Compensatory changes in cellular excitability,not synaptic scaling,contribute to homeostatic recovery of embryonic network activity

When neuronal activity is reduced over a period of days, compensatory changes in synaptic strength and/or cellular excitability are triggered, which are thought to act in a manner to homeostatically recover normal activity levels. The time course over which changes in homeostatic synaptic strength and cellular excitability occur are not clear. Although many studies show that 1–2 days of activity block are necessary to trigger increases in excitatory quantal strength, few studies have been able to examine whether these mechanisms actually underlie recovery of network activity. Here, we examine the mechanisms underlying recovery of embryonic motor activity following block of either excitatory GABAergic or glutamatergic inputs in vivo. We find that GABA_A receptor blockade triggers fast changes in cellular excitability that occur during the recovery of activity but before changes in synaptic scaling. This increase in cellular excitability is mediated in part by an increase in sodium currents and a reduction in the fast-inactivating and calcium-activated potassium currents. These findings suggest that compensatory changes in cellular excitability, rather than synaptic scaling, contribute to activity recovery. Further, we find a special role for the GABA_A receptor in triggering several homeostatic mechanisms after activity perturbations, including changes in cellular excitability and GABAergic and AMPAergic synaptic strength. The temporal difference in expression of homeostatic changes in cellular excitability and synaptic strength suggests that there are multiple mechanisms and pathways engaged to regulate network activity, and that each may have temporally distinct functions.     

Rapid metabolic evolution in human prefrontal cortex

Human evolution is characterized by the rapid expansion of brain size and drastic increase in cognitive capabilities. It has long been suggested that these changes were accompanied by modifications of brain metabolism. Indeed, human-specific changes on gene expression or amino acid sequence were reported for a number of metabolic genes, but actual metabolite measurements in humans and apes have remained scarce. Here, we investigate concentrations of more than 100 metabolites in the prefrontal and cerebellar cortex in 49 humans, 11 chimpanzees, and 45 rhesus macaques of different ages using gas chromatography-mass spectrometry (GC-MS). We show that the brain metabolome undergoes substantial changes, both ontogenetically and evolutionarily: 88% of detected metabolites show significant concentration changes with age, whereas 77% of these metabolic changes differ significantly among species. Although overall metabolic divergence reflects phylogenetic relationships among species, we found a fourfold acceleration of metabolic changes in prefrontal cortex compared with cerebellum in the human lineage. These human-specific metabolic changes are paralleled by changes in expression patterns of the corresponding enzymes, and affect pathways involved in synaptic transmission, memory, and learning.     

Development of cortical microstructure in the preterm human brain

Cortical maturation was studied in 65 infants between 27 and 46 wk postconception using structural and diffusion magnetic resonance imaging. Alterations in neural structure and complexity were inferred from changes in mean diffusivity and fractional anisotropy, analyzed by sampling regions of interest and also by a unique whole-cortex mapping approach. Mean diffusivity was higher in gyri than sulci and in frontal compared with occipital lobes, decreasing consistently throughout the study period. Fractional anisotropy declined until 38 wk, with initial values and rates of change higher in gyri, frontal and temporal poles, and parietal cortex; and lower in sulcal, perirolandic, and medial occipital cortex. Neuroanatomical studies and experimental diffusion–anatomic correlations strongly suggested the interpretation that cellular and synaptic complexity and density increased steadily throughout the period, whereas elongation and branching of dendrites orthogonal to cortical columns was later and faster in higher-order association cortex, proceeding rapidly before becoming undetectable after 38 wk. The rate of microstructural maturation correlated locally with cortical growth, and predicted higher neurodevelopmental test scores at 2 y of age. Cortical microstructural development was reduced in a dose-dependent fashion by longer premature exposure to the extrauterine environment, and preterm infants at term-corrected age possessed less mature cortex than term-born infants. The results are compatible with predictions of the tension theory of cortical growth and show that rapidly developing cortical microstructure is vulnerable to the effects of premature birth, suggesting a mechanism for the adverse effects of preterm delivery on cognitive function.     

Metabotropic glutamate and GABAB receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells

Aims/hypothesis: The neurotransmitters glutamate and γ-aminobutyric acid (GABA) could participate in the regulation of the endocrine functions of islets of Langerhans. We investigated the role of the metabotropic glutamate (mGluRs) and GABA_B (GABA_BRs) receptors in this process. Methods: We studied the expression of mGluRs and GABA _BRs in rat and human islets of Langerhans and in pancreatic α-cell and beta-cell lines using RT-PCR and immunoblot analysis. Effects of mGluR and GABA _B R agonists on insulin secretion were determined by radioimmunoassays and enzyme-linked immunoadsorbent assays (ELISAs). Results: We detected mGluR3 and mGluR5 (but not mGluR1, 6 and 7) mRNAs in all of the samples examined. Trace amount of mGluR2 was found in MIN6 beta cells; mGluR4 was identified in rat islets; and mGluR8 expression was detected in rat islets, RINm5F and MIN6 cells. GABA _BR1 a/b and 2 mRNAs were identified in islets of Langerhans and MIN6 cells. The expression of mGluR3, mGluR5, GABA_BR1 a/b and GABA_BR2 proteins was confirmed using specific antibodies. Group I (mGluR1/5) and group II (mGluR2/3) specific mGluR agonists increased the release of insulin in the presence of 3 to 10 mmol/l or 3 to 25 mmol/l glucose, respectively, whereas a group III (mGluR4/6–8) specific agonist inhibited insulin release at high (10–25 mmol/l) glucose concentrations. Baclofen, a GABA_BR agonist, also inhibited the release of insulin but only in the presence of 25 mmol/l glucose. Conclusion/interpretation: These data suggest that mGluRs and GABA_BRs play a role in the regulation of the endocrine pancreas with mechanisms probably involving direct activation or inhibition of voltage dependent Ca²⁺-channels, cAMP generation and G-protein-mediated modulation of K_ATP channels. [Diabetologia (2002) 45: 242–252] Received: 18 September 2001 and in revised form: 5 November 2001     

Rich-club organization of the newborn human brain

Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a “rich club”—a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich-club organization remains intact following premature birth, we reveal significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants.To understand the functional properties of a complex network it is necessary to examine its structural organization and topological properties. In the human brain this can be achieved at a macroscale by tracing white matter connections between brain regions with diffusion MRI; this enables the interrogation of structural network topology in vivo with millimeter-scale spatial resolution, providing complementary evidence to experimental studies (1, 2).Network analysis of the adult human structural connectome has revealed a set of highly connected cortical “hubs” predominantly located in heteromodal association cortex, that provide a foundation for coherent neuronal activation across distal cortical regions (3–5). Further, some hub regions tend to be densely connected to each other, forming a “rich club” comprised of frontal and parietal cortex, precuneus, cingulate and the insula, as well as the hippocampus, thalamus, and putamen (6). Rich-club organization has been identified in a number of complex networks (7) and represents an attractive feature for investigation in the brain because rich-club connections tend to dominate network topology (8). Rich-club architecture appears to be a fundamental feature of the mature mammalian brain with similar organization identified in animal models (9, 10).It has been suggested that the emergence of complex neurological function is associated with the integration of major hubs across the cortex (11, 12), and that the neural connectivity underlying this undergoes substantial remodeling after birth (13, 14). Initial studies of neonatal structural networks have reported only dense local connectivity within segregated modules and few long-distance connections (12, 15). In contrast, functional MRI reveals large-scale dynamic functional networks analogous to those seen in adults (16, 17) and compatible with more advanced cerebral maturation. To address the possibility that the newborn brain may be structurally more developed than previously thought, and to understand better the role of structural network architecture in emergent neurological functions, we have developed an approach to assess the topological development of structural connectivity in the human brain up to the normal time of birth.We used this approach to define network topology at ∼30 and 40 wk of gestation and, in a group of infants studied at both time points, charted the emergence of structural organization. We also explored the specific relations of cortical and deep gray matter hubs in the network. To determine whether network development was independent of environmental factors, we compared healthy term-born subjects with infants prematurely born and exposed to the extrauterine environment. We report that highly ordered cerebral structural connectivity with rich club topology is established by 30 wk gestation; additionally, we identify aspects of network organization that develop during this period and specific features that are disturbed by premature extrauterine life.     

Learning new color names produces rapid increase in gray matter in the intact adult human cortex

The human brain has been shown to exhibit changes in the volume and density of gray matter as a result of training over periods of several weeks or longer. We show that these changes can be induced much faster by using a training method that is claimed to simulate the rapid learning of word meanings by children. Using whole-brain magnetic resonance imaging (MRI) we show that learning newly defined and named subcategories of the universal categories green and blue in a period of 2 h increases the volume of gray matter in V2/3 of the left visual cortex, a region known to mediate color vision. This pattern of findings demonstrates that the anatomical structure of the adult human brain can change very quickly, specifically during the acquisition of new, named categories. Also, prior behavioral and neuroimaging research has shown that differences between languages in the boundaries of named color categories influence the categorical perception of color, as assessed by judgments of relative similarity, by response time in alternative forced-choice tasks, and by visual search. Moreover, further behavioral studies (visual search) and brain imaging studies have suggested strongly that the categorical effect of language on color processing is left-lateralized, i.e., mediated by activity in the left cerebral hemisphere in adults (hence "lateralized Whorfian" effects). The present results appear to provide a structural basis in the brain for the behavioral and neurophysiologically observed indices of these Whorfian effects on color processing.     

系统认识人类心脏整体电活动

Large amounts of information has been generated at the genetic, molecular, and cellular scales of the cardiovascular systems in the past decade. However, we did not integrate this information within and between scales to the level of the whole heart. Therefore, we really know little about the mechanisms under- lying the normal and abnormal electrical activity in the human heart because electrical activity of heart and its alteration occur at the organ level. The study of ionic currents was the major strategy to understand the normal and diseased human cardiac electrical activity in the past years. However, evidence-based medicine has demonstrated that antiarrhythmic drugs （AADs） including flecainide, encainide, moracizine, d-sotalol and amiodarone cannot improve patients＇ survival. Some AADs which block single ionic channel even increase mortality. On the contrary, other strategies such as non-antiarrhythmic drugs （β-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers） and catheter ablation can effectively suppress arrhythmias and improve outcomes, but they do not aim to any ionic channel directly. So, treatment and study of arrhythmias focused only on ionic channels have limitations. Currently, animals such as mice, rats, rabbits and dogs are used extensively in studies of cardiac electrophysiology and arrhythmogenesis. However, species differences in the distribution and kinetics of ionic channels are significant. The limitations of using animal models as means to study electrical activity suggest that we should do our best to improve our understanding of mechanisms underlying the normal and abnormal electrical activity in human heart. Despite great progress in issue, cellular and mo- lecular scales of the cardiovascular systems, we always troubled by a question ： why there are significant difference between genotype and phenotype. Fortunately, recent advances in genomics, proteomics, metabolomics, and genetic engineering have provided information and means to directly explore at will the relationship between genotype and phenotype. In conclusion, it is timely and important to begin integrating muhiscale studies, and thereby systematically understand the electrical activity in the human heart.     

Developmental differences in the sensitivity of spontaneous and miniature IPSCs to ethanol

BACKGROUND: Ethanol (EtOH) consumption by juveniles and adolescents is an important public health problem. Recent studies have indicated that adolescent animals are less sedated by EtOH than adult animals and experience less motor impairment. Thus, human adolescents may be able to consume more EtOH prior to sedation, putting them at greater risk for EtOH addiction and other negative consequences of EtOH use. However, the mechanisms underlying this developmental difference are unknown. One contributing factor may be gamma-aminobutyric acid-A (GABA(A)) receptor-mediated inhibition, which is known to produce sedation. We have shown that evoked, GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) are less powerfully enhanced by EtOH in neurons from juvenile or adolescent animals than in those from adult animals; however, the mechanisms of this developmental difference in sensitivity are unknown. METHODS: Using whole-cell recording, we tested the response of spontaneous and miniature GABA(A) receptor-mediated IPSCs (sIPSCs and mIPSCs) to EtOH in rat hippocampal slices from animals representing two distinct developmental stages: adolescent and adult. RESULTS: We found significantly greater EtOH-induced enhancement of the frequency of sIPSCs in cells from adult animals compared to those from adolescent animals. Although EtOH also increased the frequency of mIPSCs, this effect was not age dependent. EtOH did not significantly affect the kinetics of mIPSCs. CONCLUSIONS: We conclude that the sensitivity of GABA(A) receptor-mediated inhibitory processes to EtOH increases with development from the adolescent period to adulthood, and that this is likely mediated by developmental changes in the effect of EtOH on interneuron excitation.     

快速延迟整流钾通道调节胃肠道自发性电活动

目的探讨快速延迟整流钾通道（etller—a—go-go—relatedgene，erg）在CDI小鼠胃肠道的表达及对胃肠道电活动的影响。方法用逆转录聚合酶链反应（RT-PCR）检测erg mRNA在成年CDI小鼠胃肠道的表达；并用细胞外记录法记录和比较erg通道特异性阻滞剂E-4031干预前后离体结肠慢波电位的变化。结果在CDI小鼠胃肠道不同部位均存在着ergmRNA的表达；E-4031干预后，结肠慢波电位频率减慢（P〈0．01），时程延长（P（0．01），叠加在慢波电位上的快波电位数量增加，幅度增大，但慢波电位的幅度变化无统计学差异（P〉0．05）。结论erg在CDI小鼠胃肠道不同部位表达，ergK^＋通道在调节胃肠道平滑肌自发性电节律过程中扮演了重要的角色。     

Shape-specific preparatory activity mediates attention to targets in human visual cortex

The mechanisms of attention prioritize sensory input for efficient perceptual processing. Influential theories suggest that attentional biases are mediated via preparatory activation of task-relevant perceptual representations in visual cortex, but the neural evidence for a preparatory coding model of attention remains incomplete. In this experiment, we tested core assumptions underlying a preparatory coding model for attentional bias. Exploiting multivoxel pattern analysis of functional neuroimaging data obtained during a non-spatial attention task, we examined the locus, time-course, and functional significance of shape-specific preparatory attention in the human brain. Following an attentional cue, yet before the onset of a visual target, we observed selective activation of target-specific neural subpopulations within shape-processing visual cortex (lateral occipital complex). Target-specific modulation of baseline activity was sustained throughout the duration of the attention trial and the degree of target specificity that characterized preparatory activation patterns correlated with perceptual performance. We conclude that top-down attention selectively activates target-specific neural codes, providing a competitive bias favoring task-relevant representations over competing representations distributed within the same subregion of visual cortex.     

Cell cycle and tissue of origin contribute to the migratory behaviour of human fetal and adult mesenchymal stromal cells

Mesenchymal stromal cells (MSC) are potential cells for cellular therapies, in which the recruitment and migration of MSC towards injured tissue is crucial. Our data show that culture‐expanded MSC from fetal lung and bone marrow, adult bone marrow and adipose tissue contained a small percentage of migrating cells in vitro, but the optimal stimulus was different. Overall, fetal lung‐MSC had the highest migratory capacity. As fetal bone marrow‐MSC had lower migratory potential than fetal lung‐MSC, the tissue of origin may determine the migratory capacity of MSC. No additive effect in migration towards combined stimuli was observed, which suggests only one migratory MSC fraction. Interestingly, actin rearrangement and increased paxillin phosphorylation were observed in most MSC upon stromal cell‐derived factor‐1α or platelet‐derived growth factor‐BB stimulation, indicating that this mechanism involved in responding to migratory cues is not restricted to migratory MSC. Migratory MSC maintained differentiation and migration potential, and contained significantly less cells in S‐ and G2/M‐phase than their non‐migrating counterpart. In conclusion, our results suggest that MSC from various sources have different migratory capacities, depending on the tissue of origin. Similar to haematopoietic stem cells, cell cycle contributes to MSC migration, which offers perspectives for modulation of MSC to enhance efficacy of future cellular therapies.     

阵发性心房颤动大静脉电隔离后肌袖内自发电活动的特点

目的　总结阵发性心房颤动 (房颤 )患者大静脉 (肺静脉和 /或上腔静脉 )电隔离治疗后肌袖内自发电活动的特点 ,探讨其临床意义。方法　顽固性特发性房颤患者 ,在环状标测电极导管指导下行心内电生理标测以及肺静脉和 /或上腔静脉肌袖的射频导管消融电隔离治疗 ,电隔离后继续留置环状标测导管 10～ 2 0min ,观察自发电位发生情况。结果　电隔离前心内标测显示 32例患者的 36根大静脉肌袖有自发电活动。以心房 大静脉传入阻滞为终点行大静脉口部消融后 ,16根 (4 4 % )记录到大静脉内自发电活动 ,其中 2根呈偶发的单一电活动 ,11根呈平均频率 (38± 12 )次 /min的缓慢节律 ,3根呈偶发的由 3～ 6个电位组成的短阵快速节律。 15根示大静脉内电活动与心房完全分离 (93 8% ) ,1根左上肺静脉存在大静脉 心房单向传导。结论　射频导管消融电隔离大静脉后 ,出现心房 大静脉传入阻滞时多同时伴有大静脉 心房传出阻断 ,心房 大静脉传入阻滞后大静脉内的电活动频率明显变慢、减少或消失 ,说明窦性心律时的心房 大静脉传导是引起大静脉内电活动不稳定的重要原因 ,射频导管消融技术即使只阻断心房 大静脉单向传导也可通过稳定大静脉内电活动而减少或控制房颤的发作。     

Maturation of the response of human fetal pancreatic expiants to glucose

Summary The release of insulin from the human pancreas in response to glucose is known to be either poor or absent in the fetus, whereas in the infant and adult, the response is much greater. The maturation of this response was examined systematically in this study using pancreases that were initially obtained at 14–20 weeks gestation and maintained either in culture alone or by passaging them in diabetic nude mice. Stimulation with glucose was carried out in vitro using tissue of ages ranging from 14 to 58 weeks. A response to glucose was initially seen at 25 weeks and this dramatically increased in the fetal tissue that had reached an age of 55 weeks or more. One of the nude mice used for passage developed normoglycaemia and when the pancreatic implant of age 52 weeks was removed, diabetes recurred. Our findings support the idea of the use of human fetal pancreatic tissue in the treatment of diabetes mellitus.     

Proliferation and differentiation in the human fetal endocrine pancreas

Summary The morphogenesis and growth of the endocrine pancreas has not been well investigated in man although it represents an important issue in diabetology. We examined human fetal pancreas from 12 to 41 weeks of gestation immunocytochemically to evaluate proliferative activity with the Ki-67 marker, and cytodifferentiation with cytokeratin 19 (ductal cells), synaptophysin (all endocrine cells), and insulin, glucagon, somatostatin and pancreatic polypeptide (islet cell types). Ki-67 labelling was found in all these cell types but was much higher in ductal cells than in islet cells. An intermediate population expressed synaptophysin but lacked islet hormones. With increasing gestational age the Ki-67 labelling index decreased from 17 to 4 % in ductal cells, from 9 to 1 % in synaptophysin-positive cells, and from 3 to 0.1 % in insulin- or glucagon-positive cells. From 12 to 16 weeks, all epithelial cells including the endocrine islet cells expressed cytokeratin 19. Thereafter cytokeratin 19 expression decreased and eventually disappeared from most islet cells, whereas strong expression remained in the ductal cells. We show that differentiated human islet cells have only very limited proliferative capacity, and we demonstrate the existence of transitional differentiation stages between ductal and islet cells. [Diabetologia (1997) 40: 398–404] Received: 8 November 1996 and in revised form: 7 January 1997     

Testosterone synthesis and adenylate cyclase activity in the early human fetal testis appear to be independent of human chorionic gonadotropin control

Androgen secretion by the fetal testis is essential for male phenotypic differentiation. In the human fetus testosterone formation is initiated soon after the differentiation of the testis (approximately 8 weeks of gestation), and the maximal testosterone content in fetal testes is achieved between 10 and 15 weeks of fetal life. The testosterone content of the fetal testis declines at the beginning of the third trimester and remains low until after birth. In an effort to understand the regulation of the onset of testosterone formation in the human fetal testis we measured adenylate cyclase activity in response to hCG stimulation in homogenates of fetal testes obtained from first and second trimester human abortuses. Basal adenylate cyclase activity was 50 pmol/mg protein.min at 10 weeks gestation, the peak activity was 137 pmol/mg protein.min at 12 weeks gestation, and activity declined thereafter to 8 pmol/mg protein.min by 16 weeks gestation. NaF-stimulated (0.6 mmol/L) and forskolin-stimulated (50 mumol/L) activities were 4- to 8-fold greater than basal adenylate cyclase activities. The maximal forskolin-stimulated activity occurred at 11 weeks (803 pmol/mg protein.min), and it fell to 35 pmol/mg protein.min by 17 weeks gestation. In contrast, hCG-stimulated (1 mumol/L) adenylate cyclase activity was only slightly greater than basal rates at all ages examined. In addition, hCG did not stimulate baseline testosterone formation in minces of testes obtained between 12 and 18 weeks of gestation. These findings suggest that the onset of testosterone formation in human fetal testes may be independent of gonadotropin control.     

From the Cover: Communication consumes 35 times more energy than computation in the human cortex,but both costs are needed to predict synapse number

Darwinian evolution tends to produce energy-efficient outcomes. On the other hand, energy limits computation, be it neural and probabilistic or digital and logical. Taking a particular energy-efficient viewpoint, we define neural computation and make use of an energy-constrained computational function. This function can be optimized over a variable that is proportional to the number of synapses per neuron. This function also implies a specific distinction between adenosine triphosphate (ATP)-consuming processes, especially computation per se vs. the communication processes of action potentials and transmitter release. Thus, to apply this mathematical function requires an energy audit with a particular partitioning of energy consumption that differs from earlier work. The audit points out that, rather than the oft-quoted 20 W of glucose available to the human brain, the fraction partitioned to cortical computation is only 0.1 W of ATP [L. Sokoloff, Handb. Physiol. Sect. I Neurophysiol. 3, 1843–1864 (1960)] and [J. Sawada, D. S. Modha, “Synapse: Scalable energy-efficient neurosynaptic computing” in Application of Concurrency to System Design (ACSD) (2013), pp. 14–15]. On the other hand, long-distance communication costs are 35-fold greater, 3.5 W. Other findings include 1) a 108-fold discrepancy between biological and lowest possible values of a neuron’s computational efficiency and 2) two predictions of N, the number of synaptic transmissions needed to fire a neuron (2,500 vs. 2,000).

The purpose of the brain is to process information, but that leaves us with the problem of finding appropriate definitions of information processing. We assume that given enough time and given a sufficiently stable environment (e.g., the common internals of the mammalian brain), then Nature’s constructions approach an optimum. The problem is to find which function or combined set of functions is optimal when incorporating empirical values into these function(s). The initial example in neuroscience is ref. 1, which shows that information capacity is far from optimized, especially in comparison to the optimal information per joule which is in much closer agreement with empirical values. Whenever we find such an agreement between theory and experiment, we conclude that this optimization, or near optimization, is Nature’s perspective. Using this strategy, we and others seek quantified relationships with particular forms of information processing and require that these relationships are approximately optimal (1–7). At the level of a single neuron, a recent theoretical development identifies a potentially optimal computation (8). To apply this conjecture requires understanding certain neuronal energy expenditures. Here the focus is on the energy budget of the human cerebral cortex and its primary neurons. The energy audit here differs from the premier earlier work (9) in two ways: The brain considered here is human not rodent, and the audit here uses a partitioning motivated by the information-efficiency calculations rather than the classical partitions of cell biology and neuroscience (9). Importantly, our audit reveals greater energy use by communication than by computation. This observation in turn generates additional insights into the optimal synapse number. Specifically, the bits per joule optimized computation must provide sufficient bits per second to the axon and presynaptic mechanism to justify the great expense of timely communication. Simply put from the optimization perspective, we assume evolution would not build a costly communication system and then not supply it with appropriate bits per second to justify its costs. The bits per joule are optimized with respect to N, the number of synaptic activations per interpulse interval (IPI) for one neuron, where N happens to equal the number of synapses per neuron times the success rate of synaptic transmission (below).To measure computation, and to partition out its cost, requires a suitable definition at the single-neuron level. Rather than the generic definition “any signal transformation” (3) or the neural-like “converting a multivariate signal to a scalar signal,” we conjecture a more detailed definition (8). To move toward this definition, note two important brain functions: estimating what is present in the sensed world and predicting what will be present, including what will occur as the brain commands manipulations. Then, assume that such macroscopic inferences arise by combining single-neuron inferences. That is, conjecture a neuron performing microscopic estimation or prediction. Instead of sensing the world, a neuron’s sensing is merely its capacitive charging due to recently active synapses. Using this sampling of total accumulated charge over a particular elapsed time, a neuron implicitly estimates the value of its local latent variable, a variable defined by evolution and developmental construction (8). Applying an optimization perspective, which includes implicit Bayesian inference, a sufficient statistic, and maximum-likelihood unbiasedness, as well as energy costs (8), produces a quantified theory of single-neuron computation. This theory implies the optimal IPI probability distribution. Motivating IPI coding is this fact: The use of constant amplitude signaling, e.g., action potentials, implies that all information can only be in IPIs. Therefore, no code can outperform an IPI code, and it can equal an IPI code in bit rate only if it is one to one with an IPI code. In neuroscience, an equivalent to IPI codes is the instantaneous rate code where each message is IPI−1. In communication theory, a discrete form of IPI coding is called differential pulse position modulation (10); ref. 11 explicitly introduced a continuous form of this coding as a neuron communication hypothesis, and it receives further development in ref. 12.Results recall and further develop earlier work concerning a certain optimization that defines IPI probabilities (8). An energy audit is required to use these developments. Combining the theory with the audit leads to two outcomes: 1) The optimizing N serves as a consistency check on the audit and 2) future energy audits for individual cell types will predict N for that cell type, a test of the theory. Specialized approximations here that are not present in earlier work (9) include the assumptions that 1) all neurons of cortex are pyramidal neurons, 2) pyramidal neurons are the inputs to pyramidal neurons, 3) a neuron is under constant synaptic bombardment, and 4) a neuron’s capacitance must be charged 16 mV from reset potential to threshold to fire.Following the audit, the reader is given a perspective that may be obvious to some, but it is rarely discussed and seemingly contradicts the engineering literature (but see ref. 6). In particular, a neuron is an incredibly inefficient computational device in comparison to an idealized physical analog. It is not just a few bits per joule away from optimal predicted by the Landauer limit, but off by a huge amount, a factor of 108. The theory here resolves the efficiency issue using a modified optimization perspective. Activity-dependent communication and synaptic modification costs force upward optimal computational costs. In turn, the bit value of the computational energy expenditure is constrained to a central limit like the result: Every doubling of N can produce no more than 0.5 bits. In addition to 1) explaining the 108 excessive energy use, other results here include 2) identifying the largest “noise” source limiting computation, which is the signal itself, and 3) partitioning the relevant costs, which may help engineers redirect focus toward computation and communication costs rather than the 20-W total brain consumption as their design goal.     

Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence

Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating “movies” of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with “masculinization” of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.