Abstract Prenatal stress (PS) has been linked to abnormal cognitive, behavioral and psychosocial outcomes in both animals and humans. Animal studies have clearly demonstrated PS effects on the offspring's brain, however, while it has been speculated that PS most likely affects the brains of exposed human fetuses as well, no study has to date examined this possibility prospectively using an independent stressor (i.e., a stressful event that the pregnant woman has no control over, such as a natural disaster). The aim of this review is to summarize the existing animal literature by focusing on specific brain regions that have been shown to be affected by PS both macroscopically and microscopically. These regions include the hippocampus, amygdala, corpus callosum, anterior commissure, cerebral cortex, cerebellum and hypothalamus. We first discuss the mechanisms by which the effects of PS might occur. In particular, we show that maternal and fetal hypothalamic–pituitary–adrenal (HPA) axes, and the placenta, are the most likely candidates for these mechanisms. We see that, although animal studies have obvious advantages over human studies, the integration of findings in animals and the transfer of these findings to human populations remains a complex issue. Finally, we show how it is possible to circumvent these challenges by studying the effects of PS on brain development directly in humans, by taking advantage of natural or man-made disasters and assessing the impact and consequences of such stressful events on pregnant women and their offspring prospectively.
Abstract The vestibular system provides the brain with sensory signals about three-dimensional head rotations and translations. These signals are important for postural and oculomotor control, as well as for spatial and bodily perception and cognition, and they are subtended by pathways running from the vestibular nuclei to the thalamus, cerebellum and the “vestibular cortex.” The present review summarizes current knowledge on the anatomy of the thalamocortical vestibular system and discusses data from electrophysiology and neuroanatomy in animals by comparing them with data from neuroimagery and neurology in humans. Multiple thalamic nuclei are involved in vestibular processing, including the ventroposterior complex, the ventroanterior–ventrolateral complex, the intralaminar nuclei and the posterior nuclear group (medial and lateral geniculate nuclei, pulvinar). These nuclei contain multisensory neurons that process and relay vestibular, proprioceptive and visual signals to the vestibular cortex. In non-human primates, the parieto-insular vestibular cortex (PIVC) has been proposed as the core vestibular region. Yet, vestibular responses have also been recorded in the somatosensory cortex (area 2v, 3av), intraparietal sulcus, posterior parietal cortex (area 7), area MST, frontal cortex, cingulum and hippocampus. We analyze the location of the corresponding regions in humans, and especially the human PIVC, by reviewing neuroimaging and clinical work. The widespread vestibular projections to the multimodal human PIVC, somatosensory cortex, area MST, intraparietal sulcus and hippocampus explain the large influence of vestibular signals on self-motion perception, spatial navigation, internal models of gravity, one's body perception and bodily self-consciousness.
Abstract Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence implicating IL-6 in brain-related processes originated from its dysregulated expression in several neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. In addition, IL-6 was shown to be involved in multiple physiological CNS processes such as neuron homeostasis, astrogliogenesis and neuronal differentiation. The molecular mechanisms underlying IL-6 functions in the brain have only recently started to emerge. In this review, an overview of the latest discoveries concerning the actions of IL-6 in the nervous system is provided. The central position of IL-6 in the neuroinflammatory reaction pattern, and more specifically, the role of IL-6 in specific neurodegenerative processes, which accompany Alzheimer's disease, multiple sclerosis and excitotoxicity, are discussed. It is evident that IL-6 has a dichotomic action in the CNS, displaying neurotrophic properties on the one hand, and detrimental actions on the other. This is in agreement with its central role in neuroinflammation, which evolved as a beneficial process, aimed at maintaining tissue homeostasis, but which can become malignant when exaggerated. In this perspective, it is not surprising that ‘well-meant’ actions of IL-6 are often causing harm instead of leading to recovery.
Abstract Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d -serine; (ii) nucleotides, like adenosine 5′-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis.
Abstract The purpose of this article is to review the recent developments of abnormal mitochondrial dynamics, mitochondrial fragmentation, and neuronal damage in neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The GTPase family of proteins, including fission proteins, dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1), and fusion proteins (Mfn1, Mfn2 and Opa1) are essential to maintain mitochondrial fission and fusion balance, and to provide necessary adenosine triphosphate to neurons. Among these, Drp1 is involved in several important aspects of mitochondria, including shape, size, distribution, remodeling, and maintenance of mitochondria in mammalian cells. In addition, recent advancements in molecular, cellular, electron microscopy, and confocal imaging studies revealed that Drp1 is associated with several cellular functions, including mitochondrial and peroxisomal fragmentation, phosphorylation, SUMOylation, ubiquitination, and cell death. In the last two decades, tremendous progress has been made in researching mitochondrial dynamics, in yeast, worms, and mammalian cells; and this research has provided evidence linking Drp1 to neurodegenerative diseases. Researchers in the neurodegenerative disease field are beginning to recognize the possible involvement of Drp1 in causing mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases. This article summarizes research findings relating Drp1 to mitochondrial fission and fusion, in yeast, worms, and mammals. Based on findings from the Reddy laboratory and others', we propose that mutant proteins of neurodegenerative diseases, including AD, PD, HD, and ALS, interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics, ultimately causing mitochondrial dysfunction and neuronal damage.
Abstract Astrocytes as a cell population are not well defined and comprise a heterogeneous population of cells. There are at least 9 different morphological variants which can coexist within one given brain region. Human astrocytes have a considerably more complex morphology as their rodent counterparts. There are also a number of functional differences depending on brain region and developmental stage in the normal (not pathologic) brain. Astrocytes can differ in functional gap junctional coupling, expression of transmitter receptors, membrane currents, and glutamate transporters. We feel that astrocyte heterogeneity has not yet been thoroughly explored and what we report here will just be a beginning of a new field of research.
Abstract Neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system. All forms in neuropathology therefore inevitably involve glia. The neurodegenerative diseases disrupt connectivity within brain circuits affecting neuronal–neuronal, neuronal–glial and glial–glial contacts. In addition neurodegenerative processes trigger universal and conserved glial reactions represented by astrogliosis and microglial activation. The complex of recently acquired knowledge allows us to regard the neurodegenerative diseases as primarily gliodegenerative processes, in which glial cells determine the progression and outcome of neuropathological process.
Abstract Our brain does not process incoming sensory stimuli mechanistically. Instead the current brain state modulates our reaction to a stimulus. This modulation can be investigated by cognitive paradigms such as the attentional blink, which reveal that identical visual target stimuli are correctly reported only on about half the trials. Support for the notion that the fluctuating state of the brain determines stimulus detection comes from electrophysiological investigations of brain oscillations, which have shown that different parameters of ongoing oscillatory alpha activity (~ 10 Hz) can predict whether a visual stimulus will be perceived or not. The present article reviews recent findings on the role of prestimulus alpha oscillatory activity for visual perception and incorporates these results into a neurocognitive model that is able to account for various findings in temporal attention paradigms, specifically the attentional blink.
Existing evidence indicates that mu and other alpha-like rhythms are independent phenomena because of differences in source gene. ration, sensitivity to sensory events, bilateral coherence, frequency, and power. Although mu suppression and enhancement echo sensorimotor processing in frontoparietal networks, they are also sensitive to cognitive and affective influences and likely reflect more than an idling brain state. Mu rhythms are present at early stages of human development and in other mammalian species. They exhibit adaptive and dynamically changing properties, including frequency acceleration and posterior-to-anterior shifts in focus. Furthermore, individuals can learn to control mu rhythms volitionally in a very short period of time. This raises questions about the mu rhythm's open neural architecture and ability to respond to cognitive, affective, and motor imagery, implying an even greater developmental and functional role than has previously been ascribed to it. Recent studies have suggested that mu rhythms reflect downstream modulation of motor cortex by prefrontal mirror neurons, i.e., cells that may play a critical role in imitation learning and the ability to understand the actions of others. It is proposed that mu rhythms represent an important information processing function that links perception and action - specifically, the transformation of "seeing" and "hearing" into "doing." In a broader context, this transformation function results from an entrainment/gating mechanism in which multiple alpha networks (visual-, auditory-, and somatosensory-centered domains), typically producing rhythmic oscillations in a locally independent manner, become coupled and entrained. A global or 'diffuse and distributed alpha system' comes into existence when these independent sources of alpha become coherently engaged in transforming perception to action. (c) 2005 Elsevier B.V. All rights reserved.
Abstract The proposal on the existence of two main modes of intercellular communication in the central nervous system (CNS) was introduced in 1986 and called wiring transmission (WT) and volume transmission (VT). The major criterion for this classification was the different characteristics of the communication channel with physical boundaries well delimited in the case of WT (axons and their synapses; gap junctions) but not in the case of VT (the extracellular fluid filled tortuous channels of the extracellular space and the cerebrospinal fluid filled ventricular space and sub-arachnoidal space). The basic dichotomic classification of intercellular communication in the brain is still considered valid, but recent evidence on the existence of unsuspected specialized structures for intercellular communication, such as microvesicles (exosomes and shedding vesicles) and tunnelling nanotubes, calls for a refinement of the original classification model. The proposed updating is based on criteria which are deduced not only from these new findings but also from concepts offered by informatics to classify the communication networks in the CNS. These criteria allowed the identification also of new sub-classes of WT and VT, namely the “tunnelling nanotube type of WT” and the “Roamer type of VT.” In this novel type of VT microvesicles are safe vesicular carriers for targeted intercellular communication of proteins, mtDNA and RNA in the CNS flowing in the extracellular fluid along energy gradients to reach target cells. In the tunnelling nanotubes proteins, mtDNA and RNA can migrate as well as entire organelles such as mitochondria. Although the existence and the role of these new types of intercellular communication in the CNS are still a matter of investigation and remain to be fully demonstrated, the potential importance of these novel types of WT and VT for brain function in health and disease is discussed.
Abstract Epilepsy comprises a group of disorders characterized by the periodic occurrence of seizures. Currently available anticonvulsant drugs and therapies are insufficient to controlling seizure activity in about one third of epilepsy patients. Thus, there is an urgent need for new therapies that prevent the genesis of the disorder and improve seizure control in individuals already afflicted. The vast majority of epileptic cases are of idiopathic origin, and a deeper understanding of the cellular basis of hyperactivity and synchronization is essential. Neurosurgical specimens from patients with temporal lobe epilepsy typically demonstrate marked reactive gliosis. Since recent studies have implicated astrocytes in important physiological roles in the CNS, such as synchronization of neuronal firing, it is plausible that they may also have a role in seizure generation or seizure spread. In support of this view, several membrane channels, receptors and transporters in the astrocytic membrane have been found to be deeply altered in the epileptic brain, and they are now gradually emerging as new potential targets for antiepileptic therapeutic strategies. This review summarizes current evidence regarding astroglial dysfunction in epilepsy and discusses presumed underlying mechanisms.
Abstract The first scientific and experimental approaches to the study of cerebrospinal fluid (CSF) formation began almost a hundred years ago. Despite researchers being interested for so long, some aspects of CSF formation are still insufficiently understood. Today it is generally believed that CSF formation is an active energy consuming metabolic process which occurs mainly in brain ventricles, in choroid plexuses. CSF formation, together with CSF absorption and circulation, represents the so-called classic hypothesis of CSF hydrodynamics. In spite of the general acceptance of this hypothesis, there is a considerable series of experimental results that do not support the idea of the active nature of CSF formation and the idea that choroid plexuses inside the brain ventricles are the main places of formation. The main goal of this review is to summarize the present understanding of CSF formation and compare this understanding to contradictory experimental results that have been obtained so far. And finally, to try to offer a physiological explanation by which these contradictions could be avoided. We therefore analyzed the main methods that study CSF formation, which enabled such an understanding, and presented their shortcomings, which could also be a reason for the erroneous interpretation of the obtained results. A recent method of direct aqueductal determination of CSF formation is shown in more detail. On the one hand, it provides the possibility of direct insight into CSF formation, and on the other, it clearly indicates that there is no net CSF formation inside the brain ventricles. These results are contradictory to the classic hypothesis and, together with other mentioned contradictory results, strongly support a recently proposed new working hypothesis on the hydrodynamics of CSF. According to this new working hypothesis, CSF is permanently produced and absorbed in the whole CSF system as a consequence of filtration and reabsorption of water volume through the capillary walls into the surrounding brain tissue. The CSF exchange between the entire CSF system and the surrounding tissue depends on (patho)physiological conditions that predominate within those compartments.
Abstract The NG2 proteoglycan is a type 1-transmembrane protein expressed by a range of cell types within and outside the mammalian nervous system. NG2-expressing (NG2) cells are found in grey and white matter tracts of the developing and adult CNS and have previously been assumed to represent oligodendrocyte precursor cells: new work using transgenic mice has shown that NG2 cells generate oligodendrocytes, protoplasmic astrocytes and in some instances neurons in vivo. NG2 cells express GABAA receptors and the AMPA subtype of glutamate receptors. They make intimate contact to neurons prior to myelinating axons and also form electron-dense synaptic specialisations with axons in the cerebellum, cortex and hippocampus and with non-myelinated axons in the corpus callosum. These synaptic NG2 cells respond to neuronal release of glutamate and GABA. This neuron–glia interaction may thus regulate the differentiation and proliferation of NG2 cells. The C-terminal PDZ-binding motif of the NG2 protein binds several PDZ proteins including Mupp1, Syntenin and the Glutamate Receptor Interacting Protein (GRIP). Since GRIP can bind subunits of the AMPA receptors expressed by NG2 cells, the interaction between GRIP and NG2 may orientate the glial AMPA receptors towards sites of neuronal glutamate release. The origin, heterogeneity and function of NG2 cells as modulators of the neuronal network are important incompletely resolved questions.
Abstract The classical view of glial cells as simple supportive cells for neurons is being replaced by a new vision in which glial cells are active elements involved in the physiology of the nervous system. This new vision is based on the fact that astrocytes, a subtype of glial cells in the CNS, are stimulated by synaptically released neurotransmitters, which increase the astrocyte Ca2+ levels and stimulate the release of gliotransmitters that regulate synaptic efficacy and plasticity. Consequently, our understanding of synaptic function, previously thought to exclusively result from signaling between neurons, has also changed to include the bidirectional signaling between neurons and astrocytes. Hence, astrocytes have been revealed as integral elements involved in the synaptic physiology, therefore contributing to the processing, transfer and storage of information by the nervous system. Reciprocal communication between astrocytes and neurons is therefore part of the intercellular signaling processes involved in brain function.
Abstract The cerebellum is classically considered to be a brain region involved in motor processing, but it has also been implicated in non-motor, and even cognitive, functions. Though previous research suggests that the cerebellum responds to noxious stimuli, its specific role during pain is unclear. Pain is a multidimensional experience that encompasses sensory discriminative, affective motivational, and cognitive evaluative components. Cerebellar involvement during the processing of pain could thus potentially reflect a number of different functional processes. This review will summarize the animal and human research to date that indicates that (1) primary afferents conduct nociceptive (noxious) input to the cerebellum, (2) electrical and pharmacological stimulation of the cerebellum can modulate nociceptive processing, and (3) cerebellar activity occurs during the presence of acute and chronic pain. Possible functional roles for the cerebellum relating to pain will be considered, including perspectives relating to emotion, cognition, and motor control in response to pain.
Abstract Functional magnetic resonance imaging (fMRI) has become the dominant means of measuring behavior-related neural activity in the human brain. Yet the relation between the blood oxygen-level dependent (BOLD) signal and underlying neural activity remains an open and actively researched question. A widely accepted model, established for sensory neo-cortex, suggests that the BOLD signal reflects peri-synaptic activity in the form of the local field potential rather than the spiking rate of individual neurons. Several recent experimental results, however, suggest situations in which BOLD, spiking, and the local field potential dissociate. Two different models are discussed, based on the literature reviewed to account for this dissociation, a circuitry-based and vascular-based explanation. Both models are found to account for existing data under some testing situations and in certain brain regions. Because both the vascular and local circuitry-based explanations challenge the BOLD-LFP coupling model, these models provide guidance in predicting when BOLD can be expected to reflect neural processing and when the underlying relation with BOLD may be more complex than a direct correspondence.
Increasing levels of circulating estradiol during the follicular phase of the ovarian cycle act on the brain to trigger a sudden and massive release of gonadotropin-releasing hormone (GnRH) that evokes the pituitary luteinizing hormone surge responsible for ovulation in mammals. The mechanisms through which estrogen is able to exert this potent "positive feedback" influence upon the GnRH neurons are beginning to be unravelled. Recent studies utilizing mouse models with global and cell-specific deletions of the different estrogen receptors (ERs) have shown that estrogen positive feedback is likely to use an indirect pathway involving the modulation of ER alpha-expressing neurons that project to GnRH neurons. Conventional tract tracing studies in rats, and experiments involving conditional pseudorabies virus tract tracing from GnRH neurons in the transgenic mouse, indicate that the dominant populations of ER alpha-expressing neuronal afferents to GnRH neurons reside in the anteroventral periventricular, median preoptic and periventricular preoptic nuclei. Together these estrogen-sensitive afferents to GnRH neurons form a periventricular continuum that can be referred to as rostral periventricular area of the third ventricle (RP3V) neurons. The neurochemical identity of some RP3V neurons has been determined and there is mounting evidence for important roles of glutamate, GABA, kisspeptin and neurotensin-expressing RP3V neurons in estrogen positive feedback. The definition of the key cluster of estrogen-sensitive neurons responsible for activating the GnRH neurons to evoke the GnRH surge (and ovulation) should be of substantial value to on-going efforts to understand the molecular and cellular basis of the estrogen positive feedback mechanism. (c) 2007 Elsevier B.V. All rights reserved.
Abstract The major glial population of the brain is constituted by astroglia. Highly branched and ramified protoplasmic astrocytes are the predominant form in grey matter and are found in almost all regions of the central nervous system. In cerebellum and retina, there two forms of elongated radial glia exist (Bergmann glia and Müller cells, respectively) that share many features with the protoplasmic astrocytes in respect to their perisynaptic association. Although these three astroglial cell types are different in their gross morphology, they are characterized by a polarized orientation of their processes. While one or only few processes have contacts with CNS boundaries such as capillaries and pia, an overwhelming number of thin filopodia- and lamellipodia-like process terminals contact and enwrap synapses, the sites of neuronal communication. The perisynaptic glial processes are the primary compartments that sense neuronal activity. After signal integration, they can also modulate synaptic transmission, thereby contributing to neural plasticity. Despite their importance, the mechanisms that (1) target astroglial processes toward pre- and postsynaptic compartments and (2) control the interaction during plastic events of the brain such as learning or injury are poorly understood. This review will summarize our current knowledge and highlight some open questions.
Abstract The concept of the tripartite synapse proposes that in addition to the presynapse and the postsynaptic membrane closely apposed processes of astrocytes constitute an integral part of the synapse. Accordingly, astrocytes may influence synaptic activity by various ways. Thus glia- and neuron-derived neurotrophins, cytokines and metabolites influence neuronal survival, synaptic activity and plasticity. Beyond these facts, the past years have shown that astrocytes are required for synaptogenesis, the structural maintenance and proper functioning of synapses. In particular, astrocytes seem to play a key role in the organization of the brain's extracellular matrix (ECM) — most prominently the so-called perineuronal nets (PNNs), complex macromolecular assemblies of ECM components. Due to progress in cellular and molecular neurosciences, it has been possible to decipher the composition of ECM structures and to obtain insight into their function(s) and underlying mechanisms. It appears that PNN-related structures are involved in regulating the sprouting and pruning of synapses, which represents an important morphological correlate of synaptic plasticity in the adult nervous system. Perturbation assays and gene elimination by recombinant techniques have provided clear indications that astrocyte-derived ECM components, e.g. the tenascins and chondroitinsulfate proteoglycans (CSPGs) of the lectican family participate in these biological functions. The present review will discuss the glia-derived glycoproteins and CSPGs of the perisynaptic ECM, their neuronal and glial receptors, and in vitro assays to test their physiological functions in the framework of the synapse, the pivotal element of communication in the central nervous system.
Abstract Prenatal ethanol exposure is invariably detrimental to the developing central nervous system and the hippocampus is particularly sensitive to the teratogenic effects of ethanol. Prenatal ethanol exposure has been shown to result in hippocampal cell loss, altered neuronal morphology and impaired performance on hippocampal-dependent learning and memory tasks in rodents. The dentate gyrus (DG) of the hippocampus is one of the few brain regions where neurogenesis continues into adulthood. This process appears to have functional significance and these newly generated neurons are believed to play important functions in learning and memory. Recently, several groups have shown that adult hippocampal neurogenesis is compromised in animal models of fetal alcohol spectrum disorders (FASD). The direction and magnitude of any changes in neurogenesis, however, appear to depend on a variety of factors that include: the rodent model used; the blood alcohol concentration achieved; the developmental time point when alcohol was administered; and the frequency of ethanol exposure. In this review we will provide an overview of the different rodent models of FASD that are commonly used in this research, emphasizing each of their strengths and limitations. We will also present an up-to-date summary on the effects of prenatal/neonatal ethanol exposure on adult hippocampal neurogenesis and cell loss, highlighting some of the possible molecular mechanisms that might be involved.