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PubMed1996

A model of the cerebellum in adaptive control of saccadic gain. I. The model and its biological substrate.

We review data showing that the cerebellum is required for adaptation of saccadic gain to repeated presentations of dual-step visual targets and thus, presumably, for providing adaptive corrections for the brainstem saccade generator in response to any error created by the open-loop saccadic system. We model the adaptability of the system in terms of plasticity of synapses from parallel fibers to Purkinje cells in cerebellar cortex, stressing the integration of cerebellar cortex and nuclei in microzones as the units for correction of motor pattern generators. We propose a model of the inferior olive as an error detector, and use a 'window of eligibility' to insure that error signals that elicit a corrective movement are used to adjust the original movement, not the secondary movement. In a companion paper we simulate this large, realistic network of neural-like units to study the complex spatiotemporal behavior of neuronal subpopulations implicated in the control and adaptation of saccades.

Adaptation, Physiological↗
PubMed1998

The time course of nerve growth factor content in different neuropsychiatric diseases--a unifying hypothesis.

Nerve growth factor (NGF) is the prototype of related neurotrophic proteins, the so-called neurotrophins. NGF is essential for proper development of sympathetic and neural crest-derived sensory neurons of the peripheral nervous system (PNS) as well as of the neurons in the cholinergic basal forebrain (CBF). In the mature peripheral and central nervous system (CNS) NGF is also biologically active; NGF facilitates neuronal plasticity and regulates synaptic transmission and connectivity. Besides this well established neurotrophic function, recent findings suggest a role of NGF in neuroimmune and stress-associated processes, which NGF imparts not only as the classical "target-derived messenger", that is retrogradely transported within NGF-sensitive neurons, but also as para- and autocrine cytokine modulating the function of non-neuronal cells. Since neurotrophins are produced in very small amounts in vivo, NGF-sensitive cells have to compete for the limited NGF even under physiological conditions, so that normally only less than 10% of NGF receptors (NGFR) are saturated with their endogenous ligand. Consequently, it is feasable that minute changes in NGF concentrations can influence neuronal function in an extensive way. Hence, one plausible pathomechanism of disease(s) may be that a deficiency in NGF leads to malfunction of NGF-sensitive neurons. The change in NGF concentrations in the course of several diseases, namely during alcoholic and diabetic neuropathy as well as in Alzheimer's disease (AD) and several lesion-models of the CBF, indicates that fluctuations of endogenous NGF concentrations in PNS and CNS follow a distinctive pattern. An initial deficit of NGF at the onset of pathological processes is typically followed by its temporary elevation, during which some neuronal deficits may be partially ameliorated. However, if the disease progresses a decrease of NGF is typically observed, which appears to be a "normalization" of formerly elevated NGF concentrations. In our hypothesis we postulate that after acute or chronic injuries NGF is up-regulated as an intrinsic attempt to regenerate NGF-sensitive neurons. After long-term exposure to noxious processes, however, this compensatory increase of NGF cannot be maintained and eventually breaks down. The extent of such a compensatory up-regulation may depend on age and condition of NGF-sensitive neurons as well as on the type of lesion (acute or chronic). Furthermore, we also postulate that an exceeding level of NGF or its chronic elevation could even be detrimental to neuronal functioning under certain conditions. Thus, endogenous NGF has the capacity to modulate and even to compensate different kinds of harmful processes and in this way it may reinstate the homeostatic equilibrium. In our view, it seems to be a more appropriate approach to regard NGF changes as independent of classical constructs of neuropsychiatric diseases. Perhaps our understanding of NGF may even model for a new approach to the aetiology of multifactorial neuropsychiatric disorders.

Brain Diseases↗
PubMed1989

Peripheral nerve regeneration induces elevated expression of GAP-43 in the brainstem trigeminal complex of adult hamsters.

A polyclonal antibody was used to delineate the pattern of GAP-43 expression in central processes of trigeminal ganglion cells while their peripheral processes were undergoing regeneration. Two weeks after transection of the infraorbital nerve, levels of GAP-43 ipsilateral to the transection were greatly increased along the trajectory of infraorbital axons in the central trigeminal tract and also within the target neuropil. We conclude that elevated levels of GAP-43 in central processes of injured trigeminal ganglion cells occur in direct response to the regenerative response of the cell body and may have important implications for 'plasticity'-related changes seen in the adult trigeminal system.

Animals↗
PubMed1985

The postnatal development of retinocollicular projections in normal hamsters and in hamsters following neonatal monocular enucleation: a horseradish peroxidase tracing study.

The pattern of distribution of the retinal projections to the superior colliculus (SC) has been studied in developing normal hamsters and in hamsters following unilateral eye enucleation at birth, using the anterograde horseradish peroxidase (HRP) method. The results show that in normal hamsters the contralateral retinocollicular projection has already reached the caudal pole of the SC on the day of birth, and covered the entire SC by day 1. The ipsilateral retinocollicular projection is distributed only to the rostrolateral portion of the SC on day 0, but has covered the entire area of the SC on day 1. The innervation of the SC by the ipsilateral projection increases gradually until it reaches its maximum density on day 3 or day 4. Beginning on day 6, the density of the ipsilateral projection decreases markedly except in areas where there is a distinct clumping of retinal fibers. The normal adult pattern, which consists of dense clumps of ipsilateral retinal projections in the rostral half of the SC and a sparse ipsilateral retinal projection distributing in almost the entire extent of the SC, is established on day 10. In animals in which one eye was removed on the day of birth, the ipsilateral projection is observed in the rostral two-thirds of the SC on day 1, and innervates the entire extent of the colliculus on day 2. On day 3 or day 4, this projection is denser than that found in normal animals of the same age. The SC remains heavily innervated by ipsilateral fibers on and after day 6. The abnormal adult pattern, which consists of dense ipsilateral retinal projections in most parts of the SC, is observed on day 10. The anomalous ipsilateral retinocollicular projection which develops in eye-enucleated animals suggests that there is a competitive interaction between fibers from the two eyes during development which is critical in shaping the normal adult pattern of the ipsilateral retinocollicular projection. The early development of the contralateral projection is in advance of the ipsilateral projection, and removal of the contralateral fibers by eye enucleation at birth seems to result in a further delay in the development of the ipsilateral projection. This suggests that in the hamster the contralateral fibers may play a role in guiding the ipsilateral fibers to reach their target region.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Target cell stimulation and inhibition of norepinephrine uptake in dissociated rat locus coeruleus cultures.

Primary cultures from dissociated locus coeruleus (LC) neurons of 14-day-old (E14) fetal rats were grown in vitro in serum complemented medium. Noradrenergic cells were identified using immunocytochemical staining for tyrosine hydroxylase (TH) antibody. Maturation of noradrenergic neurons was assessed by measuring the high-affinity uptake of [3H]norepinephrine (NE). The presence of hippocampal cells stimulated the specific uptake of [3H]NE by LC cells only when plated at low density. Increasing the concentration of hippocampal cells resulted in a 50% decrease in NE uptake by LC cells. A similar inhibitory effect was observed with striatal cells. The inhibition exerted by striatal cells appears to be developmentally regulated, with E18 exerting a stronger inhibitory effect than E15 striatum. The decrease in [3H]NE uptake in hippocampal-LC cocultures was due to a decrease in uptake by individual noradrenergic neurons. For a given plating density, the decrease in uptake of [3H]NE per noradrenergic cell in LC culture was only half the decrease in the cocultures, suggesting a target-associated effect rather than density-derived toxic effect. In culture conditions which favored neuronal but not glial survival, the stimulatory target effect was evident, and the inhibitory effect was absent. Medium conditioned by target glial cells had a marked stimulatory effect on [3H]NE uptake. Glial feader-layer had a strong inhibitory effect on [3H]NE uptake in serum-containing medium. We suggest that both neurons and glia mediate the target-stimulatory effect, whereas the inhibitory effect is mediated by direct contact between target glia and LC neurons.

Animals↗
PubMed2005

Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies.

BACKGROUND: Changes in densities and in the morphology of dendritic spines in the hippocampus are linked to hippocampal long-term potentiation (LTP), spatial learning, and depression. Decreased brain-derived neurotrophic factor (BDNF) levels seem to contribute to depression. Through its receptor trkB, BDNF is also involved in hippocampal LTP and hippocampus-dependent learning. Conditionally gene-targeted mice in which the ablation of trkB is restricted to the forebrain and occurs only during postnatal development display impaired learning and LTP. METHODS: To examine whether there is a link among impaired hippocampal synaptic plasticity, altered spines, and trkB receptors, we performed a quantitative analysis of spine densities and spine length in the hippocampal area CA1 and the dentate gyrus in conditional mutant mice (trkB(lox/lox)CaMKII-CRE mice). TrkB protein and mRNA levels were assayed using Western blot and in situ hybridization analysis. RESULTS: Fifteen-week-old mutant mice exhibit specific reductions in spine densities and a significant increase in spine length of apical and basal dendrites in area CA1. These alterations correlate with a time- and region-specific reduction in full-length trkB mRNA in the hippocampus. CONCLUSIONS: TrkB functions in structural remodeling of hippocampal dendritic spines, which in turn may affect synaptic transmission and plasticity.

Age Factors↗
PubMedDate not supplied

Nitric oxide in brain: diffusion, targets and concentration dynamics in hippocampal subregions.

Nitric oxide (NO(*)) is a diffusible regulatory molecule involved in a wide range of physiological and pathological events. At the tissue level, a local and temporary increase in NO(*) concentration is translated into a cellular signal. From our current knowledge of biological synthesis and decay, the kinetics and mechanisms that determine NO(*) concentration dynamics in tissues are poorly understood. Generally, NO(*) mediates its effects by stimulating (e.g., guanylate cyclase) or inhibiting (e.g., cytochrome oxidase) transition metal-containing proteins and by post-translational modification of proteins (e.g., formation of nitrosothiol adducts). The borderline between the physiological and pathological activities of NO(*) is a matter of controversy, but tissue redox environment, supramolecular organization and compartmentalisation of NO(*) targets are important features in determining NO(*) actions. In brain, NO(*) synthesis in the dependency of glutamate NMDA receptor is a paradigmatic example; the NMDA-subtype glutamate receptor triggers intracellular signalling pathways that govern neuronal plasticity, development, senescence and disease, suggesting a role for NO(*) in these processes. Measurements of NO(*) in the different subregions of hippocampus, in a glutamate NMDA receptor-dependent fashion, by means of electrochemical selective microsensors illustrate the concentration dynamics of NO(*) in the sub-regions of this brain area. The analysis of NO(*) concentration-time profiles in the hippocampus requires consideration of at least two interrelated issues, also addressed in this review. NO(*) diffusion in a biological medium and regulation of NO(*) activity.

Animals↗
PubMed2006

Neural recruitment associated with anomia treatment in aphasia.

The purpose of this study was to investigate changes in the spatial distribution of cortical activity associated with anomia treatment in three persons with aphasia. Participants underwent three fMRI sessions before and after a period of intensive language treatment focused on object naming. The results revealed bilateral hemispheric recruitment associated with improved ability to name items targeted in treatment. This is the first study to employ multiple pre- and post-treatment fMRI sessions in the study of treatment-induced recovery from aphasia and has implications for future studies of brain plasticity in stroke.

Aged↗
PubMed2006

Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses.

Diets rich in vegetables and fruits are associated with reduced risk of several major diseases, including neurodegenerative disorders. Although some beneficial phytochemicals might function solely as antioxidants, it is becoming clear that many of the beneficial chemicals in vegetables and fruits evolved as toxins (to dissuade insects and other predators) that, at subtoxic doses, activate adaptive cellular stress-response pathways in a variety of cells including neurons. Examples of such 'preconditioning' or 'neurohormesis' pathways include those involving cell-survival signaling kinases, the transcription factors NRF2 and CREB, and histone deacetylases of the sirtuin family. In these ways, neurohormetic phytochemicals such as resveratrol, sulforaphanes and curcumin might protect neurons against injury and disease by stimulating the production of antioxidant enzymes, neurotrophic factors, protein chaperones and other proteins that help cells to withstand stress. Thus, as we discuss in this review, highly conserved longevity and survival pathways in neurons are the targets of many phytochemicals.

Animals↗
PubMed2006

Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission.

Neurotrophins regulate sympathetic neuron cotransmission by modulating the activity-dependent release of norepinephrine and acetylcholine. Nerve growth factor promotes excitatory noradrenergic transmission, whereas brain-derived neurotrophic factor (BDNF), acting through the p75 receptor, increases inhibitory cholinergic transmission. This regulation of corelease by target-derived factors leads to the functional modulation of myocyte beat rate in neuron-myocyte cocultures. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the control of both pre- and postsynaptic mechanisms of synaptic plasticity. We demonstrate that CaMKII acts in conjunction with p75 signaling to regulate cholinergic transmission between sympathetic neurons and heart cells. Inhibition of presynaptic CaMKII prevents the BDNF-dependent shift to inhibitory neurotransmission, whereas presynaptic expression of a constitutively active CaMKII results in inhibitory neurotransmission in the absence of added BDNF, suggesting that activation of presynaptic CaMKII is both necessary and sufficient for a shift from excitatory to inhibitory transmission. Several isozymes of CaMKII are expressed in sympathetic neurons, with the delta-CaMKII being activated by BDNF and nerve growth factor. Activated CaMKII is less effective at promoting cholinergic transmission in the absence of p75 signaling, demonstrating that p75 and CaMKII act to coordinate neurotransmitter selection in sympathetic neurons.

Animals↗
PubMed1987

Visual postural performance after loss of somatosensory and vestibular function.

Visual stabilisation of body sway in a patient with severe deficits of the vestibular system (due to gentamicin treatment) and the somatosensory system (due to polyneuropathy) was studied. With eyes open the patient was able to stand and walk slowly. With eyes closed he lost balance within one second. In order to optimise visual stabilisation he intuitively searched for nearby visual targets. His postural sway was recorded using posturography. His balance performance deteriorated significantly beyond a distance of 1 m between the eyes and the surrounding objects and with visual acuity below 0.3 (experimentally achieved with semitransparent plastic foils). With flicker illumination of decreasing frequencies of the visual surround he needed at least a visual input rate of 17 Hz in order to maintain an upright body position. The data provide clinical evidence for rapid visuo-spinal control of posture.

Adult↗
PubMed2005

Tumor cell plasticity in Ewing sarcoma, an alternative circulatory system stimulated by hypoxia.

A striking feature of Ewing sarcoma is the presence of blood lakes lined by tumor cells. The significance of these structures, if any, is unknown. Here, we report that the extent of blood lakes correlates with poor clinical outcomes, whereas variables of angiogenesis do not. We also show that Ewing sarcoma cells form vessel-like tubes in vitro and express genes associated with vasculogenic mimicry. In tumor models, we show that there is blood flow through the blood lakes, suggesting that these structures in Ewing sarcoma contribute to the circulation. Furthermore, we present evidence that reduced oxygen tension may be instrumental in tube formation by plastic tumor cells. The abundant presence of these vasculogenic structures, in contrast to other tumor types, makes Ewing sarcoma the ideal model system to study these phenomena. The results suggest that optimal tumor treatment may require targeting of these structures in combination with prevention of angiogenesis.

Adolescent↗
PubMed2025

Machine learning on multiple epigenetic features reveals H3K27Ac as a driver of gene expression prediction across patients with glioblastoma.

Epigenetic mechanisms play a crucial role in driving transcript expression and shaping the phenotypic plasticity of glioblastoma stem cells (GSCs), contributing to tumor heterogeneity and therapeutic resistance. These mechanisms dynamically regulate the expression of key oncogenic and stemness-associated genes, enabling GSCs to adapt to environmental cues and evade targeted therapies. Importantly, epigenetic reprogramming allows GSCs to transition between cellular states, including therapy-resistant mesenchymal-like phenotypes, underscoring the need for epigenetic-targeting strategies to disrupt these adaptive processes. Understanding these epigenetic drivers of gene expression provides a foundation for novel therapeutic interventions aimed at eradicating GSCs and improving glioblastoma outcomes. Using machine learning (ML), we employ cross-patient prediction of transcript expression in GSCs by combining epigenetic features from various sources, including ATAC-seq, CTCF ChIP-seq, RNAPII ChIP-seq, H3K27Ac ChIP-seq, and RNA-seq. We investigate different ML and deep learning (DL) models for this task and ultimately build our final pipeline using XGBoost. The model trained on one patient generalizes to other 11 patients with high performance. Notably, H3K27Ac alone from a single patient is sufficient to predict gene expression in all 11 patients. Furthermore, the distribution of H3K27Ac peaks across the genomes of all patients is remarkably similar. These findings suggest that GSCs share a common distributional pattern of enhancer activity characterized by H3K27Ac, which can be utilized to predict gene expression in GSCs across patients. In summary, while GSCs are known for their transcriptomic and phenotypic heterogeneity, we propose that they share a common epigenetic pattern of enhancer activation that defines their underlying transcriptomic expression pattern. This pattern can predict gene expression across patient samples, providing valuable insights into the biology of GSCs.

Glioblastoma↗
PubMed2000

Automated cover testing for binocular misalignment in awake monkeys using spectacle- mounted liquid crystal shutters.

PURPOSE: In humans, pathologic misalignment of the eyes (strabismus, or hetero-tropia) is readily detected using a clinical technique in which the visual axis of each eye is blocked briefly by a hand held occluder (i.e., the cover test, AKA the single cover test, or unilateral cover test). This manual technique is impractical for use in non-human primates. This paper reports the electronic hardware and computer software we have devised and adapted to perform an automated cover test in awake macaque monkeys (Macaca mulatta or rhesus, and Macaca nemistrina or pigtail) to facilitate the study of strabismus in this species. METHODS: Liquid crystal shutters (Displaytech LV2500OP-OEM) are mounted in aluminum spectacle frames which are positioned in front of the monkey's eyes by attaching the frame holder to an acrylic skull cap. The shutters are electrically actuated alternately to an "open" (transparent) or "closed" (opaque) state, occluding each eye in turn. The actuation signal (+/-5 volts) is generated by a single logic chip. The chip is driven by commercial data control and acquisition software (Spike 2, Cambridge Electronic Design) running on a Macintosh computer. Eye position and movement during this cover tests is monitored and recorded by the computer using surgically implanted scleral coils. Monkeys are rewarded for fixating small, moveable targets so that binocular misalignment can be measured with high precision at different or cardinal positions of horizontal and vertical gaze. RESULTS: The shutters produced occlusion of each eye as effective as that of an opaque plastic occluder used in previous experiments that required monocular viewing. Heterotropias were detected and recorded in monkeys and closely resembled those observed in human patients. It was also possible to detect heterophorias by actuating the shutters alternately. CONCLUSIONS: The shutters operated reliably, with negligible delay and transition times, providing automated, repeatable cover tests that are, in fact, in many respects superior to the standard clinical manual technique. In addition, their application to humans, using infrared electro-oculography instead of scleral coils to monitor eye position and movement, holds promise for future applications.

Animals↗
PubMed2003

Risk factors for infection during a severe dengue outbreak in El Salvador in 2000.

In 2000, El Salvador experienced a large dengue-2 virus epidemic with many severe cases. A seroepidemiologic survey was conducted in 106 randomly selected households (501 residents) in an affected community (Las Pampitas). The frequency of recent infection, documented by the presence of IgM antibodies or high-titer IgG antibodies to dengue virus, was estimated to be 9.8% (95% confidence interval [CI] = 5.8-13.7), of which at least 44% were secondary infections. The number of containers positive for Aedes mosquito larvae or pupae per 100 premises (Breteau Index) was 62 and the frequency of positive premises (House Index) was 36%; 33% (35 of 106) of the informants reported having taken action against mosquito larval habitats and 82% (87 of 106) reported having taken actions against adult mosquitoes. Recent infection was associated with the presence in the home environment of mosquito infested discarded cans (odds ratio [OR] = 4.30, 95% CI = 2.54-7.28), infested discarded plastic containers (OR = 3.98, 95% CI = 1.05-15.05), and discarded tire casings (OR = 2.57, 95% CI = 1.09-6.04). The population attributable fractions associated with these factors were 4%, 13%, and 31%, respectively. Our data suggest that targeted community cleanup campaigns, particularly those directed at discarded tires and solid waste, are likely to have the greatest impact on reducing the risk of dengue infection.

Adolescent↗
PubMed1985

Issues in speech motor control and their relation to the speech of individuals with cleft palate.

A view of speech motor control is presented that is different from conventional coarticulation models. Rather than assuming that phonetic units specify targets for peripheral events, this view is based on holistic behavioral goals. The importance of discovering strategies that organize interactions among physiologic processes of the speech motor system is stressed. The concepts of motor flexibility and plasticity are developed. These motor control issues are used as the basis for discussing the relations among speech motor processes, critical minimum velopharyngeal port size, and speech adequacy in speakers with cleft palate. Different meanings of velopharyngeal incompetency are considered, and a potential misuse of the concept is explained. Finally, the developmental character of motor plasticity is discussed, and the implications of critical periods in speech motor learning are raised for children with cleft palate.

Cleft Palate↗
PubMed1985

[Erythrocyte morphology in anemia after artificial circulation (based on scanning electron microscopic data)].

Erythrocyte stereo-ultrastructure of 58 patients operated under the conditions of extracorporeal circulation was studied by scanning electron microscopy. It is established that after the operation with extracorporeal circulation the hemoglobin level is always decreasing, 3 mg% on the average; hemoglobin decrease up to 10 mg% and less was considered as anemia, this occurring according to the approximate calculations, in 10-11% of cases. The causes of anemia in an early postoperative period are as follows: mechanical trauma of erythrocytes in the system of extracorporeal circulation; disturbance of the osmotic balance; alteration of the erythrocyte membrane plasticity due to the change of its enzyme-lipid component. Anemia in the late postoperative period is due to the purulent inflammatory processes. Morphological substrate of anemia is represented by the iron-deficient, target-like, two-pit erythrocytes, spherocytes, lacerated erythrocytes and other forms.

Adult↗
PubMed1996

cGMP-dependent protein kinase in dorsal root ganglion: relationship with nitric oxide synthase and nociceptive neurons.

Nitric oxide and cGMP influence plasticity of nociceptive processing in spinal cord. However, effectors for cGMP have not been identified in sensory pathways. We now demonstrate that cGMP-dependent protein kinase I (cGKl) occurs in the DRGs at levels comparable to that in cerebellum, the richest source of cGKl in the body. Immunohistochemical studies reveal that cGKl is concentrated in a subpopulation of small- and medium-diameter DRG neurons that partially overlap with substance P and calcitonin gene-related polypeptide containing cells. During development, cGKl expression throughout the embryo is essentially restricted to sensory neurons and to the spinal floor and roof plates. Neuronal nitric oxide synthase (nNOS) is coexpressed with cGKl in sensory neurons during embryonic development and after peripheral nerve axotomy. The primary target for cGKl in cerebellum, G-substrate, is not present in developing, mature, or regenerating sensory neurons, indicating that other proteins serve as effectors for cGKl in sensory processing. These data establish sensory neurons as a primary locus for cGMP actions during development and suggest a role for cGKl in plasticity of nociception.

Animals↗