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Key Points Cost control and complex topology are important aspects of the organization of human and other nervous systems. Efficient transfer of information between modules of brain networks confers functional advantages in terms of adaptive behaviour, but it imposes a premium in terms of wiring cost. Brain networks negotiate an economical trade-off between minimizing wiring cost and maximizing expensive but advantageous topological properties such as efficiency. Brain networks can renegotiate trade-offs between cost and efficiency dynamically over short and long timescales. High-cost components of human brain networks may be particularly vulnerable to abnormal development or pathological attack, leading to disorders of cognition or behaviour. On the basis of data from brain network science, Bullmore and Sporns propose that brain organization is shaped by an economical trade-off between minimizing wiring cost and maximizing the efficiency of information transfer between neuronal populations and discuss this idea in the context of psychiatric and neurological disorders. The brain is expensive, incurring high material and metabolic costs for its size — relative to the size of the body — and many aspects of brain network organization can be mostly explained by a parsimonious drive to minimize these costs. However, brain networks or connectomes also have high topological efficiency, robustness, modularity and a 'rich club' of connector hubs. Many of these and other advantageous topological properties will probably entail a wiring-cost premium. We propose that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations. This process of negotiating, and re-negotiating, trade-offs between wiring cost and topological value continues over long (decades) and short (millisecond) timescales as brain networks evolve, grow and adapt to changing cognitive demands. An economical analysis of neuropsychiatric disorders highlights the vulnerability of the more costly elements of brain networks to pathological attack or abnormal development.

Key Points Excitatory synapses in the brain, which use glutamate as the primary neurotransmitter, represent a crucial target for the action of stress and its mediators. Mounting evidence suggests that stress, along with the associated hormonal and neurochemical mediators (particularly glucocorticoids), induces changes in glutamate release, transmission and metabolism in cortical and limbic brain areas, thereby influencing cognitive and emotional processing and behaviour. Depending on age, gender, duration and the type of the stressors experienced, stress may either have beneficial effects on cognitive and emotional functions or induce noxious and maladaptive changes in brain tissue, which have been linked to the development of neuropsychiatric disorders. Acute stress enhances glutamatergic synaptic transmission in the prefrontal cortex and other limbic regions, thereby facilitating certain cognitive functions. Acute stress increases glutamate release, membrane trafficking of AMPA and NMDA receptors, and potentially glutamate clearance in the prefrontal cortex through various mechanisms that involve glucocorticoid regulation. Chronic stress has been associated with a loss of glutamate receptors, impaired glutamate cycling and a suppression of glutamate transmission that may be attributable to the observed impairment of prefrontal cortex-dependent cognitive functions. These findings suggest that a new line of drug development aimed at minimizing the effects of chronic stress exposure on the function of the glutamatergic neurotransmitter system may prove beneficial in clinical settings. Straightforward pharmacological intervention on different regulatory sites of the glutamate synapse is a possible strategy for bypassing the unmet therapeutic needs posed by traditional drugs based on monoaminergic mechanisms. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission in the prefrontal cortex and the hippocampus. Sanacora and colleagues review these studies and discuss the relevance of these mechanisms for normal brain functioning and for the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders. Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.

Key Points Individual differences are a hallmark of cognitive and synaptic ageing. Neurobiological differences between individuals of the same chronological age may underlie the preservation of cognitive abilities in advanced age versus cognitive impairment. In general, age-related cognitive impairments that occur in the absence of neurodegenerative diseases are not associated with loss of cortical neurons. Instead, they seem to be associated with subtle synaptic alterations. The prefrontal cortex controls higher-order, complex behaviours. A hallmark of cognitive ageing is impaired prefrontal function, including impairments in spatial working memory. One synaptic correlate of age-related impairments in working memory that has been identified in monkeys is a loss of thin spines in layer 3 of the dorsolateral prefrontal cortex. The medial temporal lobe, including the hippocampus, is responsible for memories of everyday events. Mild impairments in medial temporal lobe function are also observed in cognitive ageing. A range of synaptic alterations in hippocampal function that correlate with age-related memory impairments have been described. These have been observed in all subfields of the hippocampus and differ between subfields. A notable synaptic alteration in the aged monkey hippocampus is the loss of multisynaptic boutons in the dentate gyrus, which correlates with cognitive impairments. Cyclical oestradiol treatment of aged, surgically menopausal monkeys increases the density of thin dendritic spines in the prefrontal cortex and improves working memory. This illustrates the potential of synaptic and cognitive changes in ageing to be reversible. Loss of synapses may predispose neurons to degeneration in disease states. Thus, a better understanding of mechanisms that promote stability of synapses in ageing should lead not only to amelioration of age-related cognitive impairments but may also affect vulnerability to neurodegenerative diseases. Normal ageing is associated with impairments in cognitive function, including memory, and with specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. The authors describe these structural changes reported in monkeys and rodents, how they might affect age-associated cognitive decline and potential strategies to limit their impact. Normal ageing is associated with impairments in cognitive function, including memory. These impairments are linked, not to a loss of neurons in the forebrain, but to specific and relatively subtle synaptic alterations in the hippocampus and prefrontal cortex. Here, we review studies that have shed light on the cellular and synaptic changes observed in these brain structures during ageing that can be directly related to cognitive decline in young and aged animals. We also discuss the influence of the hormonal status on these age-related alterations and recent progress in the development of therapeutic strategies to limit the impact of ageing on memory and cognition in humans.

Key Points Recent advances have provided evidence that the loss of pre-existing synapses and the assembly and retention of new synapses may be integral components of behavioural learning and memory processes. Specific synapse gains and losses have been related conclusively to animal learning and to structural traces of the learning. Causality relationships between the new assembly of identified synapses upon learning and the behavioural expression of the learned memories could be established in at least one case. Learning triggers enhanced synapse turnover, and repeated training produces a selective long lasting retention of some of the new synapses. These are frequently clustered spatially. Mutations in many gene products important for synapse stabilization are associated with mental retardation and psychiatric conditions. Long-term potentiation experiments in slice cultures have revealed that new synapses tend to be retained in spatial clusters, suggesting mechanisms of local co-regulation for synapses that may involve the same or related learning-related memories. Behaviourally related synapses are assembled and lost within spatially close (<2 μm) stretches of dendrites in vivo , suggesting that they may encode specific memories. Enhanced plasticity promoting learning, for example, upon environmental enrichment, involves higher rates of both synapse assembly and disassembly. The presence of larger numbers of dynamic synapses before learning may facilitate learning. Reducing inhibition enhances plasticity, and augmenting inhibition closes critical periods of increased plasticity during early postnatal life. Likewise, enhancing excitation also enhances plasticity. In the adult, plasticity is reduced by molecular mechanisms that function as 'brakes' on plasticity. Structural plasticity involving inhibitory neurons can precede that by excitatory neurons and may have a critical role in regulating circuit plasticity during learning. Mechanisms regulating plasticity during critical periods of development and in the adult may involve similar major roles for inhibitory connectivity regulation. Challenges for future research include: defining the relationships between gains and losses of identified individual synapses upon learning, and the memory of what was learned at the microcircuit and systems level; and relating genes involved in psychiatric conditions to synapse and microcircuit remodelling upon learning under control and disease conditions. Future progress will depend on methods to monitor the structure and function of synaptic networks in vivo , as well as on the development of synaptic network models that combine changes in synaptic function and connectivity. Behavioural learning is accompanied by loss and gain of synapses, which is thought to be the mechanism by which circuits are altered and 'memory traces' established. Recent research, reviewed here, suggests that learning and memory events involve the rearrangement of ensembles of adjacent synapses on short stretches of dendrites. Recent studies have provided long-sought evidence that behavioural learning involves specific synapse gain and elimination processes, which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover, which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co-occur spatially within short stretches of dendrites, and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity.

Key Points GABA B receptors (GABA B Rs) are the G protein-coupled receptors for the inhibitory neurotransmitter GABA. Activation of these receptors is involved in pre- and postsynaptic inhibition, regulation of Ca 2+ and K + channels and rhythmic network activity. GABA B Rs are composed of principal GABA B1a , GABA B1b and GABA B2 subunits, which form the core of the receptor, and auxiliary KCTD8, KCTD12, KCTD12b and KCTD16 subunits, which differentially modulate receptor properties. Principal subunits form functional GABA B(1a,2) and GABA B(1b,2) heterodimers that form higher-order oligomers and bind tetramers of KCTD proteins. The principal subunits regulate the surface expression and the axonal versus dendritic distribution of GABA B Rs, whereas the auxiliary subunits determine agonist potency and the kinetics of the receptor response. Phosphorylation of the principal subunits is a prime mechanism regulating GABA B R endocytosis, recycling and degradation. GABA B Rs engage in intracellular signalling crosstalk with metabotropic and NMDA-type glutamate receptors, allowing integration of inhibitory and excitatory signals at a cellular level. GABA B Rs are implicated in a variety of neurological and psychiatric conditions. Drugs that target receptor subtypes, defined by the KCTD proteins present, may allow more-specific therapeutic interference of GABA B R-mediated signalling. GABA B receptor activity is integral to the proper functioning of many neural systems. In this Review, Gassmann and Bettler examine our understanding of the subunit composition of such receptors and how this affects GABA B receptor properties, neuronal processes and higher brain functions. GABA B receptors (GABA B Rs) are G protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the CNS. In the past 5 years, notable advances have been made in our understanding of the molecular composition of these receptors. GABA B Rs are now known to comprise principal and auxiliary subunits that influence receptor properties in distinct ways. The principal subunits regulate the surface expression and the axonal versus dendritic distribution of these receptors, whereas the auxiliary subunits determine agonist potency and the kinetics of the receptor response. This Review summarizes current knowledge on how the subunit composition of GABA B Rs affects the distribution of these receptors, neuronal processes and higher brain functions.

Key Points The cerebellum is involved in motor learning, yet the precise forms of plasticity that may underlie this form of memory formation are still under debate. Recent advances in mouse transgenics and phenomics have provided new pieces of evidence as to how different forms of plasticity at synaptic and extrasynaptic sites in the cerebellar cortex may act together to mediate particular aspects of motor learning. By systematically reviewing all forms of plasticity in the granule cell network and Purkinje cell network and integrating the behavioural phenotypes that can be observed following manipulation of these forms of plasticity, we propose that plasticity in the cerebellar cortex operates in a distributed and synergistic manner. Mediated mainly by input from the mossy fibres, plasticity in the granular layer may serve to spread diversity of coding, while climbing fibre-guided plasticity in the molecular layer may serve to select the appropriate coding required for the specific spatiotemporal demands of the motor learning paradigm involved. Owing to the distributed and synergistic character of cerebellar cortical plasticity guided by common afferent inputs, there is ample room for compensatory mechanisms so as to warrant the consecutive processes of motor performance, motor learning and motor consolidation. In this Review, De Zeeuw and colleagues discuss the types of plasticity that occur at different synapses within the cerebellar cortex. They propose that the distributed and synergistic character of the various forms of plasticity promotes optimal motor learning. Studies on synaptic plasticity in the context of learning have been dominated by the view that a single, particular type of plasticity forms the underlying mechanism for a particular type of learning. However, emerging evidence shows that many forms of synaptic and intrinsic plasticity at different sites are induced conjunctively during procedural memory formation in the cerebellum. Here, we review the main forms of long-term plasticity in the cerebellar cortex that underlie motor learning. We propose that the different forms of plasticity in the granular layer and the molecular layer operate synergistically in a temporally and spatially distributed manner, so as to ultimately create optimal output for behaviour.

Key Points Comprehensive knowledge of the architecture of neuronal networks lies at the basis of understanding their functions. Although the anatomical connections between and within the hippocampal formation (HF) and the parahippocampal region (PHR) have been and still are being investigated extensively, for several reasons some of the PHR–HF network connections have become underexposed and this probably results in biased functional concepts. We present a comprehensive interactive knowledge base of all anatomically established PHR–HF connections in the rat. Using this knowledge base, the PHR–HF circuitry is discussed and special attention is paid to underexposed connections. The role of some of these underexposed connections is discussed in relation to three topics that are strongly associated with the PHR–HF network: memory formation, navigation and temporal dynamics. Generally it is thought that only the HF is involved in memory formation, through associating different types of information. Based on the connections observed in the interactive diagram of the knowledge base, we pose that the entorhinal cortex associates information prehippocampally at a more generic level than the HF. The CA3 recurrent network is the most prominent auto-associative network in the hippocampus and is implicated in pattern-separation and pattern-completion tasks that are relevant for memory. However, there are also recurrent networks in the hilus of the dentate gyrus, CA1 and the subiculum. They might also serve a unique role in memory, but they receive little attention. Detailed anatomical knowledge lies at the basis of the discovery of grid cells that are important for navigation. Based on details of the entorhinal–hippocampal connections, we propose that there will be differences in the modulation of firing patterns along the transverse axis in CA1 and the subiculum. The proximal part of CA1 and the distal subiculum will preferentially process spatial information, whereas the distal part of CA1 and the proximal subiculum will process non-spatial information. Although most track-tracing studies do not reveal whether a connection is excitatory or inhibitory, we suggest that some of the known connections between regions of the network are likely to be identified as inhibitory interneuron projections, based on their layer of origin. These long-range GABA (γ-aminobutyric acid)-ergic connections probably mediate interregional binding. Sources of detailed knowledge, such as that presented in this Review and the accompanying interactive diagram, will prevent the loss of valuable knowledge and hopefully inspire creative minds to come up with new solutions for outstanding problems in the field. The connections within and between the hippocampus and the parahippocampal region form an intricate network. Here, Witter and colleagues present an interactive diagram of all known connections in these regions and discuss possible functional implications of some of the underexposed projections. Converging evidence suggests that each parahippocampal and hippocampal subregion contributes uniquely to the encoding, consolidation and retrieval of declarative memories, but their precise roles remain elusive. Current functional thinking does not fully incorporate the intricately connected networks that link these subregions, owing to their organizational complexity; however, such detailed anatomical knowledge is of pivotal importance for comprehending the unique functional contribution of each subregion. We have therefore developed an interactive diagram with the aim to display all of the currently known anatomical connections of the rat parahippocampal–hippocampal network. In this Review, we integrate the existing anatomical knowledge into a concise description of this network and discuss the functional implications of some relatively underexposed connections.

Key Points TAR DNA-binding protein 43 (TDP43) protein is a predominantly nuclear RNA-binding protein that is involved in multiple aspects of RNA processing, including the regulation of pre-mRNA splicing and mRNA stability. TDP43 protein is the major constituent of ubiquitylated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). These inclusions are usually mislocalized within the cytoplasm and are associated with a loss of normal nuclear TDP43 expression. Pathologic TDP43 exhibits a characteristic biochemical profile including ubiquitylation, phosphorylation and cleavage. Ubiquitylation of TDP43 is associated with attempts to degrade TDP43 protein. The identification of disease-associated ubiquilin 2 (UBQLN2) mutations indicates that abnormal protein degradation pathways may lead to TDP43 pathology. TDP43 phosphorylation, cleavage and cytoplasmic localization are all associated with TDP43 aggregation. Data from experimental models suggest that these factors are not absolutely required for TDP43-mediated neurodegeneration. A variety of genetic mutations with diverse functions lead to TDP43 pathology. Dysregulation of TDP43 seems to be a common final pathway that is tightly associated with neurodegeneration. The absence of normal nuclear TDP43 protein in affected neurons is consistent with a loss-of-nuclear-function mechanism of neurodegeneration. Nuclear clearance may be mechanistically linked to the ability of TDP43 protein to autoregulate its cognate RNA. The involvement of the RNA-binding protein TDP43 in neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration, has become well established. However, the mechanisms by which the protein is linked to the disease process remain unclear. Trojanowski and colleagues describe our current understanding of TDP43 pathology and discuss how gains of toxic function or losses of normal TDP43 function may contribute to neurodegeneration. RNA-binding proteins, and in particular TAR DNA-binding protein 43 (TDP43), are central to the pathogenesis of motor neuron diseases and related neurodegenerative disorders. Studies on human tissue have implicated several possible mechanisms of disease and experimental studies are now attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein. In addition, the distinct possibility of pleotropic or combined effects — in which gains of toxic properties and losses of normal TDP43 functions act together — needs to be considered.

Exercise is known to induce a cascade of molecular and cellular processes that support brain plasticity. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin that is also intimately connected with central and peripheral molecular processes of energy metabolism and homeostasis, and could play a crucial role in these induced mechanisms. This review provides an overview of the current knowledge on the effects of acute exercise and/or training on BDNF in healthy subjects and in persons with a chronic disease or disability. A systematic and critical literature search was conducted. Articles were considered for inclusion in the review if they were human studies, assessed peripheral (serum and/or plasma) BDNF and evaluated an acute exercise or training intervention. Nine RCTs, one randomized trial, five non-randomized controlled trials, five non-randomized non-controlled trials and four retrospective observational studies were analysed. Sixty-nine percent of the studies in healthy subjects and 86%of the studies in persons with a chronic disease or disability, showed a ‘mostly transient’ increase in serum or plasma BDNF concentration following an acute aerobic exercise. The two studies regarding a single acute strength exercise session could not show a significant influence on basal BDNF concentration. In studies regarding the effects of strength or aerobic training on BDNF, a difference should be made between effects on basal BDNF concentration and training-induced effects on the BDNF response following an acute exercise. Only three out of ten studies on aerobic or strength training (i.e. 30%) found a training-induced increase in basal BDNF concentration. Two out of six studies (i.e. 33%) reported a significantly higher BDNF response to acute exercise following an aerobic or strength training programme (i.e. compared with the BDNF response to an acute exercise at baseline). A few studies of low quality (i.e. retrospective observational studies) show that untrained or moderately trained healthy subjects have higher basal BDNF concentrations than highly trained subjects. Yet, strong evidence still has to come from good methodological studies. Available results suggest that acute aerobic, but not strength exercise increases basal peripheral BDNF concentrations, although the effect is transient. From a few studies we learn that circulating BDNF originates both from central and peripheral sources. We can only speculate which central regions and peripheral sources in particular circulating BDNF originates from, where it is transported to and to what purpose it is used and/or stored at its final destination. No study could show a long-lasting BDNF response to acute exercise or training (i.e. permanently increased basal peripheral BDNF concentration) in healthy subjects or persons with a chronic disease or disability. It seems that exercise and/or training temporarily elevate basal BDNF and possibly upregulate cellular processing of BDNF (i.e. synthesis, release, absorption and degradation). From that point of view, exercise and/or training would result in a higher BDNF synthesis following an acute exercise bout (i.e. compared with untrained subjects). Subsequently, more BDNF could be released into the blood circulation which may, in turn, be absorbed more efficiently by central and/or peripheral tissues where it could induce a cascade of neurotrophic and neuroprotective effects.

ABSTRACTThe ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.