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Steven N Roper

Publications and source records attributed to Steven N Roper.

18 recordsLinked to original sources

Derivation and large-scale expansion of multipotent astroglial neural progenitors from adult human brain.

The isolation and expansion of human neural cell types has become increasingly relevant in restorative neurobiology. Although embryonic and fetal tissue are frequently envisaged as providing sufficiently primordial cells for such applications, the developmental plasticity of endogenous adult neural cells remains largely unclear. To examine the developmental potential of adult human brain cells, we applied conditions favoring the growth of neural stem cells to multiple cortical regions, resulting in the identification and selection of a population of adult human neural progenitors (AHNPs). These nestin(+) progenitors may be derived from multiple forebrain regions, are maintainable in adherent conditions, co-express multiple glial and immature markers, and are highly expandable, allowing a single progenitor to theoretically form sufficient cells for approximately 4x10(7) adult brains. AHNPs longitudinally maintain the ability to generate both glial and neuronal cell types in vivo and in vitro, and are amenable to genetic modification and transplantation. These findings suggest an unprecedented degree of inducible plasticity is retained by cells of the adult central nervous system.

Adolescent↗

A method for a more complete in vitro Parkinson's model: slice culture bioassay for modeling maintenance and repair of the nigrostriatal circuit.

Slice culture model systems provide a unique opportunity to monitor and lesion brain circuits in a dish. Using a novel approach, we have generated parasagittal slices from mouse brains that preserve, throughout the culture process, the nigrostriatal circuit. These slices can be cultured for approximately 4 weeks with maintenance of normal neuronal cytoarchitecture. Application of the dopamine specific toxin 6-hydroxy dopamine (6-OHDA) induces a significant decline in tyrosine hydroxylase positive cell bodies and fibers. Using a transgenic mouse with green fluorescent protein (GFP) under the control of the tyrosine hydroxylase promoter, we have been able to visualize in real time the loss of GFP expression in the striatum of slices as a result of 6-OHDA exposure. Using these cultures we have demonstrated the feasibility of modeling cellular replacement strategies. GFP-positive embryonic stem cell-derived neuronal precursors can be tracked in real time throughout the experiment and are amenable to patch clamp recording within the slice environment. In addition, cell differentiation can be observed within these slices and the effects of morphogenetic proteins, like the extracellular matrix molecule laminin, drugs or small molecules can be observed. This unique culture system presents a new approach for modeling Parkinson's disease in vitro, and provides a potentially useful new method for screening cell and molecular therapies for neurodegenerative diseases.

Animals↗

Reduced excitatory drive in interneurons in an animal model of cortical dysplasia.

Cortical dysplasia (CD) is strongly associated with epilepsy. Enhanced excitability in dysplastic neuronal networks is believed to contribute to epileptogenesis, but the underlying mechanisms for the hyperexcitability are poorly understood. Cortical GABAergic interneurons provide the principal inhibition in the neuronal networks by forming inhibitory synapses on excitatory neurons. The aim of the present study was to determine if the function of interneurons in CD is compromised. In a rat model of CD, in utero irradiation, we studied spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) in cortical interneurons using whole cell recording techniques. Two types of interneurons, type I and type II, were identified based on their distinctive spike patterns and short-term synaptic plasticity. We found that the frequencies of sEPSCs and mEPSCs were significantly decreased in both types of interneurons in CD. However, the amplitude and kinetics of sEPSCs and mEPSCs were not different. Five-pulse, 20-Hz stimulation produced short-term depression in type I interneurons in both CD and control tissue. Type II interneurons showed a robust short-term facilitation in both CD and control tissue. Morphological analysis of biocytin-filled neurons revealed that dendritic trees of both types of interneurons were not altered in CD. Our results demonstrate that the excitatory drive, namely sEPSCs and mEPSCs, in two main types of interneuron is largely attenuated in CD, probably due to a reduction in the number of excitatory synapses on both types of interneurons in CD.

Animals↗

Superior divisional third cranial nerve paresis: clinical and anatomical observations of 2 unique cases.

BACKGROUND: Within the midbrain, the third nerve nucleus is composed of a complex of subnuclei. The fascicular portion of the nerve courses through the red nucleus and exists in the midbrain just medial to the cerebral peduncle. The cisternal portion of the nerve is a single structure that divides into a superior branch and an inferior branch in the region of the cavernous sinus and superior orbital fissure. OBJECTIVE: To describe 2 patients with superior divisional third cranial nerve paresis resulting from a lesion involving the cisternal portion of the nerve prior to its anatomical bifurcation. PATIENTS: Case 1 was a 77-year-old man with a superior divisional third nerve palsy as the presenting manifestation of a posterior communicating artery aneurysm. Case 2 was a 41-year-old woman who developed a superior divisional third nerve palsy following anterior temporal lobectomy for epilepsy. RESULTS: In both cases, the presumed location of the lesion was the cisternal portion of the third cranial nerve. CONCLUSIONS: Although the anatomical division of the third cranial nerve occurs in the region of the anterior cavernous sinus or superior orbital fissure, there is a topographical arrangement of the motor fibers within the cisternal portion of the nerve. The clinical evaluation of a patient with a third cranial nerve paresis requires an understanding of the regional neuroanatomy and topographical organization of the nerve.

Adult↗

Episodic memory in patients with focal frontal lobe lesions.

Episodic memory was evaluated in patients with unilateral, frontal lobe damage and matched controls using a list-method directed forgetting paradigm. Directed forgetting instructions (forget vs. remember the word), encoding instructions (learn vs. judge the word) and test format (recall vs. recognition) were manipulated in order to explore how variations in encoding and retrieval affect verbal memory. Controls demonstrated a normal directed forgetting effect in recall and less directed forgetting in recognition. Patients with left frontal (LF) damage did not show directed forgetting in either recall or recognition and patients with right frontal (RF) damage showed directed forgetting in recall, but not in recognition. Furthermore, the LF group recalled significantly more of the judge than learn words, suggesting that this group's performance improves by providing them with an encoding strategy. Conversely, the RF group's performance did not depend on encoding instructions and their recognition memory was impaired relative to the other two groups when they were instructed to judge the words. Our results suggest that (a) patients with LF damage show deficits in the rehearsal of to-be-remembered information, (b) whereas patients with RF damage show impairments in recognition memory. Furthermore, both patient groups show a lack of directed forgetting when familiarity-based processes guide performance.

Adult↗

Neuron-to-astrocyte transition: phenotypic fluidity and the formation of hybrid asterons in differentiating neurospheres.

To the extent that their fate choice and differentiation processes can be understood and manipulated, neural stem cells represent a promising therapeutic tool for a variety of neuropathologies. We have previously shown that mature astrocytes possess neural stem cell attributes, and can give rise to neurons through the formation of multipotent neurosphere clones. Here we show that relatively mature neurons generated from neurospheres derived from postnatal subependymal zone or cerebellar cortex undergo a phenotypic transformation into astrocytes that coincides with the appearance of a nonfused, hybrid cell type that shares the morphology, antigenicity, and physiology of both neurons and astrocytes. We refer to this astrocyte/neuron hybrid as an "asteron," and hypothesize that it represents an intermediate step in the trans- or dedifferentiation of neurons into astrocytes. The present finding suggests that seemingly terminally differentiated neural cells may in fact represent points along a bidirectionally fluid continuum of differentiation, with intermediate points represented by "hybrid" cells coexpressing phenotypic markers of more than one lineage.

Animals↗

Semantic priming in patients with right frontal lobe lesions.

Patients with unilateral, right frontal lobe damage (N=13) and matched controls (N=20) performed a task of lexical ambiguity resolution in order to explore the contribution of right frontal regions to lexical-semantic priming. Word triplets consisting of balanced homographs were presented to participants in four conditions: concordant, discordant, neutral, and unrelated. Controls demonstrated facilitation for concordant meanings of homographs, as evidenced by their faster reaction times in the concordant relative to the unrelated (baseline) condition, as well as a lack of facilitation for the discordant meaning relative to the neutral and concordant conditions. Results in patients with right frontal lobe damage differed depending on the site of the lesion. Patients with lesions restricted to the right medial frontal lobe only showed facilitation in the neutral condition, while those with lesions encroaching upon the right dorsolateral region demonstrated facilitation of both discordant and concordant meanings relative to the baseline condition. These results support a role for the right frontal lobe in semantic priming and suggest possible specialization within the right prefrontal cortex for the processing of lexical-semantic information.

Adult↗

Attentional inhibition in patients with focal frontal lobe lesions.

Patients with unilateral, frontal lobe damage and matched controls performed an identity negative priming task as a measure of inhibition in selective attention. Control participants demonstrated a normal negative priming effect, as evidenced by slower reaction times when a previously to-be-ignored item became the target on a subsequent trial (distractor suppression). On the other hand, patients with left medial frontal lobe damage showed positive priming in the distractor suppression condition suggesting facilitation of distractor information. Patients with right frontal lobe damage showed an unreliable pattern of negative priming, some demonstrating an absence of negative priming and others demonstrating enhanced negative priming in the distractor suppression condition. Neither patient group nor controls demonstrated slower responses on a target-to-distractor condition included to evaluate a noninhibitory (i.e., episodic retrieval) account of negative priming. Taken together, our results suggest that (a) the negative priming effect represents active inhibition of a distractor representation, rather than a noninhibitory mismatch between retrieval episodes, and (b) that the frontal lobes, especially the left frontal lobes, contribute to this active inhibition.

Adult↗

Tonic activity of metabotropic glutamate receptors is involved in developmental modification of short-term plasticity in the neocortex.

Maturation of many synapses of the CNS is characterized by a reduction in initial release probability and associated alterations in short-term plasticity (STP). We investigated the role of tonic activity of metabotropic glutamate receptors (mGluRs) in this process in glutamatergic synapses of rat neocortex. Consistent with previous reports, STP of excitatory postsynaptic currents (EPSCs) evoked by five-pulse stimulation was found to switch from depression at postnatal days 13-17 (P13-17) to facilitation at postnatal days 28-42 (P28-42). (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine, a specific mGluR2/3 agonist, strongly depressed EPSCs both at the early stage and the late stage of cortical development. This was accompanied by a switch from depression to facilitation of STP at the early stage and an increase in facilitation at the late stage. While application of 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl) propanoic acid (LY341495), an mGluR antagonist that is most potent at mGluR2/3, had no significant effect at the early stage, it significantly enhanced EPSC amplitude and reduced short-term facilitation at the late stage. Blocking glutamate transporter activity with l-trans-pyrrolidine-2,4-dicarboxylate (tPDC) significantly reduced EPSC amplitude and short-term depression in the younger group but had no effect in the older specimens. The effect of tPDC was blocked by LY341495. These results suggest that a progressive increase in tonic mGluR activity during postnatal development contributes to a reduction of release probability in excitatory cortical synapses. They also indicate that glutamate transporter activity in the neocortex decreases during postnatal development. This may play a role in increasing tonic activity of mGluRs by increasing ambient glutamate levels in the perisynaptic extracellular space.

Aging↗

Cortical dysplasia and epilepsy: animal models.

Cortical dysplasia syndromes--those conditions of abnormal brain structure/organization that arise during aberrant brain development--frequently involve epileptic seizures. Neuropathological and neuroradiological analyses have provided descriptions and categorizations based on gross anatomical and cellular histological features (e.g., lissencephaly, heterotopia, giant cells), as well as on the developmental mechanisms likely to be involved in the abnormality (e.g., cell proliferation, migration). Recently, the genes responsible for several cortical dysplastic conditions have been identified and the underlying molecular processes investigated. However, it is still unclear how the various structural abnormalities associated with cortical dysplasia are related to (i.e., "cause") chronic seizures. To elucidate these relationships, a number of animal models of cortical dysplasia have been developed in rats and mice. Some models are based on laboratory manipulations that injure the brain (e.g., freeze, undercut, irradiation, teratogen exposure) of immature animals; others are based on spontaneous genetic mutations or on gene manipulations (knockouts/transgenics) that give rise to abnormal cortical structures. Such models of cortical dysplasia provide a means by which investigators can not only study the developmental mechanisms that give rise to these brain lesions, but also examine the cause-effect relationships between structural abnormalities and epileptogenesis.

Animals↗

The GABAergic system of the developing neocortex has a reduced capacity to recover from in utero injury in experimental cortical dysplasia.

Cortical dysplasia is frequently associated with epilepsy but mechanisms underlying this association are poorly understood. Rats irradiated in utero serve as an injury-based model of cortical dysplasia. Prior studies in mature rats have shown a selective reduction in the number of neocortical interneurons after in utero irradiation. This study attempted to clarify the nature of the radiation injury to the developing neocortical GABAergic system after exposure to gamma-irradiation on the 17th day of gestation (E17). Stereological methods were used to quantify absolute numbers of total neurons (TN) and GABAergic neurons in the neocortex on E21 and postnatal day 6 (P6). In irradiated rats, TN was decreased to about 50% of controls at both time points. However, TN doubled between the 2 time points, even in irradiated animals. In controls, GABAergic neurons increased 10-fold between E21 and P6, but there was no difference in GABAergic counts between the 2 time points in irradiated animals. This led to a dramatic reduction in the percentage of neocortical neurons that were GABAergic in irradiated animals at P6 (9% vs 18%). This study shows that, in contrast to non-GABAergic neurons, the neocortical GABAergic system has a limited capacity to recover from radiation-induced in utero injury.

Animals↗

PKA and PKC enhance excitatory synaptic transmission in human dentate gyrus.

cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) are two major modulators of synaptic transmission in the CNS but little is known about how they affect synaptic transmission in the human CNS. In this study, we used forskolin, a PKA activator, and phorbol ester, a PKC activator, to examine the effects of these kinases on synaptic transmission in granule cells of the dentate gyrus in human hippocampal slices using whole-cell recording methods. We found that both forskolin and phorbol ester increased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) but left the amplitude unaffected. Inactive forskolin and phorbol ester had no effect on sEPSCs in human dentate granule cells. Prior application of forskolin occluded the effects of phorbol ester on mEPSC frequency. Tetanic stimulation applied to the perforant path induced short-term depression in dentate gyrus granule cells. Both forskolin and phorbol ester significantly enhanced this short-term depression. Taken together, these results demonstrate that PKA and PKC are involved in up-regulation of excitatory synaptic transmission in human dentate granule cells, primarily by presynaptic mechanisms. In addition, the occlusion experiments suggest that the two kinases may share a common signal pathway.

Adolescent↗

Water diffusion measurements in perfused human hippocampal slices undergoing tonicity changes.

Diffusion MRI has the potential to probe the compartmental origins of MR signals acquired from human nervous tissue. However, current experiments in human subjects require long diffusion times, which may confound data interpretation due to the effects of compartmental exchange. To investigate human nervous tissue at shorter diffusion times, and to determine the relevance of previous diffusion studies in rat hippocampal slices, water diffusion in 20 perfused human hippocampal slices was measured using a wide-bore 17.6-T magnet equipped with 1000-mT/m gradients. These slices were procured from five patients undergoing temporal lobectomy for epilepsy. Tissue viability was confirmed with electrophysiological measurements. Diffusion-weighted water signal attenuation in the slices was well-described by a biexponential function (R(2) > 0.99). The mean diffusion parameters for slices before osmotic perturbation were 0.686 +/- 0.082 for the fraction of fast diffusing water (F(fast)), 1.22 +/- 0.22 x 10(-3) mm(2)/s for the fast apparent diffusion coefficient (ADC), and 0.06 +/- 0.02 x 10(-3) mm(2)/s for the slow ADC. Slice perturbations with 20% hypotonic and 20% hypertonic artificial cerebrospinal fluid led to changes in F(fast) of -8.2% and +10.1%, respectively (ANOVA, P < 0.001). These data agree with previous diffusion studies of rat brain slices and human brain in vivo, and should aid the development of working models of water diffusion in nervous tissue, and thus increase the clinical utility of diffusion MRI.

Analysis of Variance↗

Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

In spite of their popular uses as recreational drugs and their potential therapeutic uses, little direct information has been obtained about the synaptic effects of cannabinoids in the human brain. In the present study, patch-clamp recordings were performed on granule cells of the human dentate gyrus and the effects of cannabinoid receptor-1 (CB1) activation on inhibitory synaptic activity were examined. Activation of CB1 receptors by WIN55212-2 significantly suppressed both frequency and amplitude of spontaneous inhibitory synaptic currents (IPSCs) to about 50% of control. The suppressive effects were completely abolished in the presence of the CB1 receptor antagonist, AM251. WIN55212-2 also suppressed evoked IPSCs. However, neither frequency nor amplitude of miniature IPSCs were affected by WIN55212-2. These results provide electrophysiological evidence for the role of CB1 receptors in modulating inhibitory activity in human dentate gyrus.

Adolescent↗

Altered corticogenesis and neuronal morphology in irradiation-induced cortical dysplasia: a Golgi-Cox study.

Cortical dysplasia has a strong clinical association with epilepsy and mental retardation, but the relationship between alterations in cortical structure and function in dysplasia-related disorders is poorly understood. The cerebral cortex of irradiated rats, an experimental model of cortical dysplasia, was studied using cresyl violet-stained sections and the Golgi-Cox method. The irradiated cortex is characterized by reductions in size, volume, and number of neurons and fibers reflecting the original lethal injury to neuronal precursors. Consequently, only neurons that survived this injury were able to continue their, albeit altered, development. The result is an altered corticogenesis characterized by neuronal, fiber circuitry, and microvascular alterations. Abnormal aggregates (nodules) of excitatory pyramidal neurons with altered dendritic profiles and functional territories are found between 200 and 400 microm from the pial surface. Their horizontal dendritic profiles and functional territories contrast with the vertical (columnar) dendritic profiles and functional territories of normal pyramidal neurons. This horizontal concentration of spiny dendrites and, hence, of excitatory synaptic contacts suggests a response to the presence of an abnormal horizontal plexus of afferent fibers terminals. Stellate neurons, some morphologically compatible with inhibitory basket cells, are also essential components of these nodules. Some neuronal nodules are characterized by a rich plexus of anastomotic capillaries that contrasts with the sparser vasculature of surrounding gray matter tissue. The presence of well-vascularized aggregates of altered pyramidal and inhibitory neurons suggests a high level of metabolic activity. Well-vascularized deep heterotopias are also found. We propose that the functional activity of well-vascularized neuronal nodules and heterotopias could play a role in the abnormal cortical function in this model.

Aging↗

Reduction of spontaneous inhibitory synaptic activity in experimental heterotopic gray matter.

Neuronal heterotopia has a strong association with epilepsy, but the mechanisms that underlie this relationship are largely unknown. We have utilized the in utero irradiated rat model to study circuit abnormalities in experimentally induced subcortical heterotopic gray matter. Spontaneous and miniature inhibitory (IPSCs) and excitatory (EPSCs) postsynaptic currents were recorded from visualized heterotopic pyramidal neurons in in vitro hemispheric slices and compared with control neocortical pyramidal neurons using the whole cell patch-clamp technique. The frequency of spontaneous and miniature IPSCs was significantly reduced in pyramidal neurons from heterotopic cortex. Amplitude and kinetics of IPSCs were not different between the two groups. Spontaneous and miniature EPSCs were not different between the two groups. Short-term synaptic plasticity of stimulus-evoked EPSCs showed depression in heterotopic neurons and facilitation in control pyramidal neurons. This study shows a selective impairment of the GABAergic circuitry in experimental heterotopic gray matter. We have reported similar findings in normotopic dysplastic cortex from this model. Taken together, these studies demonstrate a pervasive defect in inhibition throughout the cortex of irradiated rats with cortical dysplasia and neuronal heterotopia. This may have important implications regarding cortical development and function following in utero injuries.

Animals↗

Category-specific naming deficits for objects and actions: semantic attribute and grammatical role hypotheses.

Research on category-specific naming deficits and on noun and verb naming has raised questions about how organization of knowledge in the brain impacts word retrieval. The semantic attribute hypothesis posits that lexical access is mediated by brain systems that process the most definitive attributes of specific concepts. For example, it has been suggested that the most definitive attribute of living things is their visual form, whereas the most definitive attribute of non-living things is their function. The competing grammatical role hypothesis posits that access to a word depends on the grammatical role it plays in a sentence. Since nouns and verbs have different roles, it is assumed that the brain uses different systems to process them. These two hypotheses were tested in experimental subjects who had undergone left anterior temporal lobectomy (LATL) or right anterior temporal lobectomy (RATL) by assessing confrontation naming of living things, tools/implements, non-human actions, and human actions. The names of living things and implements are nouns and the names of actions are verbs. Within each grammatical class, items were characterized either predominantly by visual attributes (living things and non-human actions) or by attributes related to human activity (implements and human actions). Our results support the semantic attribute hypothesis. Patients with LATL were worse at naming tools/implements and human actions than RATL patients. Dysfunction in or removal of the left anterior temporal lobe disrupts fronto-temporal connections from the uncinate fasciculus. These connections may mediate activation of action-related information (i.e. movement plan and/or motor use) that facilitates the retrieval of names for tools/implements and human actions.

Adult↗

Cortical dysgenesis and epilepsy.

Cortical dysgenesis (CD) describes a wide spectrum of brain anomalies that involve abnormal development of the cerebral cortex. There is a strong association between CD and epilepsy, and it comprises a significant proportion of children and adults whose epilepsy cannot be controlled with medications. There has been intense effort to define the relationship between CD and epilepsy so that more effective therapies can be devised. These efforts have ranged from detailed study of people with CD and epilepsy from a clinical standpoint to single-cell analysis of mRNA expression and postsynaptic receptor function. Animal models have also been developed to mimic certain aspects of CD in a situation when quantitative, controlled, and interventional experiments can be performed that would not be possible in a clinical setting. This review will give an overview of human CD syndromes and their causes, when possible, and describe some specific abnormalities in dysplastic cortex that may underlie its epileptogenic potential. It will also review several animal models of CD that have been studied mechanistically from the standpoint of epileptogenesis. In conclusion, some general trends will be proposed based on human and animal studies to encapsulate our current understanding of CD and how it causes epilepsy.

Animals↗