Actin in the nervous system

Since synaptic plasticity is an important property of the brain, it is timely to try to understand the possible mechanisms underlying this phenomenon. The role of the cytoplasm for neuronal functions has until now been largely overlooked, the main emphases being on the plasma membrane for fast electrical events and on cytoplasmic organelles for the slower metabolic processes. However, recent studies on the cytoplasm of non-muscle cells have stressed the importance of contractile proteins, like actin, on maintaining the cell shape and a number of vital cellular functions which may be related to the phase transitions in the cytoplasm. The necessary versatility is conferred on the actin networks by actin-associated proteins and by the free cytosolic calcium. In the nervous system, in addition to actin and myosin, a number of actin regulatory proteins was recently isolated, and they were shown to have properties similar to those of other non-muscle cells. Consequently, actin networks in neurons like those in non-muscle cells may be capable of contraction and phase transitions. The phase transitions have a rapid onset, and they may be quickly terminated or they may last over extended periods of time. In this way actin networks may gain control over the state of the cytoplasm and hence over the function of the neuron. Actin may be therefore uniquely suited to regulate various plastic reactions. The cytoplasm of growth cones and dendritic spines contains solely actin networks and is devoid of microtubules and neurofilaments. Since both these structures contain myosin and since growth cones are endowed with a considerable motility, dendritic spines also may have a likewise property. The necessary regulation of the levels of free cytosolic calcium may be provided by the spine apparatus in addition to calcium pumps in the plasma membrane and calcium regulatory proteins in the spine cytoplasm. Various types of stimulation which change the level of free cytosolic calcium may induce contraction of the spine actin network which may be responsible for the morphometric changes observed following different experimental interventions and pathological conditions. Although most of the conclusions in this review are rather speculative they may provide directions for future research in the spine and synaptic plasticity.     

Actin in the nervous system

Since synaptic plasticity is an important property of the brain, it is timely to try to understand the possible mechanisms underlying this phenomenon. The role of the cytoplasm for neuronal functions has until now been largely overlooked, the main emphases being on the plasma membrane for fast electrical events and on cytoplasmic organelles for the slower metabolic processes. However, recent studies on the cytoplasm of non-muscle cells have stressed the importance of contractile proteins, like actin, on maintaining the cell shape and a number of vital cellular functions, which may be related to the phase transitions in the cytoplasm. The necessary versatility is conferred on the actin networks by actin-associated proteins and by the free cytosolic calcium. In the nervous system, in addition to actin and myosin, a number of actin regulatory proteins was recently isolated, and they were shown to have properties similar to those of other non-muscle cells. Consequently, actin networks in neurons like those in non-muscle cells may be capable of contraction and phase transitions. The phase transitions have a rapid onset, and they may be quickly terminated or they may last over extended periods of time. In this way actin networks may gain control over the state of the cytoplasm and hence over the function of the neuron. Actin may be, therefore, uniquely suited to regulate various plastic reactions. The cytoplasm of growth cones and dendritic spines contains solely actin networks and is devoid of microtubules and neurofilaments. Since both these structures contain myosin and since growth cones are endowed with a considerable motility, dendritic spines also may have a likewise property. The necessary regulation of the levels of free cytosolic calcium may be provided by the spine apparatus in addition to calcium pumps in the plasma membrane and calcium regulatory proteins in the spine cytoplasm. Various types of stimulation which change the level of free cytosolic calcium may induce contraction of the spine actin network which may be responsible for the morphometric changes observed following different experimental interventions and pathological conditions. Although most of the conclusions in this review are rather speculative, they may provide directions for future research in the spine and synaptic plasticity.     

Affectivity in the nervous system

Affectivity is an ambiguous term, related altogether to, mood, well-being, ill-being, emotional states, and at the same time to individual sensitivity, capacity to feel moved, as well as feelings and passions. We want to show that those states, as different as they may seem, belong to the perception by the central nervous system of past or present modifications, of an organism reacting to situations it has to cope with. Opposite to common opinion, this affectivity is not "generated" by the cerebral cortex but by the central brain. It results from memory input by the limbic system and from information processing by the hypothalamus and the reticular system, and from processing of mood and emotional rates provoked by self reactions in order to perpetuate survival, protection or one's own species. Considered as "favourable" or "unfavourable" after analyses by the limbic cortex, those states become in the central brain "pleasure" or "aversion", and generate motivation for action, to follow-on or to stop. From the limbic cortex, those motivations are transmitted to the contiguous prefrontal cortex. The prefrontal cortex is a center for action imitation. One may imagine it as a center for conscious cortical activity and for affective memory. This organisation of affectivity and affective memory settings in 2 different centers and at two different levels of the nervous system: the limbic cortex and the prefrontal neo-cortex. The prefrontal neo-cortex only is conscious, but the limbic cortex, although unconscious, is a source of motivation. One is led to describe an unconscious affectivity. It is impossible to talk about this affectivity without mentioning Freud's unconscious.     

Oxidative injury in the nervous system

A free radical is a highly reactive chemical species that can react with organic macromolecules leading to cell and tissue damage and consequent functional disruption. Free radical or oxidative injury is increasingly recognized as an important factor in the pathophysiology of many human diseases, including those that affect the nervous system. This review summarizes important evidence implicating oxidative injury in the pathogenesis and progression of many important neurological disorders, including cerebrovascular disease, epilepsy, amyotrophic lateral sclerosis, and Huntington's disease. Results of controlled clinical trials of various antioxidant therapies in neurological disease performed to date are also highlighted.     

Gliogenesis in the central nervous system

Multipotential neuroepithelial stem cells are thought to give rise to all the differentiated cells of the central nervous system (CNS). The developmental potential of these multipotent stem cells becomes more restricted as they differentiate into progressively more committed cells and ultimately into mature neurons and glia. In studying gliogenesis, the optic nerve and spinal cord have become invaluable models and the progressive stages of differentiation are being clarified. Multiple classes of glial precursors termed glial restricted precursors (GRP), oligospheres, oligodendrocyte-type2 astrocyte (O-2A) and astrocyte precursor cells (APC) have been identified. Similar classes of precursor cells can be isolated from human neural stem cell cultures and from embryonic stem (ES) cell cultures providing a non-fetal source of such cells. In this review, we discuss gliogenesis, glial stem cells, putative relationships of these cells to each other, factors implicated in gliogenesis, and therapeutic applications of glial precursors.     

Hemangiopericytomas in the central nervous system

Hemangiopericytomas, which are more aggressive than meningiomas, are rare in the central nervous system (CNS). We analyzed the clinical, radiological and histological features and treatment of 26 patients with hemangiopericytomas in the CNS. The ratio of male to female patients was 1:1. Most tumors were located in the parasagittal and falx regions. The tumors were dense or mixed as assessed by CT scans, and most were homogeneously enhanced. Most tumors were isointense on T1-weighted MRI, and high or mixed intensity on T2-weighted MRI; they were homogeneously or heterogeneously enhanced. Histological examination indicated numerous small vascular spaces in the tumor. All tumors were immunohistochemically positive for vimentin. All patients were treated with surgery, and some of them underwent subsequent radiotherapy. The recurrence rate for hemangiopericytoma in this study was high. Our observations suggest that the biological behavior of hemangiopericytoma differs markedly from that of meningioma. Surgical removal and post-operative radiotherapy are thus critical for the treatment of this tumor.     

Lactoferrin in the central nervous system

Lactoferrin (LF) is a protein secreted by the tissues of ectodermal origin. Its structure is similar to transferrin. LF appeared to be multifunctional, but its main functions are connected with the natural defense system of mammals. The biological role and origin of LF within brain in normal and disease processes are as yet uncharted. LF expression is greatly upregulated during neurodegenerative disorders and in elderly brains. LF may exert an antiinflammatory function via its inhibitory effect on hydroxyl radical formation. By antioxydative properties, LF prevents DNA damage and consequently tumor formation in the CNS. Moreover, LF specifically transactivates the p53 tumor suppressor gene. LF suppresses distress perception via opioid mediated mechanism and prevents a decrease of the immune system activity caused by psychosocial stress. Furthermore, LF possibly modulates behavior in man and in animals.     

Angiotensin receptors in the nervous system

In addition to its traditional role as a circulating hormone, angiotensin is also involved in local functions through the activity of tissue renin-angiotensin systems that occur in many organs, including the brain. In the brain, both systemic and presumptive neurally derived angiotensin and angiotensin metabolites act through specific receptors to modulate many functions. This review examines the distribution of these specific angiotensin receptors and discusses evidence regarding the function of angiotensin peptides in various brain regions. Angiotensin AT₁ and AT₂ receptors occur in characteristic distributions that are highly correlated with the distribution of angiotensin-like immunoreactivity in nerve terminals. Acting through the AT₁ receptor in the brain, angiotensin has effects on fluid and electrolyte homeostasis, neuroendocrine systems, autonomic pathways regulating cardiovascular function and behavior. Angiotensin AT₁ receptors are also found in many afferent and efferent components of the peripheral autonomic nervous system. The role of the AT₂ receptor in the brain is less well understood, although recent knockout studies point to an involvement with behavioral and cardiovascular functions. In addition to the AT₁ and AT₂ receptors, receptors for other fragments of angiotensin have been proposed. The AT₄ binding site, which binds angiotensin [3–8], has a widespread distribution in the brain quite distinct from that of the AT₁ and AT₂ receptors. It is associated with many cholinergic neuronal groups and also several sensory nuclei, but its function remains to be determined. Our discovery that another brain-derived peptide binds to the AT₄ binding site in the brain and may represent the native ligand is discussed. Overall, the distribution of angiotensin receptors in the brain indicate that they play diverse and important physiological roles in the nervous system.     

Collateralization in the mammalian nervous system

After reviewing the loci of origin for neurons with collateralized axons, some hypotheses on their distribution in the mammalian nervous system, on their functional contributions and on their significance in the course of encephalization are discussed. In principle, the distribution of collateralized neurons seems to be restricted to anatomical circuits subserving unspecific activation of forebrain regions and controlling body balance and movements. Concerning the limbic system, a minor degree of collateralization seems to exist only in less encephalized species. Based on a number of anatomical and functional arguments, it is assumed that the significance of collateralization fades in the course of encephalization.     

Immunolocalization of cathepsin D in the human central nervous system and central nervous system neoplasms

The cellular distribution of the lysosomal proteinase cathepsin D was studied in a series of 76 neoplasms and 18 non-neoplastic tissues from the human central nervous system, using a well-characterized polyclonal antibody in a peroxidase-antiperoxidase technique. In the normal and developing brain, cathepsin D is confined to neurons and choroid plexus epithelium. Strong granular cytoplasmic staining was present in neuronal and choroid plexus neoplasms, and in reactive macrophages. A large variety of other neoplasms also exhibited positive cytoplasmic staining, albeit usually of a weaker diffuse type. Cathepsin D cannot be considered a specific marker for neuronal or choroid plexus neoplasms, but the antiserum used in this study may be of value in antibody panels for the investigation of these tumours. Its localization may also be of value in embryological studies, particularly in the cerebellum, and in investigations of steroid hormone receptor-associated proteins in meningiomas and Schwannomas.     

Testing the autonomic nervous system

Noninvasive, well-validated clinical tests of autonomic function are available and are in relatively wide use. These comprise an evaluation of sudomotor, cardiovagal, and adrenergic functions. These tests are very useful and have resulted in the recognition of milder degrees of autonomic failure and the presence of orthostatic intolerance that previously were missed. An extensive normative database and commercial equipment is available. The main limitations of the tests relate to the fact that they evaluate mainly the function of target tissues so that the status of autonomic reflexes are inferred. The tests can be affected by medications. There are more invasive, more time-consuming, or less validated tests of autonomic function that can directly record from sympathetic nerve fibers (microneurography) and mesenteric bed to study cerebral vasoregulation and the status of the veins.     

Vasculitis of the nervous system

PURPOSE OF REVIEW: Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. When unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability making this a disorder of paramount importance to all clinicians. RECENT FINDINGS: Remarkable progress has been made in the pathogenesis, diagnosis, and treatment of vasculitis of the central (CNS) and peripheral nervous system (PNS). The classification of vasculitis affecting the nervous system includes (1) Systemic vasculitis disorders (necrotizing arteritis of the polyarteritis type, hypersensitivity vasculitis, systemic granulomatous vasculitis, giant cell arteritis, diverse connective tissue disorders; viral, spirochete, fungal, and retroviral infection; (2) Paraneoplastic disorders; (3) Amphetamine abuse; (4) Granulomatous angiitis of the brain; (5) Isolated peripheral nerve vasculitis, each in the absence of systemic involvement; and (6) diabetes mellitus, associated wtih inflammatory PNS vasculopathy. SUMMARY: Vasculitis is diagnosed with assurance after intensive evaluation. Successful treatment follows ascertainment of the specific vasculitic disorder and the underlying cytochemical mechanism of pathogenesis. Clinicians must choose from among the available immunomodulating, immunosuppressive, and targeted immunotherapies, unfortunately without the benefit of prospective clinical trials, tempered by the recognition of all of the possible medication related side effects.