific connection reciprocity.

Conclusions

Our results demonstrate that local, reciprocal neural connections are selectively formed and retained between clonal neurons in layer 4 of the barrel cortex during postnatal development, and that Dnmt3b and cPcdhs are required for the establishment of lineage-specific reciprocal connections. These findings indicate that lineage-specific connection reciprocity is predetermined by Dnmt3b during embryonic development, and that the cPcdhs contribute to postnatal cortical neuron identification to guide lineage-dependent synaptic connections in the neocortex.

     

Pattern Association and Consolidation Emerges from Connectivity Properties between Cortex and Hippocampus

The basic structure of the cortico-hippocampal system is highly conserved across mammalian species. Comparatively few hippocampal neurons can represent and address a multitude of cortical patterns, establish associations between cortical patterns and consolidate these associations in the cortex. In this study, we investigate how elementary anatomical properties in the cortex-hippocampus loop along with synaptic plasticity contribute to these functions. Specifically, we focus on the high degree of connectivity between cortex and hippocampus leading to converging and diverging forward and backward projections and heterogenous synaptic transmission delays that result from the detached location of the hippocampus and its multiple loops. We found that in a model incorporating these concepts, each cortical pattern can evoke a unique spatio-temporal spiking pattern in hippocampal neurons. This hippocampal response facilitates a reliable disambiguation of learned associations and a bridging of a time interval larger than the time window of spike-timing dependent plasticity in the cortex. Moreover, we found that repeated retrieval of a stored association leads to a compression of the interval between cue presentation and retrieval of the associated pattern from the cortex. Neither a high degree of connectivity nor heterogenous synaptic delays alone is sufficient for this behavior. We conclude that basic anatomical properties between cortex and hippocampus implement mechanisms for representing and consolidating temporal information. Since our model reveals the observed functions for a range of parameters, we suggest that these functions are robust to evolutionary changes consistent with the preserved function of the hippocampal loop across different species.     

Developmental patterns of doublecortin expression and white matter neuron density in the postnatal primate prefrontal cortex and schizophrenia

Postnatal neurogenesis occurs in the subventricular zone and dentate gyrus, and evidence suggests that new neurons may be present in additional regions of the mature primate brain, including the prefrontal cortex (PFC). Addition of new neurons to the PFC implies local generation of neurons or migration from areas such as the subventricular zone. We examined the putative contribution of new, migrating neurons to postnatal cortical development by determining the density of neurons in white matter subjacent to the cortex and measuring expression of doublecortin (DCX), a microtubule-associated protein involved in neuronal migration, in humans and rhesus macaques. We found a striking decline in DCX expression (human and macaque) and density of white matter neurons (humans) during infancy, consistent with the arrival of new neurons in the early postnatal cortex. Considering the expansion of the brain during this time, the decline in white matter neuron density does not necessarily indicate reduced total numbers of white matter neurons in early postnatal life. Furthermore, numerous cells in the white matter and deep grey matter were positive for the migration-associated glycoprotein polysialiated-neuronal cell adhesion molecule and GAD65/67, suggesting that immature migrating neurons in the adult may be GABAergic. We also examined DCX mRNA in the PFC of adult schizophrenia patients (n?=?37) and matched controls (n?=?37) and did not find any difference in DCX mRNA expression. However, we report a negative correlation between DCX mRNA expression and white matter neuron density in adult schizophrenia patients, in contrast to a positive correlation in human development where DCX mRNA and white matter neuron density are higher earlier in life. Accumulation of neurons in the white matter in schizophrenia would be congruent with a negative correlation between DCX mRNA and white matter neuron density and support the hypothesis of a migration deficit in schizophrenia.