Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function.
The majority of research on functional cerebral lateralization in primates revolves around vocal abilities, addressing the evolutionary origin of the human language faculty and its predominance in the left hemisphere of the brain.Right hemisphere specialization in spatial cognition is commonly reported in humans.This functional asymmetry is especially evident in the context of the unilateral neglect, a deficit in attention to and awareness of one side of space, that more frequently occurs after right-side rather than left-side brain damage.Since most of the research efforts are concentrated on vocalization in primates, much less is known about the presence or absence of spatial functions lateralization.Obtaining this knowledge can provide insight into the evolutionary aspect of the functionally lateralized brain of Homo sapiens and deliver refinement and validation of the nonhuman primate unilateral neglect model.This paper reviews the literature on functional brain asymmetries in processing spatial information, limiting the search to nonhuman primates, and concludes there is no clear evidence that monkeys process spatial information with different efficiency in the two hemispheres.We suggest that lateralization of spatial cognition in humans represents a relatively new feature on the evolutionary time scale, possibly developed as a by-product of the left hemisphere intrusion of language competence.Further, we argue that the monkey model of hemispatial neglect requires reconsideration.
The third paper by Camillo Golgi on his new method was on the olfactory bulb. This paper has never been translated into English, but is of special interest both for its pioneering description of olfactory bulb cells and for containing the first illustration by Golgi of cells stained with his new method. A translation into English is provided in this paper, together with commentaries on the significant points in his descriptions. These results are placed in the perspective of Cajal's subsequent first publication on the olfactory bulb and brief mention of the work of other early histologists. This perspective allows one to see more clearly Golgi's fundamental contributions to the olfactory bulb in particular and to the description of the neuronal architecture of the brain in general.
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.
Adult rodents picked up by the tail and slowly descending towards a horizontal surface extend all four limbs in anticipation of contact. Mouse mutants with pathologies in various brain regions and the spinal cord display instead a flexion response, often characterized by paw-clasping and a bat-like posture. These phenotypes are observed in mice with lesions in cerebellum, basal ganglia, and neocortex, as well as transgenic models of Alzheimer's disease. The underlying mechanism appears to include cerebello-cortico-reticular and cortico-striato-pallido-reticular pathways, possibly triggered by changes in noradrenaline and serotonin transmission.
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.
Neuronal dysfunctions and neurodegeneration are often associated with defects in membrane transport. Synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathological feature--insoluble aggregates composed largely of the protein α-synuclein in certain populations of neurons and glia. The actual physiological function of the brain-enriched α-synuclein is still not particularly clear. What is obvious is that when the protein is present in pathologically high amounts, or in mutant forms with enhanced membrane association and oligomerization, it causes neuronal demise with manifestations of impaired neuronal traffic, heightened oxidative stress, mitochondrial degeneration and defects in lipid metabolism. α-synuclein's direct association with the activities of key components of the eukaryotic membrane traffic machinery, namely Rabs and the soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptors (SNAREs), has highlighted a key role for membrane transport defects in α-synuclein-mediated pathology. Here, we summarize and discuss recent findings in this regard, and their implications in the molecular aspects of synucleinopathy.
The Camillo Golgi's school of Histology and General Pathology in Pavia played an important role in the development of medical-biological studies in Italy in the period after Unification of the state. Founded around 1880 when Golgi (1843–1926) began to wield power at the University of Pavia, the school soon became famous for the distinctive morphological basis of its studies. Many of its staff members made important discoveries and won international acclaim. The school however went into decline after 1910 because of its rigid adherence to the morphological approach that had characterized its golden years at a time when the international scientific world was developing other fundamental methodological criteria for medical–biological studies.
Spinal cord injuries in mammals, including humans, have devastating long-term consequences. Despite substantial research, therapeutic approaches developed in mammalian model systems have had limited success to date. An alternative strategy in the search for treatment of spinal cord lesions is provided by regeneration-competent vertebrates. These organisms, which include fish, urodele amphibians, and certain reptiles, have a spinal cord very similar in structure to that of mammals, but are capable of spontaneous structural and functional recovery after spinal cord injury. The present review aims to provide an overview of the current status of our knowledge of spinal cord regeneration in one of these groups, teleost fish. The findings are discussed from a comparative perspective, with reference to other taxa of regeneration-competent vertebrates, as well as to mammals.
Giuseppe Moruzzi was born one century ago; he was an outstanding Italian neurophysiologist, who was particularly famous for his contributions to the study of the mechanisms underlying the control of the sleep–waking cycle in mammals. In 1990, Rita Levi-Montalcini, Moruzzi's great friend and admirer, used the occasion of an invitation by the University of Parma, where Moruzzi graduated in medicine in 1933, to celebrate Moruzzi's scientific achievements. She wished to pay a tribute to Moruzzi's human and ethical qualities by portraying him as a “perfect model” for the young generation wishing to pursue scientific research. The transcription of “Rita's” tribute to Moruzzi links two of the greatest figures of Italian neuroscience and also provides a lively account of how the personal histories of two promising young scientists intertwined with the great and tragic events of world history in the past century.
Late-life depressive syndromes often arise in the context of predementia, dementia syndromes, and Alzheimer's disease (AD). Conversely, patients with a history of mood disorders are at higher risk of developing cognitive impairment. The high rate of co-occurrence of these two disorders is becoming a major health problem in older subjects for both their epidemiological impact and the negative outcomes in terms of disability and increased mortality. In this perspective, it is possible to speculate on the presence of a mirror relationship between depressive and cognitive disorders in late-life. Indeed, although a causal contribution of genetic, environmental, and social factors is widely recognized in these disorders, the neurobiological links still remain largely unknown. l-glutamic acid and γ-aminobutyric acid are the principal excitatory and inhibitory neurotransmitters in the central nervous system, respectively, and increasing evidence suggests that alterations in this neurotransmitter system may contribute to the neurobiology linking depression and cognitive impairment. In the present review article, we examined the neurobiological bases of the relationship between late-life depressive syndromes and AD, with a particular attention to glutamatergic pathway signalling like a bridge connecting these two conditions. In addition, attempts have been made to explain changes in glutamatergic pathway, depression in older age, and dementia through the analysis of signal transduction mechanisms associated with these disabling disorders.
Author(s): Bentivoglio, Marina; Jones, Edward G; Mazzarello, Paolo; Ribak, Charles E; Shepherd, Gordon M; Swanson, Larry W
Several bis-terephthalamides based on methyl esters of amino acids including glycine (1), β-alanine (2), γ-aminobutyric acid (3) and ε-aminocaproic acid (4), X(CH2)nHNOCC6H4CONH(CH2)nX (XCO2CH3, n = 1, 2, 3 and 5), have been synthesized and characterized by single-crystal X-ray diffraction and spectroscopic methods: FT-IR, polarized FT-IR, Raman, 1H NMR and 13C NMR. The four structures assemble via classical NH⋯O hydrogen bonds between amide functionalities linking the molecules into chains parallel to the short axis. The analysis of polarized IR spectra of pure and deuterated compounds reveals that a weak interchain (“through-space”) exciton coupling involves two closely-spaced hydrogen bonds belonging to two different adjacent chains. The exciton coupling magnitude decreases with the addition of methylene groups to the terephthalamide system. Isotope effects in terephthalamides show that the distribution of protons and deuterons in the crystalline lattice depends on the strength of the exciton couplings involving hydrogen bonds.
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.
Contrary to Golgi's "reticular" theory of nervous structure, it is clear that the synapse rules over communication among nerve cells. Spreading depression, however, does not follow synaptic pathways. It sweeps across gray matter like a political revolution, ignoring structural boundaries and carefully established regulatory mechanisms. Neurons form alliances with their usually subordinate partners, the astrocytes, to cause a perturbation of function that strains resources necessary for recovery. Innocent bystanders, the blood vessels, are obliged to try to ameliorate the disturbance but may not be able to respond optimally in the chaotic environment. Under extreme circumstances, a purge of some of the instigators may ensue. This anarchic picture of interactions among the elements of nervous tissue does little to rescue the reticular theory that was one of Golgi's most important intellectual offerings. Nevertheless, it reminds us that the behavior of populations of nerve cells need not necessarily be limited by the pathways dictated by synaptic junctions. Spreading depression is a multifactorial phenomenon, in which intense depolarization of neurons and/or astrocytes leads to perturbations that include release of K(+), release of glutamate, increase in intracellular Ca(++), release of ATP and local anoxia, as well as vascular changes. This process plays a role in migraine and contributes to the damage produced by brain anoxia, trauma, stroke, and subarachnoid hemorrhage. It may provide clues to new treatments for the damaged brain.
According to the traditional hypothesis, the cerebrospinal fluid (CSF) is secreted inside the brain ventricles and flows unidirectionally along subarachnoid spaces to be absorbed into venous sinuses across arachnoid villi and/or via paraneural sheaths of nerves into lymphatics. However, according to recent investigations, it appears that interstial fluid (ISF) and CSF are formed by water filtration across the walls of arterial capillaries in the central nervous system (CNS), while plasma osmolytes are sieved (retained) so that capillary osmotic counterpressure is generated, which is instrumental in ISF/CSF water absorption into venous capillaries and postcapillary venules. This hypothesis is supported by experiments showing that water, which constitutes 99% of CSF and ISF bulk, does not flow along CSF spaces since it is rapidly absorbed into adjacent CNS microvessels, while distribution of other substances along CSF spaces depends on the rate of their removal into microvessels: faster removal means more limited distribution. Furthermore, the acute occlusion of aqueduct of Sylvius does not change CSF pressure in isolated ventricles, suggesting that the formation and the absorption of CSF are in balance. Multidirectional distribution of substances inside CSF, as well as between CSF and ISF, is caused by to-and-fro pulsations of these fluids and their mixing. Absorption of CSF into venous sinuses and/or lymphatics under the physiological pressure should be of minor importance due to their minute surface area in comparison to the huge absorptive surface area of microvessels.
The ingestion of alcohol/ethanol during pregnancy can result in abnormal fetal development in both humans and a variety of experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol, a myriad of structural and functional deficits can be observed. These teratogenic effects are thought to result from the ethanol-induced dysregulation of a variety of intracellular pathways ultimately culminating in toxicity and cell death. For instance, ethanol exposure can lead to the generation of reactive oxygen species (ROS) and produce an imbalance in the intracellular redox state, leading to an overall increase in oxidative stress. In the present review we will provide an up-to-date summary on the effects of prenatal/neonatal ethanol exposure on the levels of oxidative stress in the central nervous system (CNS) of experimental models of fetal alcohol spectrum disorders (FASD). We will also review the evidence for the use of antioxidants as potential therapeutic strategies for the treatment of some of the neuropathological deficits characteristic of both rodent models of FASD and children afflicted with these disorders. We conclude that an imbalance in the intracellular redox state contributes to the deficits seen in FASD and suggest that antioxidants are potential candidates for the development of novel therapeutic strategies for the treatment of these developmental disorders.
The name of Camillo Golgi is inextricably associated, in the mind of most neuroscientists, with the theory that nerve cells communicate with one another by means of an intricate network of anastomosing axonal branches contained in the neuropil intervening between cell bodies in the gray matter of the brain and spinal cord. Examination, however, of Golgi's drawings in the papers published in the decade intervening between publication of his method (1873) and the beginning of his studies on malaria (1885) shows that axonal arborization in the cerebellar cortex and olfactory bulb are depicted as independent of one other. This is in striking contrast with the drawings included by Golgi in his 1906 Nobel lecture where the entire granular layer of the cerebellar cortex is occupied by a network of branching and anastomosing nerve processes. Thus, Golgi in his original papers on the cerebellum represents nerve cells as discrete units and only later in life merges axonal arborizations in the context of a lecture in defense of the reticular theory.
Many of the axons that carry messages to the thalamus for relay to the cerebral cortex are branched in a pattern long known from Golgi preparations. They send one branch to the thalamus and the other to motor centers of the brainstem or spinal cord. Because the thalamic branches necessarily carry copies of the motor instructions their messages have the properties of efference copies. That is, they can be regarded as providing reliable information about impending instructions contributing to movements that will produce changes in inputs to receptors, thus allowing neural centers to compensate for these changes of input. We consider how a sensory pathway like the medial lemniscus, the spinothalamic tract or the optic tract can also be seen to act as a pathway for an efference copy. The direct connections that ascending and cortical inputs to the thalamus also establish to motor outputs create sensorimotor relationships that provide cortex with a model of activity in lower circuits and link the sensory and the motor sides of behavior more tightly than can be expected from motor outputs with a single, central origin. These transthalamic connectional patterns differ from classical models of separate neural pathways for carrying efference copies of actions generated at higher levels, and introduce some different functional possibilities.
