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The intracerebral injection of β-amyloid-containing brain extracts can induce cerebral β-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with β-amyloid-rich extracts induced β-amyloidosis in the brains of β-amyloid precursor protein transgenic mice after prolonged incubation times.

Synaptic plasticity is a key mechanism for chronic pain. It occurs at different levels of the central nervous system, including spinal cord and cortex. Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain. We found that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKMζ in the ACC acts to maintain neuropathic pain. PKMζ could thus be a new therapeutic target for treating chronic pain.

Key Points Insulin-like peptides (ILPs), which comprise insulin, insulin-like growth factor 1 (IGF1) and IGF2, influence overall brain development by affecting proliferation, survival and differentiation of brain cells and by having modulatory roles in the refinement of brain circuitries. Peripheral ILPs enter the brain through the blood–cerebrospinal fluid barrier and blood–brain barrier in a tonic fashion (dependent on circulating levels) and in a phasic manner according to local brain activity. The adult brain is a major target of ILPs; here, they act as modulators of synaptic plasticity to orchestrate and control energy allocation. We propose that central and peripheral ILPs cooperate as a functional network in brain physiology and disease. The brain is a major target of insulin and insulin-like growth factors (IGFs). Fernandez and Torres-Alemán describe how these peptides enter the CNS to reach specific brain areas and review their actions in the developing and adult brain. They propose that insulin and IGFs regulate diverse processes that are all ultimately involved in energy homeostasis. Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy availability. In the adult brain each ILP has distinct effects, but together their actions ultimately regulate energy homeostasis — they affect nutrient sensing and regulate neuronal plasticity to modulate adaptive behaviours involved in food seeking, including high-level cognitive operations such as spatial memory. In essence, the multifaceted activity of ILPs in the brain may be viewed as a system organization involved in the control of energy allocation.

Key Points The 'social brain' is the network of brain regions that are involved in understanding other people, and includes the medial prefrontal cortex (mPFC) and the posterior superior temporal sulcus (pSTS). These regions are key to the process of mentalizing — that is, the attribution of mental states to oneself and to other people. Recent functional neuroimaging research has shown that activity in parts of the social brain during social cognitive tasks changes during adolescence. In particular, there is some indication that activity in the PFC during face-processing tasks increases from childhood to adolescence and then decreases from adolescence to adulthood. Consistent with this, there is evidence that activity in the mPFC during mentalizing tasks decreases between adolescence and adulthood. The prefrontal cortex is one of the brain regions that undergo structural development, including synaptic reorganization, during adolescence. Synaptic density, reflected in grey-matter volume in MRI scans, decreases during adolescence. It is argued that the synaptic reorganization in the PFC might underlie the functional changes that are seen in the social brain during adolescence, as well as the social cognitive changes that are characteristic of this period of life. Social behaviour changes dramatically during adolescence. Sarah-Jayne Blakemore reviews the recent evidence of structural and functional alterations in areas of the social brain during this period and discusses how these changes might contribute to the development of social behaviour in adolescents. An interview with Sarah-Jayne Blakemore is available for download from the Neuropod podcast (April 2008). The term 'social brain' refers to the network of brain regions that are involved in understanding others. Behaviour that is related to social cognition changes dramatically during human adolescence. This is paralleled by functional changes that occur in the social brain during this time, in particular in the medial prefrontal cortex and the superior temporal sulcus, which show altered activity during the performance of social cognitive tasks, such as face recognition and mental-state attribution. Research also indicates that, in humans, these parts of the social brain undergo structural development, including synaptic reorganization, during adolescence. Bringing together two relatively new and rapidly expanding areas of neuroscience — social neuroscience and the study of brain development during adolescence — will increase our understanding of how the social brain develops during adolescence.

Key Points The primary somatosensory cortex is composed of four subregions: Brodmann area 3a (BA3a), which is primarily proprioceptive; BA3b and BA1, which are primarily tactile; and BA2, which combines tactile and proprioceptive information Of the somatosensory cortices, only BA2 and the secondary somatosensory cortex (SII) have direct connections with brain regions that are known to contain neurons that respond to visual and auditory stimuli. This could provide an anatomical pathway for these regions to respond to the sight of other people's somatosensory experiences. SII shows elevated activity when people are touched and when they see other people, and in some studies objects, being touched. BA2 shows elevated activity both when people manipulate objects and when they see the actions of other individuals, especially when these actions are directed at objects. SI and SII are activated when people experience somatic pain and when they attend to other people's somatic pain. Interfering with activity in BA2 and SII impairs the perception of other people's facial expressions. Mirror-touch synaesthetes experience observed touch on their own body, and one-third of the population experiences pain on their own body when they see the injuries of other people. Both groups activate their SI and SII more strongly than other people when viewing the touch and injuries, respectively, of others, linking SI and SII activity with the vivid sharing of other people's somatosensory states. Unlike BA2 and SII, BA3 seems to be exclusively involved in processing our own somatosensory states. This may help to distinguish our own states from those we perceive in others. Anatomical and functional data converge to show that the somatosensory cortices, and BA2 and SII in particular, can contribute to our perception of other people's inner states by activating representations 'as if' we were experiencing similar tactile, proprioceptive and nociceptive stimuli on our own body. Keysers and colleagues review evidence that perceiving the sensations, actions and somatic pain of others induces activation in the somatosensory cortex. Perhaps similar to the mirror system for action understanding, this capacity might contribute to our understanding of other individuals' experiences. The discovery of mirror neurons in motor areas of the brain has led many to assume that our ability to understand other people's behaviour partially relies on vicarious activations of motor cortices. This Review focuses the limelight of social neuroscience on a different set of brain regions: the somatosensory cortices. These have anatomical connections that enable them to have a role in visual and auditory social perception. Studies that measure brain activity while participants witness the sensations, actions and somatic pain of others consistently show vicarious activation in the somatosensory cortices. Neuroscientists are starting to understand how the brain adds a somatosensory dimension to our perception of other people.

Key Points An object can be defined as a 'thing' that is presented to the senses. Thus, an odour object can be defined as a smell that is presented to the olfactory sense. Although the visual and olfactory systems have evolved under different ecological pressures, many of the basic principles underlying visual object perception hold for olfactory object perception. Studies in which olfactory behavioural states and brain activity are monitored simultaneously in the same animal offer a direct way to relate odour object percepts to their underlying cortical signatures. These approaches, in combination with high-resolution functional MRI and multivariate statistical analysis, have advanced our understanding of odour object perception. The human piriform cortex is situated at the junction of the frontal and temporal lobes and is the main recipient of afferent sensory input from the olfactory bulb. Its unique anatomy, physiology and connectivity suggest that this brain region is well-suited for encoding odour objects. Recent data indicate that the piriform cortex is involved in key elements of odour object perception, including feature synthesis, figure–ground segregation, perceptual categorization and discrimination, and attentional selection. The chemical identity of an odour stimulus is encoded in the anterior piriform cortex, whereas the integrated perceptual representation of an odour object is encoded in posterior piriform cortex. Categorical percepts of odour objects take the form of spatially dispersed patterns across the piriform cortex in the apparent absence of localized clusters of activity. These distributed ensemble representations may be crucial for the olfactory brain to execute content-addressable memory and pattern completion, in which object-specific patterns can be fully reconstituted from degraded or noisy odour inputs, helping to achieve perceptual constancy. The principal neocortical projection area of the piriform cortex is the orbitofrontal cortex, which itself sends return projections to the piriform cortex. A plausible hypothesis of olfactory orbitofrontal function is that it provides a top-down signal that helps to resolve odour object representations in the piriform cortex, particularly under conditions of high stimulus uncertainty. The brain encodes representations of smells through the synthesis of different olfactory inputs into a unified whole. Jay Gottfried discusses the central mechanisms of perception of these 'odour objects' and describes the role of the piriform cortex in this process. The stimulus complexity of naturally occurring odours presents unique challenges for central nervous systems that are aiming to internalize the external olfactory landscape. One mechanism by which the brain encodes perceptual representations of behaviourally relevant smells is through the synthesis of different olfactory inputs into a unified perceptual experience — an odour object. Recent evidence indicates that the identification, categorization and discrimination of olfactory stimuli rely on the formation and modulation of odour objects in the piriform cortex. Convergent findings from human and rodent models suggest that distributed piriform ensemble patterns of olfactory qualities and categories are crucial for maintaining the perceptual constancy of ecologically inconstant stimuli.

Chronic fatigue is a typical symptom of neurological diseases, and is most disabling in multiple sclerosis, postpoliomyelitis, poststroke, and in chronic fatigue syndrome. Disorders of neuromuscular junction transmission and metabolic diseases cause muscle fatigability, which is characterised by failure to sustain the force of muscle contraction (peripheral fatigue). Fatigue is also seen in diseases that affect the central, peripheral, and autonomic nervous systems (central fatigue). Enhanced perception of effort and limited endurance of sustained physical and mental activities are the main characteristics of central fatigue. Metabolic and structural lesions that disrupt the usual process of activation in pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centre are implicated in the pathophysiological process of central fatigue. A state of pre-existing relative hypocortisolaemia might sensitise the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress. The contributions of physiological, cognitive, and affective changes underlying fatigue are variable, and treatment is largely symptomatic and rehabilitative.

An inflammatory process in the central nervous system (CNS) is believed to play an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases including Parkinsons disease, Alzheimers disease, prion diseases, multiple sclerosis and HIV-dementia. The inflammatory response is mediated by the activated microglia, the resident immune cells of the CNS, which normally respond to neuronal damage and remove the damaged cells by phagocytosis. Activation of microglia is a hallmark of brain pathology. However, it remains controversial whether microglial cells have beneficial or detrimental functions in various neuropathological conditions. The chronic activation of microglia may in turn cause neuronal damage through the release of potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. Therefore, suppression of microglia-mediated inflammation has been considered as an important strategy in neurodegenerative disease therapy. Several anti-inflammatory drugs of various chemical ingredients have been shown to repress the microglial activation and to exert neuroprotective effects in the CNS following different types of injuries. However, the molecular mechanisms by which these effects occur remain unclear. In recent years, several research groups including ours have attempted to explain the potential mechanisms and signaling pathways for the repressive effect of various drugs, on activation of microglial cells in CNS injury. We provide here a comprehensive review of recent findings of mechanisms and signaling pathways by which microglial cells are activated in CNS inflammatory diseases. This review article further summarizes the role of microglial cells in neurodegenerative diseases and various forms of potential therapeutic options to inhibit the microglial activation which amplifies the inflammation-related neuronal injury in neurodegenerative diseases.

Key Points Combined molecular and functional analyses have revealed that astrocytes are direct, active communication partners of neurons. They comprise a heterogeneous group of cells that are distinguished by their morphology, molecular assembly, functional characteristics and regional distribution within the CNS. Defective astrocytes are involved in various neurological disorders. Dysfunction of glial glutamate transporters seems to represent a spanning phenomenon common to many pathological conditions. The hippocampus of patients with temporal lobe epilepsy shows severe histopathological abnormalities. Recent studies showed that in the sclerotic hippocampus dislocation of water channels (aquaporin 4; AQP4) and reduced expression of inwardly rectifying K + (Kir) channels in astrocytes could contribute to impaired K + buffering and increased seizure propensity. Moreover, dysregulation of glial glutamate uptake, slowed glutamate–glutamine cycling and subsequent extracellular transmitter accumulation seem to contribute to seizure generation in hippocampal sclerosis. Astrocytes contribute to the pathology of sporadic amyotrophic lateral sclerosis (ALS). Dysfunction of glial glutamate transporters causes increases in extracellular glutamate concentrations and excitotoxic neuronal damage. In hereditary forms of ALS, mutations of Cu/Zn superoxide dismutase (SOD1) lead to oxidative stress and aberrant biochemistry in motor neurons and astrocytes. Apparently, fatal dysregulation of neuron–glia interactions leads to neurotoxicity through the release of reactive oxygen species, prostaglandins, mutant SOD1 and neurotransmitters. The realization that several membrane proteins are highly segregated in astrocytes, with AQP4 and Kir channels being prominent examples, provides a molecular basis to view astrocytes as fundamental regulators of neurovascular units. Redistribution and functional impairment of these molecules, which is seen following ischaemia and stroke, suggests that they represent potential targets for therapeutic interventions. Moreover, astrocytes are becoming increasingly recognized as the source of a plethora of regulatory molecules that influence neurogenesis, neuritogenesis and vasculogenesis, and, as such, could function as orchestrators of these processes in development and regeneration. Hepatic insufficiency leads to hyperammonaemia and elevated concentrations of ammonia in cerebrospinal fluid. Enhanced uptake of ammonia/ammonium ions by astrocytes affects the glutamate–glutamine cycle, resulting in swelling, perturbed K + homeostasis and reduced glutamate uptake. Although the role of astrocytes in hepatic encephalopathy has been well studied, a useful molecular target to prevent their dysfunction has not yet been identified. Although a vast body of evidence documents astroglial dysfunction and dysregulation of astroglia-specific functions in various diseases, it seems premature to try to construe a unifying picture from these data. In particular, it is still often unclear whether glial changes are causative of a given disease or represent an accompanying phenomenon. A better definition of astroglial subtypes should promote our understanding of their specific roles in pathophysiology and the development of cell-centred therapeutic approaches. Astrocytes are not mere 'brain glue', but direct, active communication partners of neurons. Seifert and colleagues discuss their roles in the pathogenesis of several neurological disorders, and argue that these cells might present a therapeutic target in treating these diseases. Recent work on glial cell physiology has revealed that glial cells, and astrocytes in particular, are much more actively involved in brain information processing than previously thought. This finding has stimulated the view that the active brain should no longer be regarded solely as a network of neuronal contacts, but instead as a circuit of integrated, interactive neurons and glial cells. Consequently, glial cells could also have as yet unexpected roles in the diseased brain. An improved understanding of astrocyte biology and heterogeneity and the involvement of these cells in pathogenesis offers the potential for developing novel strategies to treat neurological disorders.